McKees Pathology of The Skin

Aung Kyaw Oo
McKee’s
Pathology
of the Skin
Commissioning Editor: William R. Schmitt
Development Editors: Louise Cook & Rachael Harrison
Editorial Assistant: Kirsten Lowson
Project Manager: Nancy Arnott
Design: Kirsteen Wright
Illustration Manager: Merlyn Harvey
Marketing Manager (USA): Tracie Pasker

Fourth Edition
McKee’s
Pathology
of the Skin
with Clinical Correlations
Volume 1
Eduardo Calonje MD, DipRCPath Alexander Lazar MD, PhD

Director of Dermatopathology Associate Professor
Department of Dermatopathology Departments of Pathology and Dermatology
St John's Institute of Dermatology Sections of Dermatopathology and Sarcoma Pathology
St Thomas' Hospital Faculty, Sarcoma Research Center and Graduate School
London, UK of Biomedical Science
The University of Texas M.D. Anderson Cancer Center
Thomas Brenn MD, PhD, FRCPath Houston, Texas, USA
Consultant Dermatopathologist and Honorary Senior
Lecturer Editor-in-Chief
Department of Pathology
Western General Hospital and The University
Phillip H McKee MD, FRCPath
Formerly Associate Professor of Pathology and
of Edinburgh
Director, Division of Dermatopathology
Edinburgh, UK
Department of Surgical Pathology
Brigham and Women's Hospital and Harvard Medical
School
Boston, MA, USA
For additional online references and video content visit expertconsult.com

SAUNDERS an imprint of Elsevier Limited
© 2012, Elsevier Limited All rights reserved.
First edition 1989

Second edition 1996
Third edition 2005
Fourth edition 2012
The right of Eduardo Calonje, Thomas Brenn, Alexander Lazar and Phillip H McKee to be identified as author
of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in
writing from the publisher. Details on how to seek permission, further information about the Publisher's
permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the
Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the
individual contributions contained in it are protected under copyright by the Publisher (other than as may be
noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they
should be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current
information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered,
to verify the recommended dose or formula, the method and duration of administration, and contraindications.
It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make
diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate
safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability
for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or
from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
British Library Cataloguing in Publication Data
McKee's Pathology of the Skin. – 4th ed.

1. Skin–Diseases. 2. Skin–Histopathology.
I. Pathology of the skin II. Calonje, Eduardo. III. McKee,
Phillip H. Pathology of the skin.
616.5'07-dc22
ISBN-13: 978 1 4160 5649 2
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Contents
List of Contributors vii

Preface to the fourth edition x
Acknowledgements xi
Dedications xii
Glossary xiii
Volume 1
1 The structure and function of skin 1 11 Diseases of the oral mucosa 362
John A. McGrath Sook-Bin Woo
2 Specialized techniques in dermatopathology 32 12 Diseases of the anogenital skin 437

Pratistadevi A. Ramdial, Boris C. Bastian, John Goodlad, Eduardo Calonje, Sallie Neill, Chris Bunker,
John K. McGrath and Alexander Lazar Nick Francis, Alcides Chaux and Antonio C Cubilla
3 Disorders of keratinization 46 13 Degenerative and metabolic diseases 520

Dieter Metze Nooshin Brinster and Eduardo Calonje
4 Inherited and autoimmune subepidermal blistering 14 Cutaneous adverse reactions to drugs 590
diseases 99 Nooshin Brinster
5 Acantholytic disorders 151
15 Neutrophilic and eosinophilic
6 Spongiotic, psoriasiform and pustular dermatoses 631
dermatoses 180
16 Vascular diseases 658
7 Lichenoid and interface dermatitis 219
17 Idiopathic connective tissue
Wei-Lien Wang and Alexander Lazar disorders 711
Bostjan Luzar and Eduardo Calonje
8 Superficial and deep perivascular inflammatory
dermatoses 259
18 Infectious diseases of the skin 760
9 Granulomatous, necrobiotic and perforating Wayne Grayson
dermatoses 281
10 Inflammatory diseases of the subcutaneous fat 326
Volume 2
19 Human immunodeficiency virus (HIV) 22 Diseases of the hair 967

and acquired immunodeficiency Rodrigo Restrepo and Eduardo Calonje
syndrome (AIDS)-associated cutaneous
diseases 896 23 Diseases of the nails 1051
Pratistadevi K. Ramdial and Wayne Grayson Josette Andre, Ursula Sass and Anne Theunis
20 Disorders of pigmentation 912 24 Tumors of the surface epithelium 1076

21 Diseases of collagen and elastic tissue 935 25 Melanocytic nevi 1150
Wei-Lien Wang and Alexander Lazar Bostjan Luzar, Boris C. Bastian and Eduardo Calonje
vi Contents
26 Melanoma 1221 30 Cutaneous metastases and Paget's disease

Boris C. Bastian and Alexander Lazar of the skin 1421
Doina Ivan, Alexander Lazar and Eduardo Calonje
27 Tumors of the conjunctiva 1268
Jacob Péer and Shahar Frenkel 31 Tumors of the hair follicle 1445
32 Tumors and related lesions of the sebaceous
28 Sentinel lymph node biopsies 1296
glands 1488
Alistair J. Cochran
33 Tumors of the sweat glands 1508
29 Cutaneous lymphoproliferative
diseases and related 34 Cutaneous cysts 1571
disorders 1311 35 Connective tissue tumors 1588
John Goodlad and Eduardo Calonje
Index I1
Chapter
List of Contributors
Josette André, MD Alistair J. Cochran, MD

Head of the Dermatology and Dermatopathology Department. Distinguished Professor of Pathology and Laboratory
CHU Saint-Pierre - CHU Brugmann Medicine and Surgery
Hôpital Universitaire des Enfants Reine Fabiola Department of Pathology and Laboratory Medicine
Université Libre de Bruxelles David Geffen School of Medicine at UCLA
Brussels, Belgium Los Angeles, CA, USA
Ch 23: Diseases of the nails with Ursula Sass and Anne Ch 28: Sentinel node biopsies
Theunis
Boris C. Bastian, MD Antonio C. Cubilla, MD

Instituto de Patología e Investigación
Chairman, Department of Pathology
Asuncion, Paraguay
The James Ewing Alumni Chair
Ch 12: Diseases of the anogenital skin with Eduardo
Member, Human Oncology and Pathogenesis Program
Calonje, Sallie Neill, Chris Bunker, Nick Francis and Alcides
Memorial Sloan-Kettering Cancer Center
Chaux
Professor of Pathology
Weill Cornell Medical College
New York, NY, USA Nick Francis, FRCPath
Ch 2: Specialized techniques in dermatopathology with
Consultant Histopathologist
Pratistadevi K Ramdial, John Goodlad, John A. McGrath and
Imperial College Healthcare NHS trust
Alexander Lazar
Honorary Senior Lecturer
Ch 25: Melanocytic nevi with Eduardo Calonje
Imperial College Faculty of Medicine
Ch 26: Melanoma with Alexander Lazar
London, UK
Ch 12: Diseases of the anogenital skin with Eduardo
Nooshin K. Brinster, MD Calonje, Sallie Neill, Chris Bunker, Alcides Chaux, Antonio C
Assistant Professor Cubilla
Department of Pathology and Dermatology
Director of Dermatopathology
VCU Medical Center Shahar Frenkel, MD, PhD
Richmond, VA, USA Ocular Oncologist and Ophthalmic Pathologist
Ch 13: Degenerative and metabolic diseases Specialized Ocular Oncology Service
Ch 14: Cutaneous adverse reactions to drugs Ophthalmic Pathology Laboratory
Jerusalem, Israel
Chris Bunker, MA, MD, FRCP Lecturer in Ophthalmology
Department of Ophthalmology
Consultant Dermatologist
Hadassah – Hebrew University Medical Center
University College and Chelsea and Westminster Hospitals
Jerusalem, Israel
London;
Ch 27: Tumors of the conjunctiva with Jacob Pe'er
Professor of Dermatology
University College London
London, UK John Goodlad, MD, FRCPath
Ch 12: Diseases of the anogenital skin with Eduardo Calonje,
Consultant Haematopathologist and Honorary
Sallie Neill, Nick Francis, Alcides Chaux, Antonio C Cubilla
Senior Lecturer
Alcides Chaux, MD Western General Hospital and University of Edinburgh
GU Research Fellow, Edinburgh, UK
Department of Pathology Ch 2: Specialized techniques in dermatopathology with
Johns Hopkins University School of Medicine Pratistadevi K Ramdial, Boris C. Bastian, John A. McGrath and
Baltimore, MD, USA Alexander Lazar
Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Ch 29 Cutaneous lymphoproliferative diseases and related
Sallie Neill, Chris Bunker, Nick Francis, and Antonio C Cubilla disorders with Eduardo Calonje
viii List of Contributors
Wayne Grayson, MBChB, PhD, FCPath(SA) Sallie Neill, MB ChB, FRCP

Consultant Anatomical Pathologist and Dermatopathologist Consultant Dermatologist
AMPATH National Laboratories; Guys and St Thomas' NHS Trust
Honorary Associate Professor London, UK
School of Pathology Ch 12: Diseases of the anogenital skin with Eduardo Calonje,
University of the Witwatersrand, Johannesburg Chris Bunker, Nick Francis, Alcides Chaux, Antonio C Cubilla
Johannesburg, South Africa
Ch 18: Infectious diseases of the skin
Ch 19: Human immunodeficiency virus (HIV) and Jacob Pe'er, MD
acquired immunodeficiency syndrome Professor and Chairman
(AIDS)-associated cutaneous diseases with Department of Ophthalmology
Pratistadevi K Ramdial Jonas Friedenwald Professor of Ophthalmic Research
Hadassah – Hebrew University Medical Center
Jerusalem, Israel
Doina Ivan, MD Ch 27: Tumors of the conjunctiva with Shahar Frenkel
Assistant Professor
Departments of Pathology and Dermatology
Section of Dermatopathology Pratistadevi K. Ramdial, MBChB, FCPath(SA)
The University of Texas M.D. Anderson Cancer Center Professor and Head
Houston, TX, USA Department of Anatomical Pathology
Ch 30: Cutaneous metastases and Paget's disease Nelson R. Mandela School of Medicine
of the skin with Alexander Lazar and Eduardo Calonje University of Kwazulu-Natal and the National Health
Laboratory Service
Durban, South Africa
Boštjan Luzar, MD, PhD Ch 2: Specialized techniques in dermatopathology with
Professor of Pathology Boris C. Bastian, John Goodlad, John A. McGrath and
Consultant Pathologist Alexander Lazar
Institute of Pathology Ch 19: Human immunodeficiency virus (HIV) and acquired
Medical Faculty University of Ljubljana immunodeficiency syndrome (AIDS)-associated cutaneous
Ljubljana, Slovenia diseases with Wayne Grayson
Ch 10: Inflammatory diseases of the subcutaneous fat with
Eduardo Calonje
Ch 17: Idiopathic connective tissue disorders with Eduardo Rodrigo Restrepo, MD
Calonje Director, Dermatopathology Fellowship Program
Universidad CES;
Professor of Dermatopathology
John A. McGrath, MD, FRCP Universidad Pontificia Bolivariana;
Professor of Molecular Pathology Director, Laboratory of Pathology
St John's Institute of Dermatology Clinica Medellin
King's College London Medellin, Colombia
Guy's Hospital Ch 22: Diseases of the hair with Eduardo Calonje
London, UK
Ch 1: The structure and function of skin
Ch 2: Specialized techniques in dermatopathology with Ursula Sass, MD
Pratistadevi K Ramdial, Boris C. Bastian, John Goodlad and Assistant Professor
Alexander Lazar Dermatology and Dermatopathology Department
CHU Saint-Pierre
Université Libre de Bruxelles
Dieter Metze, MD Brussels, Belgium
Professor of Dermatology Ch 23: Diseases of the nails with Josette André and Anne
Director, Dermatopathology Unit Theunis
Department of Dermatology
University Hospital Münster
Münster, Germany
Ch 3: Disorders of keratinization
List of Contributors ix
Anne Theunis, MD Sook-Bin Woo, DMD, MMSc

Assistant Professor Associate Professor
Dermatopathology and Pathology Department Department of Oral Medicine, Infection and Immunity
CHU Saint-Pierre and Institut Bordet Harvard School of Dental Medicine, Boston, MA, USA;
Université Libre de Bruxelles Attending Dentist and Consultant Pathologist
Brussels, Belgium Brigham and Women's Hospital
Ch 23: Diseases of the nails with Josette André and Ursula Boston, MA, USA
Sass Co-Director
Center for Oral Pathology Strata Pathology Services Inc.
Wei-Lien Wang, MD Lexington, MA, USA
Assistant Professor Ch 11: Diseases of the oral mucosa
Sections of Dermatopathology and Sarcoma Pathology
The University of Texas M.D. Anderson Cancer Center
Houston, TX, USA
Ch 7: Lichenoid and interface dermatoses with Alexander
Lazar
Ch 21: Diseases of collagen and elastic tissue with Alexander
Lazar
Preface to the fourth edition
It is hard to believe that sometime in 1988, when I was just starting my Thomas Brenn and Alex Lazar are also both very close friends and also
training in dermatopathology, I met Phillip McKee at a course on soft tissue regarded by me as members of the family. They both took on much greater
tumors organized in London by an unforgettable teacher, Dr Chris Fletcher. responsibilities in the fourth edition than in the third edition and have done
When Phillip heard about my interest in dermatopathology he said to me a wonderful job. I am deeply indebted to them. Similar to Eduardo this was
“I am writing a textbook in dermatopathology and you must buy it”. So I accomplished in a background of both a heavy routine workload and research
did, little suspecting that I was going to become heavily involved in the third commitment.
edition and the main editor to the fourth edition with the invaluable help When planning a new edition, it has been my practice to try to make the
of Thomas Brenn and Alex Lazar. During the 1980s immunohistochemistry new edition as different as possible from the preceding one to ensure that
was a relatively new diagnostic technique becoming in this age an invaluable people who buy the book get true value for money. To this end, a number
ancillary tool that has been instrumental in research and in diagnostic pathol- of new chapters have been added including, specialized techniques in der-
ogy. During the same period molecular biology was being developed as a matopathology, sentinel lymph node biopsy pathology, the pathology of
powerful research mechanism in pathology, becoming an additional and cru- HIV/AIDS and tumors of the conjunctiva. The oral pathology chapter has
cial aid in diagnosis in the fields of hematopathology and soft tissue tumors in been expanded to include tumors of the salivary glands. We have taken
the 1990s. Furthermore, some of these developments in the latter fields have on a large number of very experienced excellent new authors to bring per-
allowed an understanding of many aspects of the pathogenesis of neoplasia, sonal experience to many of the more difficult topics and this has certainly
and this has led to the ever expanding use of targeted therapy in the 21st cen- paid dividends. Much progress has been achieved in our understanding of
tury. These advances have had an important impact in dermatopathology, and the pathogenesis of disease and this is reflected in the new text with up-to-
more exciting developments have followed in research, diagnosis and under- date scientific data. I am deeply indebted to all of our new contributors.
standing of the pathogenesis of neoplastic processes that are of particular The Fourth edition is certainly a very different book than the first edition
importance in the skin, particularly melanocytic neoplasms. This is ongoing which I wrote for fun almost single handedly as an atlas with integrated
work with many questions still unanswered and although with great limita- text.
tions particularly in the field of diagnosis, it has nonetheless allowed immense In order to increase valuable space for the increased figures, enlarged text and
understanding of pathogenesis and the development of some targeted thera- new chapters, it was decided to make the references an online only component
pies for melanoma some with very promising although limited results. of the book. This has allowed us to considerably expand the text and increase
In this edition we have invited a number of experts to contribute in their the number of figures in the book, a large proportion of which are new.
areas of expertise realizing that it is very difficult if not impossible for a hand- I am also heavily indebted to my two friends in the publishing world -
ful of people to cover such an extensive area as dermatopathology. We have Louise Cook and Bill Schmitt. I have been associated with Louise for more
tried to include as much material as possible encompassing most of what is years than I choose to remember and she has always proven to be a pillar of
new in the literature but realize that inevitably this cannot be achieved to support particularly during the numerous episodes of stress that are inevi-
complete satisfaction. The third edition of this book was received with great table in a task of this magnitude. I thank her for always being there when
enthusiasm by many people all over the world and we hope to have fulfilled help was necessary. I met Bill when I moved to the United States and he has
the task and answered their criticisms in this new edition. also become a great friend in addition to being the senior Elsevier represen-
tative overseeing the progress of the book. Similar to Louise he has had to
Eduardo Calonje
put up with much from me and has always steered the project with a steady
hand during all of its crises which have been innumerable. Producing the
The fourth edition has been a huge undertaking and taken an immense amount
Fourth edition would have been an even harder task without their input.
of time and energy. I would first like to congratulate Eduardo Calonje for doing
More recently I have worked with Nancy Arnott in Edinburgh. She has been
a wonderful job against a background of a heavy daily workload and lecture
the senior editor of the project and most certainly done a wonderful job. The
commitment. I decided that having left hospital practice and been in charge of
editors and contributors owe her an awful lot.
the book for three editions, that it was high time for new blood to take over
Lastly and most importantly, I owe so much as always to Gracie. She has
control of the new edition while I became overall editor-in-chief. I have known
had to put up with me for the past 4 years while working on the new edition.
Eduardo since the early 1980's during which time he has become more than just
This has been no mean feat. She has let my ill temper and moods of depres-
a close friend; both Gracie and I regard him as one of the family. He is a superb
sion and anxiety wash over her and in her own thoughtful quiet way made
dermatopathologist (without question Europe's leading light) and I had every
the seemingly impossible possible. I would never have been able to complete
confidence that he would produce a wonderful new edition of Pathology of the
this task without her loyalty, support and love.
Skin. Needless to say he has gone beyond my greatest expectation and produced
a truly magnificent fourth edition. Words cannot express my gratitude. Phillip H. McKee
Acknowledgements
Working for so many years on a book of this proportion, especially when the Academic life is a complex web of mentors, colleagues and students. I have
task is something that has to be done as a “hobby” after formal work hours, been lucky to have worked with a number of fine mentors and colleagues
represents a daunting task. I often wondered in times of despair whether the who strongly influenced my thinking in pathology in general and/or in der-
job was ever going to be finished. It has finally been completed and I would matopathology specifically: Chris Fletcher, Scott Granter, George Murphy,
not have been able to achieve this without the invaluable help of many peo- Ramzi Cotran (deceased), Chris Crum, Bill Welch, Rob Odze, Jon Aster,
ple. They not only gave me emotional support but often went out of their Felix Brown (deceased), Jason Hornick, John Iafrate, Marcus Bosenberg,
way to help me with the many details necessary to finalize the numerous Jonathan Fletcher, Marty Mihm, Lyn Duncan, Steve Tahan, Steve Lyle, Victor
tasks that this job entailed. My wife Claudia has always given me her unwav- Prieto, Harry Evans, Sharon Weiss, Bogdan Czerniak, Frasier Symmans,
ering support no matter how trying the challenge ahead. My children Mateo Ken Aldape, Russell Broaddus, Greg Fuller, Mike Davies, Jon Reed, John
and Isabella have given me their patience and understanding. Numerous col- Goldblum, David Berman, Vinay Kumar, Marc Ladanyi, Matt van de Rijn,
leagues, many of them visiting fellows from many different countries, have Brian Rubin, Jesse McKenney, Steve Billings, Howard Gerber, Ron Rapini,
made my life easy in millions of ways and I cannot thank them enough for Julia Bridge, Paula dal Cin, Andre Oliveira, Pancras Hogendoorn, Paulo Dei
their patience, hard work and mainly for being wonderful human beings sup- Tos, Andrew Folpe, Judith Bovee, Lola Lopez-Terrada, Cristina Antonescu,
porting me in what for many reasons were the darkest days of my life. I espe- along with numerous others I have encountered either directly or through
cially want to show my appreciation to Drs Maiko Tanaka, Anoud Zidan, their writing and lecturing. This extended list testifies not only to my good
Vicki Howard, Viky Damaskou, Thomas Brenn, Bostjan Luzar, Ravi Ratnavel, fortune in meeting so many wonderful people, but also the generosity of
Rathi Ramakrishnan and Gregory Spiegel (who sadly died last year). academic pathologists as a group. I have many other friends in pathology
and medicine who shall have to remain nameless due to space constraints,
EC but this line hails that brilliant group. The other authors and editors of
this present work have been a joy to work with and I have benefited much
The path of life is often determined by the people we encounter. There are
from these interactions. The Dermatopathology Section at my institution
many ways in which certain individuals touch our hearts, steer us in the right
has a delightful combination of great people and fascinating diagnostic
direction and help us achieve goals which would have been unattainable oth-
material. My former Chairman of Pathology, Janet Bruner, was enthusi-
erwise. Words aren't ever enough to really show one's true appreciation for
astic and supportive of this project from our first conversation regarding
the generosity, support and motivation received over the years.
it. Another group of colleagues including Ralph Pollock, Dina Lev and the
My wonderful, loving parents, Sonja and Walter, have always been there
entire Sarcoma Research Center have done more than their share to help
for me and supported my every move. My wife and daughter, Anne and Yaëlle,
me balance the demands of clinical work, research, grants, papers and this
have had a terrible time dealing with my tempers throughout the writing of
book. The talented staff at Elsevier provided invaluable support through-
this book. They have always stood by my side and saved a smile for me for
out this project. Last, but certainly not least, I am indebted to my trainees.
which I am ever so grateful. My professional life could have gone very wrong
On a daily basis, they remind me of the marvels of what we do, ask difficult
indeed had it not been for the kindness and gracious support from these truly
and challenging questions, prompt re-examination of assumptions, expose
unique mentors and teachers Uta Francke, Heinz Furthmayr, Ramzi Cotran
biases, and force clarity and reproducibility in diagnostic criteria; may we
and Christopher Fletcher. Finally, there is so much I owe to these two won-
all retain these characteristics of motivated students throughout our career.
derful individuals who have become very close friends, Phillip McKee and
For all of this, I am humbled and grateful.
Eduardo Calonje.
TB AL
Dedications
To my wife Claudia who always gives without expecting anything in return.

To my children Mateo and Isabella and to the memory of my parents Julio
and Alicia both of whom passed away while this edition was in production.
EC
To Anne, Yaelle, Sanja and Walter.

TB
I am assured that my two beautiful children, Elliott and Abigail, have no

memories that predate me working on this book. I hope that this example of
what fascination with a subject, continued application to a task, and working
as a disciplined team can accomplish will be a small, but meaningful substi-
tution for the time designated to this endeavor. My wife, Victoria, has been
ever supportive in every way despite having an extremely busy and demand-
ing career in law as has been my mother-in-law Sara. My parents, Joe and
Glenda, always allowed me the freedom to pursue my own interests and the
encouragement and support to accomplish them, a wonderful gift I hope to
pass on to my children as well.
AL
This new edition is dedicated to my wife and best friend Gracie with all my
love
PHM
Glossary
5-ARD 5-a-reductase CRASP complement regulator-acquiring surface FAMMM familial atypical multiple mole
AA alopecia areata protein melanoma [syndrome]
ACE angiotensin converting enzyme CREST calcinosis, Raynaud’s phenomenon, FAP familial adenomatous polyposis
[inhibitor] esophageal dysfunction, sclerodactyly, FAPA fever, aphthous stomatitis, pharyngitis,
AgNORS argyrophilic nucleolar organizer regions telangiectasis [syndrome] adenitis [syndrome]
AHNMD associated clonal hematological CTCL cutaneous T-cell lymphoma FHIT fragile histidine triad
non-mast cell lineage disease dcSSc diffuse cutaneous systemic sclerosis FIGURE facial idiopathic granulomata with
AIDS acquired immunodeficiency syndrome DDEB dominant dystrophic epidermolysis regressive evolution
AILD angioimmunoblastic lymphadenopathy bullosa FISH fluorescent in situ hybridization
with dysproteinemia DEB dystrophic epidermolysis bullosa GA granuloma annulare
ALA aminolevulinic acid DH dermatitis herpetiformis GABEB generalized atrophic benign
ALK anaplastic lymphoma kinase DIC disseminated intravascular coagulation epidermolysis bullosa
ALK1 activin-like receptor kinase 1 DIMF direct immunofluorescence GCDFP gross cystic disease fluid protein
ALM acral lentiginous melanoma DLE discoid lupus erythematosus G-CSF granulocyte-colony stimulating
AN acanthosis nigricans DNCB dinitrochlorobenzene factor
ANA antinuclear antibodies DSAP disseminated superficial actinic GFAP glial fibrillary acidic protein
ANCA antineutrophil cytoplasmic antibodies porokeratosis GM-CSF granulocyte–macrophage colony
API2 apoptosis inhibitor-2 Dsc desmocollin stimulating factor
ARC AIDS-related complex dsDNA double-stranded DNA GSE gluten-sensitive enteropathy
ATF1 activating transcription factor 1 Dsg desmoglein GVHD graft-versus-host disease
ATLL adult T-cell leukemia/lymphoma DSP disseminated superficial porokeratosis HA hyperandrogenism
BANS back, arm, neck and scalp [sites] EB epidermolysis bullosa HAART highly active antiretroviral therapy
BB mid borderline leprosy EBA epidermolysis bullosa acquisita HAIR-AN hyperandrogenism–insulin resistance–
BCC basal cell carcinoma EBS epidermolysis bullosa simplex acanthosis nigricans [syndrome]
BCG bacille Calmette–Guérin EBS-DM epidermolysis bullosa simplex, HBV hepatitis B virus
B-FGF basic fibroblast growth factor Dowling–Meara HDL high density lipoprotein
BIDS brittle sulfur-deficient hair, intellectual EBS-K epidermolysis bullosa simplex, Koebner HF hemorrhagic fever
impairment, decreased fertility and EBS-MD epidermolysis bullosa simplex with HG herpes gestationis
short stature muscular dystrophy HHV human herpesvirus
BL borderline lepromatous leprosy EBS-WC epidermolysis bullosa simplex, HIT heparin-induced thrombocytopenia
BLAISE Blaschko linear acquired inflammatory Weber–Cockayne [syndrome]
skin eruption EBV Epstein–Barr virus HIV human immunodeficiency virus
BMP bone morphogenetic protein ECE endothelin-converting enzyme HLA human leukocyte antigen
BP bullous pemphigoid ECM extracellular membrane HMFG human milk fat globulin
BPA bullous pemphigoid antigen EDS Ehlers–Danlos syndrome HNPCC hereditary non-polyposis colorectal
BSAP B-cell-specific activator protein EGFR endothelial growth factor receptor carcinoma [syndrome]
BSLE bullous systemic lupus erythematosus ELAM endothelial leukocyte adhesion HPF (hpf) high power fields
BT borderline tuberculoid leprosy molecule HPL hyperlipoproteinemia
C3NeF C3 nephritic factor ELISA enzyme-linked immunosorbent assay HPV human papillomavirus
CAD chronic actinic dermatitis EM electron microscopy HRF histamine-releasing factor
cAMP cyclic adenosine 3'-5'- monophosphate EMA epithelial membrane antigen HSP heat shock protein
c-ANCA cytoplasmic-antineutrophil cytoplasmic ENA extractable nuclear antigen HSV herpes simplex virus
antibodies ENL erythema nodosum leprosum HTLV human T-cell lymphotropic virus
CDC Centers for Disease Control and EPPER eosinophilic, polymorphic and hTR telomerase RNA
Prevention pruritic eruption associated with HUS hemolytic uremic syndrome
CEA carcinoembryonic antigen radiotherapy IBIDS ichthyosis and BIDS (see BIDS above)
CGRP calcitonin-gene-related polypeptide EPPK epidermolytic palmoplantar ICAM intercellular adhesion molecule
CHILD congenital hemidysplasia with keratoderma ICH indeterminate cell histiocytosis
ichthyosiform nevus and limb defects EPS extracellular polysaccharide substance IDL intermediate density lipoproteins
[syndrome] ESR erythrocyte sedimentation rate IEN intraepidermal neutrophilic [IgA
CK cytokeratin ETA exfoliative toxin A dermatosis variant]
CLA cutaneous lymphocyte antigen ETB exfoliative toxin B IFAP ichthyosis follicularis–alopecia–
CLL chronic lymphocytic leukemia EV epidermodysplasia verruciformis photophobia [syndrome]; intermediate
CMG capillary morphogenesis protein EWSR1 Ewing’s sarcoma [proto-oncogene] filament associated protein
CNS central nervous system FACE facial Afro-Caribbean childhood IFN interferon
CP cicatricial pemphigoid (mucous membrane eruption Ig immunoglobulin
pemphigoid) FADS fetal akinesia deformation sequence IIMF indirect immunofluorescence
xiv Glossary
ILVEN inflammatory linear verrucous NFII neurofibromatosis type II SALE summertime actinic lichenoid eruption
epidermal nevus NFP neurofilament protein SALT skin-associated lymphoid tissue
IMF immunofluorescence NIH National Institutes of Health SAPHO synovitis, acne, pustulosis, hyperostosis,
IP inducible protein; immunoprecipitation NISH non-isotopic in situ hybridization osteitis [syndrome]
IR insulin resistance NK natural killer SCC squamous cell carcinoma
ISSVD International Society for the Study of NL necrobiosis lipoidica SCH squamous cell hyperplasia
Vulvovaginal Disease NRAMP1 natural resistance-associated SCID severe combined immunodeficiency
JEB junctional epidermolysis bullosa macrophage protein 1 SCLE subacute cutaneous lupus
JEB-H junctional epidermolysis bullosa, NSAIDs non-steroidal anti-inflammatory drugs erythematosus
Herlitz NSE neuron-specific enolase scRNP small cytoplasmic ribonuclear protein
JEB-nH junctional epidermolysis bullosa, OL-EDA- osteopetrosis, lymphedema, SEA staphylococcal enterotoxin A
non-Herlitz ID anhidrotic ectodermal dysplasia, SEB staphylococcal enterotoxin B
JEB-PA junctional epidermolysis bullosa with immunodeficiency [syndrome] Shh Sonic Hedgehog
pyloric atresia ORF open reading frame SIBIDS osteosclerosis and IBIDS (see IBIDS
KID keratitis–ichthyosis–deafness PAIN perianal intraepithelial neoplasia above)
[syndrome] p-ANCA perinuclear-antineutrophil cytoplasmic SIL squamous intraepithelial lesion
KOH potassium hydroxide antibodies SLE systemic lupus erythematosus
KPAF keratosis pilaris atrophicans facei PAPA pyogenic sterile arthritis, pyoderma SLL small lymphocytic lymphoma
L&H cells lymphocytic and/or histiocytic gangrenosum and acne [syndrome] SMA smooth muscle actin
Reed–Sternberg cell variants PAS periodic acid–Schiff snRNP small nuclear ribonuclear protein
LAD linear IgA disease PBG porphobilinogen SPD subcorneal pustular dermatosis
LATS long-acting thyroid stimulator PCNA proliferating cell nuclear antigen SPRRs small proline rich proteins/cornifins
LCA leukocyte common antigen PCR polymerase chain reaction SPTL subcutaneous panniculitis-like T-cell
LCH Langerhans’ cell histiocytosis PDGFβ platelet-derived growth factor b lymphoma
lcSSc limited cutaneous systemic sclerosis PECAM platelet endothelial cell adhesion SRP signal recognition particle
LDL low density lipoprotein molecule ssDNA single-stranded DNA
LE lupus erythematosus PEComa perivascular epithelioid cell tumor SSSS staphylococcal scalded skin syndrome
LFA lymphocyte function-associated PGL phenolic glycolipid STD sexually transmitted disease
antigen PGP protein gene product sub-LD sub-lamina densa
LH–RH luteinizing hormone–releasing hormone PGWG purely granulomatous Wegener’s TCR T-cell receptor
LL lamina lucida; lepromatous leprosy granulomatosis TEN toxic epidermal necrolysis
LP lichen planus PI protease inhibitor TFIIH transcription/DNA repair factor IIH
LPP lichen planus pemphigoides PIBIDS photosensitivity and IBIDS (see IBIDS TGF transforming growth factor
LS lichen sclerosus above) thio- triethylene thiophosphoramide
LYVE lymphatic vessel endothelial PILA papillary intralymphatic TEPA
[hyaluronan receptor] angioendothelioma TIMP tissue inhibitor of metalloproteinase
MAC membrane attack complex PLEVA pityriasis lichenoides et varioliformis acuta TNF tumor necrosis factor
MAI M. avium intracellulare PNET primitive neuroectodermal tumor TORCH toxoplasmosis, other infections, rubella,
MALT mucosa-associated lymphoid tissue POEMS polyneuropathy, organomegaly, cytomegalovirus and herpes simplex
MART-1 melanoma antigen recognized by endocrinopathy, M-protein and skin [syndrome]
T-cells 1 changes [syndrome] TRAPS tumor necrosis factor receptor-
MBP myelin basic protein PPD purified protein derivative associated periodic syndrome
MC1R melanocortin-1 receptor PPDL pure and primitive diffuse leprosy TSST toxic shock syndrome toxin
MCGN mesangiocapillary glomerulonephritis PPK palmoplantar keratoderma TT tuberculoid leprosy
MCP molecule chemoattractant protein pRB retinoblastoma protein tTA tetracycline transactivator [transcription
M-CSF macrophage colony stimulating factor PSS progressive systemic sclerosis factor]
MCTD mixed connective tissue disease PTEN phosphatase and tensin homolog TTF-1 thyroid-transcription factor 1
MDR multidrug resistance gene PUPPP pruritic urticarial papules and plaques tTG tissue transglutaminase
Mel-CAM melanoma cell adhesion molecule of pregnancy TTP thrombotic thrombocytopenic
MEN multiple endocrine neoplasia PUVA psoralen plus ultraviolet light of purpura
[syndrome] A [long] wavelength UPS undifferentiated pleomorphic sarcoma
MFH malignant fibrous histiocytoma r IL-2 recombinant interleukin 2 URO uroporphyrinogen
MGS/ melanoma growth stimulatory RBC red blood cell URO-D uroporphyrinogen decarboxylase
GRO activity RDEB recessive dystrophic epidermolysis URR upstream regulatory region
MHC major histocompatibility complex bullosa UV ultraviolet
miH minor histocompatibility complex RDEB-HS recessive dystrophic epidermolysis UVA ultraviolet A
MITF microphthalmia transcription factor bullosa, Hallopeau–Siemens UVB ultraviolet B
MMP matrix metalloproteinase RDEB- recessive dystrophic UVL ultraviolet light
MMR mismatch repair nHS epidermolysis bullosa, non-Hallopeau– VCAM vascular cell adhesion molecule
MSA muscle-specific actin Siemens VEGF vascular endothelial growth factor
MSI microsatellite instability RER rough endoplasmic reticulum VEGFR vascular endothelial growth factor receptor
NADH nicotine adenine dinucleotide, reduced RNP ribonucleoprotein VIN vulval intraepithelial neoplasia
nDNA native [double-stranded] DNA RT-PCR reverse transcription polymerase chain VIP vasoactive intestinal peptide
NEMO nuclear factor [NF]-kappaB gene reaction VLDL very low density lipoprotein
modulator SA syphilitic alopecia VZV varicella-zoster virus
NF necrotizing fasciitis SA1 slowly adapting type-1 wrfr wrinkle free [mouse model]
NFI neurofibromatosis type I [mechanoreceptor] XP xeroderma pigmentosum
The structure and function Chapter
See
www.expertconsult.com
for references and
additional material
of skin
John A. McGrath
1
Properties of skin 1 Melanocytes 10 Dermal elastic tissue 24
Normal epidermal histology 1 Merkel cells 12 Ground substance 26
Regional variations in skin anatomy 2 Intercellular junctions 13 Fibroblast biology 26
Skin development 2 Pilosebaceous units 15 Cutaneous blood vessels and
lymphatics 27
Keratinocyte biology 5 Eccrine glands 17
Nervous system of the skin 28
Epidermal stem cells 6 Apocrine glands 19
Subcutaneous fat 30
Skin barrier 8 Dermal–epidermal junction 21
Skin immunity 9 Dermal collagen 22
Skin is a double-layered membrane covering the exterior of the body and

consists of a stratified cellular epidermis and an underlying dermis of con- Normal epidermal histology
nective tissue. In adults, the skin weighs over 5 kg and covers a surface area
approaching 2 m2. The epidermis is mainly composed of keratinocytes and is Although the basic structure is relatively constant at various skin sites, there
typically 0.05–0.1 mm in thickness. The dermis contains collagen, elastic tis- are often clear differences which enable one to determine the site of origin.
sue and ground substance and is of variable thickness, from 0.5 mm on the The epidermis consists of four clearly defined layers or strata:
eyelid or scrotum to more than 5 mm on the back (Fig. 1.1). • Basal cell layer (stratum basale)
The dermis is subdivided into a more superficial component (the papillary • Prickle cell layer (stratum spinosum)
dermis) which is bounded inferiorly by the superficial vascular plexus and an • Granular cell layer (stratum granulosum)
underlying much thicker reticular dermis. Below the dermis is a layer of sub- • Keratin layer (stratum corneum)
cutaneous fat which is separated from the rest of the body by a vestigial layer An eosinophilic acellular layer known as the stratum lucidum is sometimes
of striated muscle. seen in skin from the palms and soles (Fig. 1.2).
Basal cells are cuboidal or columnar with a large nucleus typically con-
taining a conspicuous nucleolus. Small numbers of mitoses may be evident.
Properties of skin Clear cells are also present in the basal layer of the epidermis; these repre-
sent melanocytes. Cells with clear cytoplasm seen in the stratum spinosum
A key role of skin is to provide a mechanical barrier against the external represent Langerhans cells. Very occasional Merkel cells may also be present
environment. The cornified cell envelope and the stratum corneum restrict but these are not easily identified in hematoxylin and eosin stained sections.
water loss from the skin while keratinocyte-derived endogenous antibiot- Histologically, prickle cells are polygonal in outline, have abundant eosino-
ics (defensins and cathelicidins) provide an innate immune defense against philic cytoplasm and oval vesicular nuclei, often with conspicuous nucleoli.
bacteria, viruses and fungi. The epidermis also contains a network of about Keratohyalin granules typify the granular cell layer (Fig. 1.3). Further matu-
2 × 109 Langerhans cells which serve as sentinel cells whose prime function ration leads to loss of nuclei and flattening of the keratinocytes to form the
is to survey the epidermal environment and to initiate immune responses plates of the keratin layer (stratum corneum). Adjacent cells are united at
against microbial threats. Melanin, which is mostly found in basal keratino- their free borders by intercellular bridges (prickles), which are most clearly
cytes, provides some protection against DNA damage from ultraviolet radia- identifiable in the prickle cell layer and in disease states of the skin where
tion. An important function of skin is thermoregulation. Vasodilatation or there is marked intercellular edema (spongiosis) (Fig. 1.4).
vasoconstriction of the blood vessels in the deep or superficial plexuses helps Toker cells represent an additional clear cell population, which may be
regulate heat loss. Eccrine sweat glands are found at all skin sites and are found in nipple epidermis of both sexes in up to 10% of the population.1 The
present in densities of 100–600/cm2; they play a role in heat control and cells are large, polygonal or oval and have abundant pale staining or clear
aspects of metabolism. Secretions from apocrine sweat glands contribute to cytoplasm with vesicular nuclei often containing prominent, albeit small,
body odor. Skin lubrication and waterproofing is provided by sebum secreted nucleoli. The cytoplasm is mucicarmine and PAS negative.1 The cells may be
from sebaceous glands. Subcutaneous fat has important roles in cushioning distributed singly but more often they are found as small clusters, not uncom-
trauma as well as providing insulation and a calorie reserve. Fat also has an monly forming single layered ductules.1 They are located along the basal layer
endocrine function and contributes to tissue remodeling and phagocytosis. of the epidermis or suprabasally and are also sometimes seen within the epi-
Nails provide protection to the ends of the fingers and toes as well as being thelium of the terminal lactiferous duct.
important in pinching and prising objects. Hair may have important social Toker cells are of particular importance as they may be mistaken by the
and psychological value. Skin also has a key function in synthesizing various unwary as Paget cells. They are thought to be the source of mammary Paget's
metabolic products, such as vitamin D. disease in those exceptional cases where an underlying ductal carcinoma is
2 The structure and function of skin
Fig. 1.1
Skin from forearm: there is a fairly thin epidermis. Compare the thickness of the Fig. 1.4
dermis with that from the back (see Fig. 1.5). Spongiosis: the
intercellular bridges
(prickles) are stretched
and more visible in this
biopsy from a patient with
acute eczema.
absent.2 Toker cells express CK7, AE1, CAM 5.2, epithelial membrane anti-
gen (EMA), cerbB2, estrogen and progesterone receptors.3,4 They do not
express p53 or CD138. Carcinoembryonic antigen (CEA) may also be present
albeit weakly.4 Paget's cells by way of contrast are often negative for estrogen
and progesterone receptors and are p53 and CD138 positive.4
Regional variations in skin anatomy

There are two main kinds of human skin: glabrous skin (nonhairy skin)
and hair-bearing skin. Glabrous skin is found on the palms and soles. It
has a grooved surface with alternating ridges and sulci giving rise to the
dermatoglyphics (fingerprints). Glabrous skin has a compact, thick stratum
corneum, and contains encapsulated sense organs within the dermis but no
hair follicles or sebaceous glands. In contrast, hair-bearing skin has both
Fig. 1.2
Skin from palm: note the eosinophilic stratum lucidum clearly separating the
hair follicles and sebaceous glands but lacks encapsulated sense organs.
granular cell layer from the overlying stratum corneum. Hair follicle size, structure and density can vary between different body
sites. For example, the scalp has large hair follicles that may extend into
subcutaneous fat whereas the forehead has only small vellus hair-producing
follicles although sebaceous glands are large. The number of hair follicles
does not alter until middle life but there is a changing balance between vel-
lus and terminal hairs throughout life. In hair-bearing sites, such as the
axilla, there are apocrine glands in addition to the eccrine sweat glands.
Sebaceous glands are active in the newborn, and from puberty onwards,
and the relative activity modifies the composition of the skin surface lipids.
The structure of the dermal–epidermal junction also shows regional vari-
ations in the number of hemidesmosomal-anchoring filament complexes
(more in the leg than the arm). In the dermis, the arrangement and size
of elastic fibers varies from very large fibers in perianal skin to almost no
fibers in the scrotum. Marked variation in the cutaneous blood supply is
found between areas of distensible skin such as the eyelid and more rigid
areas such as the fingertips.
Regional variation in skin structure is illustrated in Figures 1.5–1.20.
Skin development
Two major embryological elements juxtapose to form skin. These comprise
Fig. 1.3 the prospective epidermis that originates from a surface area of the early
Skin from palm: there is a conspicuous granular cell layer. gastrula, and the prospective mesoderm that comes into contact with the
Skin development 3
Fig. 1.7
Fig. 1.5 Skin from the sole of the foot: this is typified by a thickened stratum corneum
Skin from the lower and prominent epidermal ridge pattern. The dermis is relatively dense at this site.
back: at this site the Similar features are seen on the palms and ventral aspects of the fingers and toes.
dermis is very thick
and is characterized by
broad parallel fascicles of
collagen.
Fig. 1.8
Skin from the scalp: there are numerous terminal hair follicles with many of the
bulbs in the subcutaneous fat.
Fig. 1.6
Skin of the nose: there are conspicuous sebaceous glands: at this site, they often
drain directly onto the skin surface. These appearances should not be confused 14 to 21, fibroblasts are numerous and active, and perineural cells, pericytes,
with that of sebaceous hyperplasia.
melanoblasts, Merkel cells and mast cells can be individually identified. Hair
follicles and nails are evident at 9 weeks. Sweat glands are also noted at 9
weeks on the palms and the soles.3 Sweat glands at other sites and sebaceous
inner surface of the epidermis during gastrulation. The mesoderm generates glands appear at 15 weeks. Touch pads become recognizable on the fingers
the dermis and is involved in the differentiation of epidermal structures such and toes by the sixth week and development is maximal by the 15th week.
as hair follicles.1 Melanocytes are derived from the neural crest. After gastru- The earliest development of hair occurs at about 9 weeks in the regions of the
lation, there is a single layer of neuroectoderm on the embryo surface: this eyebrow, upper lip and chin. Sebaceous glands first appear as hemispherical
layer will go on to form the nervous system or the skin epithelium, depend- protuberances on the posterior surfaces of the hair pegs and become differ-
ing on the molecular signals (e.g., fibroblast growth factors or bone mor- entiated at 13–15 weeks. Langerhans cells are derived from the monocyte–
phogenic proteins) it receives.2 The embryonic epidermis consists of a single macrophage–histiocyte lineage and enter the epidermis at about 12 weeks.
layer of multipotent epithelial cells which is covered by a special layer known Merkel cells appear in the glabrous skin of the fingertips, lip, gingiva and
as periderm that is unique to mammals. Periderm provides some protection nail bed, and in several other regions, around 16 weeks. Although some cells
to the newly forming skin as well as exchange of material with the amniotic of the dermis may migrate from the dermatome (venterolateral part of the
fluid. The embryonic dermis is at first very cellular and at 6–14 weeks three somite) and take part in the formation of the skin, most of the dermis is
types of cell are present: stellate cells, phagocytic macrophages and granule- formed by mesenchymal cells that migrate from other mesodermal areas.4
secretory cells, either melanoblasts or mast cells (Fig. 1.21). From weeks These mesenchymal cells give rise to the whole range of blood and connective
Fig. 1.9 Fig. 1.11 Fig. 1.12

Skin from axilla: apocrine glands as seen at the Skin from the outer aspect of the lip: note the Mucosal aspect of lip: at this site the squamous
bottom of the field are typical for this site. keratinizing stratified squamous epithelium and epithelium does not normally keratinize. Minor salivary
skeletal muscle fibers. glands as shown in this field are not uncommonly present.
Fig. 1.13
Mucosal aspect of lip:
close-up view of the
salivary gland shown in
Figure 1.12.
Fig. 1.10
Skin of areola: there are abundant smooth muscle
fibers: lactiferous ducts may also sometimes be
present (not shown).
Fig. 1.14
Mucosal aspect of lip:
the cytoplasm of the
keratinocytes is often rich
in glycogen.
Keratinocyte biology 5
A B
Fig. 1.15 Fig. 1.16

Skin from the ear: note the vellus hairs, and a fairly (A, B) Vulval vestibule: at this site the stratum corneum is absent and there is no granular cell layer. The
thin dermis overlying the auricular cartilage. suprabasal keratinocytes have clear cytoplasm due to abundant glycogen and revealed by the periodic
acid-Schiff reaction.
Fig. 1.17 Fig. 1.18

Variation of skin: sample of skin from the forearm of a 92-year-old female. Note the Stasis change: skin from the lower leg. Although abnormal, the presence of
epidermal thinning and dermal atrophy. stasis change characterized in this example by papillary dermal lobular capillary
proliferation is a very common feature at this site.
tissue cells, including the fibroblasts and mast cells of the dermis and the fat
7–10 nm in diameter, known as intermediate filaments. There are six types
cells of the subcutis. In the second month, the dermis and subcutis are not
of intermediate filaments of which keratins are the filaments in keratinocytes
discernible as distinct skin layers but collagen fibers are evident in the dermis
(Figs 1.22, 1.23). The human genome possesses 54 functional keratin genes
by the end of the third month. Later, the papillary and reticular layers become
located in two compact gene clusters, as well as many nonfunctional pseudo-
established and, at the fifth month, the connective tissue sheaths are formed
genes, scattered around the genome.1 Keratin genes are very specific in their
around the hair follicles. Elastic fibers are first detectable at 22 weeks.
expression patterns. Each one of the many highly specialized epithelial tissues
has its own profile of keratins. Hair and nails express modified keratins con-
Keratinocyte biology taining large amounts of cysteine which forms numerous chemical cross-links
to further strengthen the cytoskeleton. The genes encoding the keratins fall
The cytoskeleton of all mammalian cells, including epidermal keratinocytes, into two gene families: type I (basic) and type II (acidic) and there is coex-
comprises actin containing microfilaments ≈7 nm in diameter, tubulin contain- pression of particular acidic–basic pairs in a cell- and tissue-specific manner.
ing microtubules 20–25 nm in diameter, and filaments of intermediate size, Keratin heterodimers are assembled into protofibrils and protofilaments by
Fig. 1.21
A (A, B)Development of
normal human fetal skin:
(A) at 7 week's gestation,
the epidermis is only
two cell layers thick but
the dermis appears very
cellular; (B) at 19 weeks
gestation the skin has
an outer layer specific
to mammals known as
periderm. This contains
surface blebs which are
Fig. 1.19 full of glycogen (G). Also
Stasis change: high-power present is a hair peg
view. (H). This downgrowth
of the epidermis is the
first histologic step in
B generating a hair follicle.
Bar = 25 μm.
Fig. 1.20
Variation of normal skin: in dark-skinned races, the presence of intense basal cell
melanin pigmentation is a normal histological finding.
Fig. 1.22
Cytoskeleton of a keratinocyte: the major intermediate filament of a keratinocyte is
keratin, highlighted in green.
an antiparallel stagger of some complexity. Simple epithelia are characterized
by the keratin pair K8/K18, and the stratified squamous epithelia by K5/K14.
Suprabasally, keratins K1/K10 are characteristic of epidermal differentiation
genetic disorder of keratin to be described was epidermolysis bullosa sim-
(Fig. 1.24). K15 is expressed in some interfollicular basal keratinocytes as
plex, which involves mutations in the genes encoding K5 or K14 (Fig. 1.25).
well as keratinocytes within the hair-follicle bulge region at the site of pluri-
About half of the keratin genes are expressed in the hair follicle, and muta-
potential stem cells. K9 and K2e expression is site restricted in skin: K9 to
tions in these genes may underlie cases of monilethrix as well as hair and nail
palmoplantar epidermis and K2e to superficial interfollicular epidermis.
ectodermal dysplasias.5
Apart from their structural properties, keratins may also have direct roles
in cell signaling, the stress response and apoptosis.2 In epidermal hyperprolif-
eration, as in wound healing and psoriasis, expression of suprabasal keratins Epidermal stem cells
K6/K16/K17 is rapidly induced.
Currently, 21 of the 54 known keratin genes have been linked to monogenic To maintain, repair and regenerate itself, the skin contains stem cells which
genetic disorders, and some have been implicated in more complex traits, reside in the bulge area of hair follicles, the basal layer of interfollicular epi-
such as idiopathic liver disease or inflammatory bowel disease.3,4 The first dermis and the base of sebaceous glands (Fig. 1.26).1 Stem cells are able to
Epidermal stem cells 7
Fig. 1.25
Clinicopathological consequences of mutations in the keratin 14 gene: (left) typical
Fig. 1.23 appearances of Dowling-Meara epidermolysis bullosa simplex which results from
Mid-prickle cell layer of normal epidermis: the abundant keratin filaments heterozygous missense mutations in the KRT14 gene; (right) ultrastructurally, there
(tonofibrils) form a distinct interlacing lattice within the cytoplasm of keratinocytes. is keratin filament disruption and clumping as well as a plane of blistering just above
the dermal–epidermal (DE) junction.
Epidermis
Epidermal Sebocyte
stem cells stem cells
Sebaceous gland
Bulge stem cells
Hair shaft
Fig. 1.24
Normal skin: suprabasal keratinocytes preferentially express keratins 1 and 10 as
Outer root sheath
shown in this picture. Anti-Keratin1 antibody courtesy of I.M. Leigh, MD, Royal
London Hospital Trust, London, UK.
Inner root sheath

self-renew as well as give rise to differentiating cells.2 It is not clear, however,
whether every basal keratinocyte or only a proportion of cells is a stem cell.3
Two possible hypotheses have emerged. One theory divides basal keratino- Dermal papilla
cytes into epidermal proliferation units, which comprise one self-renewing
stem cell and about 10 tightly packed transient amplifying cells, each of which Fig. 1.26
is capable of dividing several times and then exiting the basal layer to undergo Diagrammatic representation of the location of stem cells in human skin: stem cells
terminal differentiation.4 This unit gives rise to a column of larger and flat- are located within the bulge area of hair follicles (where the arrector pili muscle
ter cells that culminates in a single hexagonal surface. The process of divi- attaches) as well as in the basal keratinocyte layer in the interfollicular epidermis
sion of basal cells in this model is viewed as a symmetrical process in which and at the base of sebaceous glands. Stem cells from the bulge area are capable of
equal daughter cells are generated with the basal cells progressively reducing regenerating all parts of the pilosebaceous unit and interfollicular skin.
their adhesiveness to the underlying epidermal basement membrane, delami-
nating and committing to terminal differentiation. The alternative theory is Hair follicle stem cells are found in the bulge regions below the sebaceous
that some basal cells (perhaps up to 70% of cells) can undergo asymmetrical glands. These stem cells are slow cycling and express the cell surface mol-
cell division, shifting their spindle orientation from lateral to perpendicular.5 ecules CD34 and VdR as well as the transcription factors TCF3, Sox9, Lhx2
Asymmetrical cell divisions provide a means of maintaining one proliferative and NFATc1 (Fig. 1.27). The bulge area stem cells generate cells of the outer
daughter while the other daughter cell is committed to terminal differentia- root sheath, which drive the highly proliferative matrix cells next to the mes-
tion. Asymmetrical cell divisions, therefore, can bypass the need for transient enchymal papillae. After proliferating, matrix cells differentiate to form the
amplifying cells. hair channel, the inner root sheath and the hair shaft. Hair follicle stem cells
Markers of interfollicular stem cells

α6 integrin
β1 integrin
p63
Markers of hair follicle bulge stem cells

DNA label retention
CD34
NFATc1
Vitamin D receptor
TCF3
Fox9
Lhx2
Fig. 1.27
Markers of sebocyte stem cells
Molecular markers of stem cells in the
Blimp 1 skin.
can also differentiate into sebocytes and interfollicular epidermis. Despite this
multipotency, however, the follicle stem cells only function in pilosebaceous
unit homeostasis and do not contribute to interfollicular epidermis unless the Fig. 1.28
Granular cell layer: note the keratohyalin and membrane coating granules (arrowed).
skin is wounded.6
Stem cells are also found in the base of sebaceous glands: the progeny of
these cells differentiate into lipid-filled sebocytes. Apart from stem cells in
the hair follicles, sebaceous glands and interfollicular epidermis, other cells the cell membrane. They fuse with the plasma membrane, dispersing their
in the dermis and subcutis may have stem cells properties. These include cells contents into the intercellular space. Polar lipids from the lamellar granules
that have been termed skin-derived precursors (SKPs), which can differentiate are remodeled into neutral lipids in the intercellular space between corneo-
into both neural and mesodermal progeny.7 In addition, a subset of dermal cytes, thereby contributing to the barrier.
fibroblasts can have adipogenic, osteogenic, chondrogenic, neurogenic and Within the granular layer of the epidermis, the main keratinocyte pro-
hepatogenic differentiation potential.8 teins are keratin and filaggrin, which together contribute approximately
80–90% of the mass of the epidermis and are ultrastructurally represented
by the keratohyalin granules (Fig. 1.29). Filaggrin is initially synthesized as
Skin barrier profilaggrin, a ≈500-kDa highly phosphorylated, histidine-rich polypeptide.
During the post-translational processing of profilaggrin, the individual filag-
A major function of the epidermis is to form a barrier against the external grin polypeptides, each ≈35 kD, are proteolytically released. These are then
environment. To achieve this, terminal differentiation of keratinocytes results dephosphorylated, a process that assists keratin filament aggregation and
in formation of the cornified cell envelope. This physical barrier is rendered explains the origin of the name ‘filaggrin’ (filament aggregating protein) (Fig.
highly insoluble by the formation of glutamyl-lysyl isodipeptide bonds between 1.30). Typically, there are 10 highly homologous filaggrin units, although the
envelope proteins, catalyzed by transglutaminases.1 Several different proteins number of filaggrin repeat units is variable and genetically determined, with
contribute to construction of the cornified cell envelope, including involucrin,
and the family of small proline-rich proteins (SPR1) including cornifin or
SPR1 and pancornulins. Other envelope proteins include SKALP/elafin and
keratolinin/cystatin. Some precursors of the cornified envelope are delivered
by granules: small, smooth, sulfur-rich L granules contain the cysteine-rich
protein loricrin, and accumulate in the stratum granulosum.2 Loricrin is the
major component of the cornified envelope. Profilaggrin in F granules may
make a minor contribution to the envelope. Membrane-associated proteins
that contribute to the cornified envelope include the plakin family members,
periplakin, envoplakin, epiplakin, desmoplakin as well as plectin. Formation
of the cornified cell envelope is triggered by a rise in intracellular calcium
levels.3 This leads to cross-link formation between plakins and involucrin
catalyzed by transglutaminases. Other desmosomal proteins are then also
cross-linked, forming a scaffold along the entire inner surface of the plasma
membrane. Ceramides from the secreted contents of lamellar bodies are then
esterified onto glutamine residues of the scaffold proteins. The cornified cell
envelope is reinforced by the addition of a variable amount of SPRs, repe-
tin, trichohyalin, cystostatin α, elafin and LEP/XP-5 (skin-specific protein).
Although most desmosomal components are degraded, keratin intermediate
filaments (mostly K1, K10 and K2e) may be cross-linked to desmoplakin and
envoplakin remnants.
In the upper stratum spinosum and stratum granulosum lipid is synthe-
sized and packaged into lamellated membrane-bound organelles known as
membrane-coating granules, lamellar granules or Odland bodies (Fig. 1.28).4
They are found adjacent to the cell membrane with alternating thick and Fig. 1.29
thin dense lines separated by lighter lamellae of equal width, consistent with Stratum corneum:
packing of flattened discs within a membrane boundary. These granules con- keratohyalin granules are
tain phospholipids, glycolipids and free sterols and move towards the plasma present just beneath the
membrane as the cells move through the granular layer where they cluster at keratin lamellae.
Skin immunity 9
Epidermal barrier: Keratohyalin granules composed of profilaggrin Micro-organisms

mechanical strength;
prevent water loss;
restrict allergen penetration External allergens
Stratum corneum
Stratum Filaggrin deaminated Fig. 1.32
corneum and degraded Innate immunity in the
Granular layer
Granular skin: the physical barrier is
layer complemented by an innate
Upper spinous layer immune response that
targets bacteria, viruses
Spinous Inflammatory cells and fungi and prevents
layer them from invading the
Constitutive anti-microbial peptides (psoriasin) skin. These peptides
include constitutive and
Inducible anti-microbial peptides
(β-defensins, RNASE7, LL-37) inducible substances
against a broad range of
Basal layer Pro-inflammatory cytokines (IL-1, TNFα, etc) organisms.
Dermal-
epidermal
junction Profilaggrin cleaved into Keratinocyte Langerhans cell peptides occurs as a result of unique structural characteristics that enable
10-12 filaggrin peptides Melanocyte
them to disrupt the microbial cell membrane while leaving human cell mem-
Fig. 1.30 branes intact. The antimicrobial peptides can have immunostimulatory and
Function of filaggrin in human skin: this is the major component of keratohyalin immunomodulatory capacities as well as being chemotactic for distinct sub-
granules. In the granular layer profilaggrin is cleaved into filaggrin peptides populations of leukocytes and other inflammatory cells.5 Some peptides have
subsequent deamination and degradation provides the skin with mechanical additional roles in signaling host responses through chemotactic, angiogenic,
strength and restricts transepidermal water loss. Filaggrin also prevents allergen growth factor and immunosuppressive activity. These peptides are known as
penetration. In the absence of filaggrin, for example caused by common mutations
alarmins.6 Alarmins may also stimulate parts of the host defense system, such
in the filaggrin gene, external allergens may penetrate the epidermis and encounter
as barrier repair and recruitment of inflammatory cells.
Langerhans cells. This may lead to the development of atopic dermatitis as well as
other atopic manifestations and systemic allergies. Skin immunity is also provided by a distinct population of antigen present-
ing cells in the epidermis known as Langerhans cells (Fig. 1.33). These are
dendritic cells that were first described by Langerhans, who demonstrated their
duplications of filaggrin repeat units 8 and/or 10 in some individuals. Fewer existence in human epidermis by staining with gold chloride. Without stimula-
filaggrin repeats leads to dryer skin. Loss-of-function mutations in filaggrin tion, Langerhans cells exhibit a unique motion termed ‘Dendrite Surveillance
are very common, occurring in up to 10% of the European population. These Extension And Retraction Cycling Habitude (dSEARCH)’.7 This is charac-
mutations lead to reduced or absent keratohyalin granules, and are the cause terized by rhythmic extension and retraction of dendritic processes between
of ichthyosis vulgaris as well as constituting a major risk factor for atopic intercellular spaces. When exposed to antigen, there is greater dSEARCH
dermatitis (Fig. 1.31).5 motion and also direct cell-to-cell contact between adjacent Langerhans
cells which function as intraepidermal macrophages, phagocytosing antigens
among keratinocytes. Langerhans cells then leave the epidermis and migrate
Skin immunity via lymphatics to regional lymph nodes. In the paracortical region of lymph
nodes the Langerhans cell expresses protein on its surface to present to a T
Skin possesses both innate and adaptive immune responses to defend against lymphocyte that can then undergo clonal proliferation. Langerhans cells, in
microbial pathogens and thereby prevent infection. One of the primary mech- combination with macrophages and dermal dendrocytes, represent the skin's
anisms is the synthesis, expression and release of antimicrobial peptides (Fig. mononuclear phagocyte system.8 By electron microscopy, Langerhans cells
1.32).1 There are more than 20 antimicrobial peptides in the skin, includ- have a lobulated nucleus, a relatively clear cytoplasm and well-developed
ing cathelicidins, β-defensins, substance P, RANTES, RNase 2, 3, and 7, and endoplasmic reticulum, Golgi complex and lysosomes. They also possess
S100A7. Many of these peptides have antimicrobial action against bacteria, characteristic granules which are rod or racquet-shaped (Fig. 1.34). These
viruses, and fungi. In the stratum corneum there is an effective chemical bar- ‘Birbeck’ granules represent subdomains of the endosomal recycling compart-
rier maintained by the expression of S100A7 (psoriasin).2 This antimicro- ment and form at sites where the protein Langerin accumulates.
bial substance is very effective at killing Escherichia coli. Subjacent to this Besides antigen detection and the processing role by epidermal Langerhans
in the skin there is another class of antimicrobial peptides, such as RNASE7, cells, cutaneous immune surveillance is also carried out in the dermis by an
which is effective against a broad spectrum of microorganisms, especially array of macrophages, T cells and dendritic cells. These immune sentinel and
enterococci.3 Below this in the living layers of the skin are other antimicro- effector cells can provide rapid and efficient immunologic back-up to restore
bial peptides including the β-defensins.4 The antimicrobial activity of most tissue homeostasis if the epidermis is breached. The dermis contains a very
May cause Are the cause of Are a major risk factor Are associated with atopic
hyperlinearity of the palms ichthyosis vulgaris for atopic dermatitis dermatitis persisting into adulthood
Occur in up to 10% Loss-of function Are a major risk factor for

of the population mutations in the FLG gene asthma with atopic dermatitis
Fig. 1.31
Functional consequences of
loss-of-function mutations in the
Are not associated with Can modify clinical Are implicated in development Are associated with increased filaggrin gene, which can affect up to
psoriasis or non-atopic asthma expression of other diseases of systemic allergies severity of atopic asthma
10% of the people in some populations.
large number of resident T cells. Indeed, there are approximately 2 × 1010

resident T cells, which is twice the number of T cells in the circulating blood.
Dermal dendritic cells may also have potent antigen-presenting capacities
or the potential to develop into CD1a-positive and Langerin-positive cells.
Dermal immune sentinels are capable of acquiring an antigen-presenting
mode, a migratory mode or a tissue resident phagocytic mode.9
Melanocytes
Melanocytes are pigment-producing cells and are found in the skin, inner ear,
choroid and iris of the eye. In skin, melanocytes are located in the basal keratino-
cyte layer. The ratio of melanocytes to basal cells ranges from approximately 1:4
on the cheek to 1:10 on the limbs. They appear as vacuolated cells in hematoxylin
and eosin stained sections (Fig. 1.35). Ultrastructurally, melanocytes have pale
cytoplasm and are devoid of tonofilaments and desmosomes (Fig. 1.36). They are
easily recognized by their specific cytoplasmic organelles (melanosomes) which
are derived from the smooth endoplasmic reticulum. Melanosomes are believed
to represent a specialized variant of lysosome (Fig. 1.37). The function of mel-
Fig. 1.33 anocytes is the production of melanin, a pigment that varies in color from yel-
Langerhans cells express S-100 protein: note the conspicuous dendritic processes. low to brown or black and accounts for the various skin colors within and
Fig. 1.34
(A, B) Langerhans cell:
(A) note the characteristic
lobulated nucleus. Dendritic
processes are evident,
(B) typical rod forms with
the characteristic trilaminar
A B
structure.
Fig. 1.35
(A, B) Normal epidermis:
melanocytes are seen
along the basal layer of the
epidermis. The cytoplasmic
vacuolation is a fixation
artifact; (B) melanocytes
can be highlighted
with S100-protein
immunohistochemistry.
A Note the dendritic
B
processes.
Melanocytes 11
Melanin is transferred from melanocytes in melanosomes to neighboring

keratinocytes in the epidermis and into the growing shaft in hair follicles and
can be identified by silver techniques such as the Masson-Fontana reaction
(Fig. 1.38). Transport occurs along the dendritic processes of the melanocytes
and the melanosomes are engulfed as membrane-bound (lysosomal) single
or compound melanosomes by a group of adjacent largely basally located
keratinocytes (epidermal melanin unit) where they are typically seen in an
umbrella-like distribution over the outer aspect of the nucleus (Fig. 1.39).
A compound melanosome typically contains from three to six single melano-
somes. In heavily pigmented skin and dark hair, melanosomes remain solitary
and are longer than those seen in melanogenesis in paler races. Other cells
that may contain compound melanosomes include macrophages (melano-
phages), melanoma cells and, occasionally, Langerhans cells, the other type of
epidermal dendritic cell. Macromelanosomes (giant melanosomes) measure
several microns in diameter and therefore are readily visible in hematoxylin
and eosin stained sections (Fig. 1.40). They may be encountered in normal
skin, in lentigines, dysplastic nevi, Spitz nevi, in the café-au-lait macules of
neurofibromatosis and in albinism. A key protein involved in melanosome
assembly is NCKX5, encoded by the gene SLC24A5.4 Loss of expression of
Fig. 1.36 this gene in mice results in marked changes in skin color with loss of pigment.
Normal melanocyte: it has abundant pale cytoplasm and scattered solitary
melanosomes. Note the absence of tonofibrils and desmosomes.
Fig. 1.38
Normal epidermis: this section of black skin has been stained by the Masson–
Fontana reaction for melanin. Note the heavy pigmentation, which is present in
Fig. 1.37 both melanocytes and keratinocytes.
Melanosome: note the typical striated internal structure.
among races. Melanin protects the mitotically active basal epidermal cells from
the injurious effects of ultraviolet light, which accounts for individuals with
less pigmentation (fair-haired and light-skinned) having a much greater risk of
sunburn and developing cutaneous malignancies (squamous cell and basal cell
carcinomas, and melanoma). The mechanism involves absorbing or scatter-
ing ultraviolet radiation and/or its photoproducts. Other functions of melanin
include control of vitamin D3 synthesis and local thermoregulation.
In skin and hair, two forms of melanin pigment are produced; eumelanin
and pheomelanin. Eumelanin is a brown or black pigment and is synthe-
sized from tyrosine; it is particularly found in dark-colored races, whereas,
pheomelanin has a yellow-red color and is synthesized from tyrosine and
cysteine; it predominates in Caucasian skin.
Melanocytes also possess melanocyte-specific receptors including melano-
cortin-1 (MC1R) and melatonin receptors.1 The activation or the inhibition
of melanocyte-specific receptors can augment normal melanocyte function,
skin color, and photoprotection. Moreover, receptor polymorphisms are
known to underlie red hair phenotypes.2 Hair graying reflects abnormalities
in melanocyte signaling. Notably, Notch transcription factor signaling in mel- Fig. 1.39
anocytes is essential for the maintenance of proper hair pigmentation, includ- Melanin pigment: actinically damaged skin. Note that the melanin pigment is
ing regeneration of the melanocyte population during hair follicle cycling.3 located in a ‘cap’ overlying the keratinocyte nuclei.
Fig. 1.41
Merkel cells: separated human epidermis showing a striking linear arrangement
Fig. 1.40 (troma-1 antibody). By courtesy of J.P. Lacour, MD, and J.P. Ortonne, MD, University
Macromelanosomes: of Nice, France.
note the large spherical
melanosomes in the
cytoplasm of the
melanocytes.
Mature melanosomes of eumelanin are ellipsoidal in shape, while pheomela-

nin-producing melanosomes are spherical.
Merkel cells
Merkel cells are postmitotic cells scattered throughout the epidermis of ver-
tebrates and constitute 0.2–0.5% of epidermal cells.1 Merkel cells represent
part of the affector limb in cutaneous slowly adapting type-1 (SA1) mechano-
receptors and are therefore particularly concerned with touch sensation. They
are located amongst basal keratinocytes and are mainly found in hairy skin,
tactile areas of glabrous skin, taste buds, the anal canal, labial epithelium
and eccrine sweat glands. In glabrous skin, the density of Merkel cells is ≈50
per mm2. Sun-exposed skin may contain twice as many Merkel cells as non-
Fig. 1.42
sun-exposed skin.2 Numerous Merkel cells can be found in actinic keratoses.3
Merkel cell: positive labeling for CAM 5.2 identifies Merkel cells in this obliquely
Merkel cells cannot be recognized in conventional hematoxylin and eosin sectioned epidermal ridge.
stained sections. Rather, immunocytochemistry, particularly using antikeratin
antibodies, or electron microscopy, is necessary for their identification (Figs
1.41 and 1.42). Human skin contains an extensive neural network that contains cholin-
Ultrastructurally, Merkel cells appear oval with a long axis of ≈15 μm ori- ergic and adrenergic nerves and myelinated and unmyelinated sensory fibers.
entated parallel to the basement membrane (Fig. 1.43). They also have a large Moreover, the skin also contains several transducers involved in the percep-
bilobed nucleus and clear cytoplasm which reflects a relative scarcity of intra- tion of touch, pressure, and vibration, including Ruffini organs surrounding
cellular organelles. Merkel cells contain numerous neurosecretory granules, hair follicles, Meissner's corpuscles, Vater–Pacini corpuscles located in the
each 50 nm to 160 nm across; these are found opposing the junctions with deep layer of the dermis, and nerve endings which pass through the epider-
the sensory nerve ending (Fig. 1.44). Merkel cells contain keratin filaments, mal basement membrane. Some of these contain Merkel cells which form the
particularly keratin filament types 8, 18, 19, and 20, which are characteris- Merkel cell–neurite complex, while others are free nerve endings. The cell
tic of simple epithelium and fetal epidermis. Immunocytochemically, Merkel bodies for all these neurons reside in the dorsal root ganglion. The Merkel
cells also express neuropeptides including synaptophysin, vasoactive intes- cell–neurite complexes are thought to serve as mechanoreceptors and to be
tinal peptide (VIP) and calcitonin gene-related polypeptide (CGRP).4,5 They responsible for the sensation of touch. They are clustered near unmyelinated
contain neuron-specific proteins including neuron-specific enolase (NSE) and sensory nerve endings, where they group and form ‘touch spots’ at the bottom
protein gene product (PGP) 9.5.6 In addition, Merkel cells express desmo- of rete ridges. These complexes are also known as hair discs, touch domes,
somal proteins, membranous neural cell adhesion molecule and nerve growth touch corpuscles, or Iggo discs. The complex is innervated by a single, slowly
factor receptor.7–9 Merkel cells show a positive uranaffin reaction.10 Merkel adapting type 1 nerve fiber. In hairy skin, Merkel cells also cluster in the
cells form close connections with sensory nerve endings and secrete or express rete ridges and in the outer root sheath of the hair follicle where the arrector
a number of these peptides.11 The close contact between Merkel cells and pili muscles attach. The function of Merkel cells in hair follicles is unclear,
nerve fibers represents a Merkel cell–neurite complex, but there is no clear although they may be involved in the induction of new anagen cycles.
evidence of synaptic transmission, although numerous vesicles can be identi- There are two hypotheses for the origin of Merkel cells: one possibility is
fied in neurons apposed to Merkel cells.12 that they differentiate from epidermal keratinocyte-like cells and the other
Intercellular junctions 13
Intercellular junctions
Desmosomes are the major intercellular adhesion complexes in the epider-
mis. They anchor keratin intermediate filaments to the cell membrane and
link adjacent keratinocytes (Fig. 1.45). Desmosomes are found in the epider-
mis, myocardium, meninges and cortex of lymph nodes. Ultrastructurally,
desmosomes contain plaques of electron-dense material running along
the cytoplasm parallel to the junctional region, in which three bands can
be distinguished: an electron-dense band next to the plasma membrane, a
less dense band, and then a fibrillar area (Fig. 1.46).1 Identical components
are present on opposing cells which are separated by an intercellular space
of 30 nm within which there is an electron-dense midline. There are three
main protein components of desmosomes in the epidermis: the desmosomal
cadherins, the armadillo family of nuclear and junctional proteins, and the
plakins (Fig. 1.47).2 The transmembranous cadherins comprise mostly het-
erophilic associations of desmogleins and desmocollins. There are four main
epidermis-specific desmogleins (Dsg1–4) and three desmocollins (Dsc1–3).
These show differentiation-specific expression. For example, Dsg1 and Dsc1
Fig. 1.43
Merkel cell: a heavily
granulated Merkel
cell is present in the
midfield. This is located
immediately adjacent to a
small nerve fiber.
Fig. 1.45
Mid-prickle cell layer of normal epidermis: there are complex interdigitations
between adjacent cell membranes with numerous desmosomal junctions.
Fig. 1.44
Merkel cell granules: they are membrane bound and measure approximately
150 nm in diameter. By courtesy of A.S. Breathnach, MD (1977) Electron
microscopy of cutaneous nerves and receptors. Journal of Investigative
Dermatology 69, 8–26. Blackwell Publishing Inc., USA.
is that they arise from stem cells of neural crest origin that migrated during
embryogenesis, in similar fashion to melanocytes.13 Merkel cell hyperplasia is
a common histological finding and may accompany keratinocyte hyperpro-
liferation as well as being frequently seen in adnexal tumors such as nevus
sebaceus, trichoblastomas, trichoepitheliomas, and nodular hidradenomas.14
Merkel cell hyperplasia is associated with hyperplasia of nerve endings that
occurs in neurofibromas, neurilemomas, nodular prurigo, or neurodermati-
tis. It is not clear whether Merkel cell carcinoma originates from Merkel cells Fig. 1.46
or their precursors but the latter may be more likely given that many dermal Mid-prickle cell layer of normal epidermis showing the stratified nature of the
Merkel cell carcinomas do not connect with the epidermis. desmosome.
Autosomal dominant Autosomal recessive
Ectodermal dysplasia -
Plakophilin 1
Skin fragility syndrome
Arrhythmogenic right Arrhythmogenic right

Plakophilin 2
ventricular cardiomyopathy ventricular cardiomyopathy
Woolly hair, keratoderma, Woolly hair, keratoderma,

cardiomyopathy +/- cardiomyopathy
Arrhythmogenic right
Desmoplakin
ventricular cardiomyopathy
Striate palmoplantar Lethal acantholytic

keratoderma epidermolysis bullosa
Plakoglobin Naxos disease
Desmoglein Plakoglobin Desmoplakin ventricular cardiomyopathy
Desmocollin Plakophilin Keratin Striate palmoplantar

Desmoglein 1
keratoderma
Fig. 1.47
Protein composition of a desmosome junction between adjacent keratinocytes. The Arrhythmogenic right Arrhythmogenic right
Desmoglein 2
keratin filament network of two keratinocytes is linked by a series of desmosomal ventricular cardiomyopathy ventricular cardiomyopathy
plaque proteins and transmembranous molecules to create a structural and
signaling bridge between the cells. Localized recessive
Desmoglein 4
hypotrichosis
Recessive monilethrix
are found predominantly in the superficial layers of the epidermis whereas
Hypotrichosis with
Dsg3 and Dsc3 show greater expression in basal keratinocytes. The intra- Desmocollin 3
scalp vesicles
cellular parts of the cadherins interact with the keratin filament network
via the desmosomal plaque proteins, mainly desmoplakin, plakoglobin and Desmocollin 2
ventricular cardiomyopathy
plakophilin.1
Clues to the biologic function of these desmosomal components have arisen Hypotrichosis simplex Corneodesmosin
from various inherited and acquired human diseases.3,4 Naturally occurring
Fig. 1.48
human mutations have been reported in ten different desmosome genes with
Genetic disorders of desmosomes: autosomal dominant or autosomal recessive
variable skin, hair and heart abnormalities and several desmosomal proteins mutations in ten different structural components of desmosomes may give rise to
serve as autoantigens in immunobullous blistering skin diseases such as pem- specific diseases that can affect skin, hair or heart or combinations thereof.
phigus (Figs 1.48 and 1.49).5 Antibodies to multiple desmosomal proteins
may develop in diseases such as paraneoplastic pemphigus through the phe-
nomenon of epitope spreading.6 Cleavage of the extracellular domain of Dsg1 Immunobullous diseases
has also been demonstrated as the basis of staphylococcal scalded skin syn-
drome and bullous impetigo.7 Desmoglein 3 Pemphigus vulgaris
Adherens junctions are recognized ultrastructurally as electron-dense trans-
Pemphigus foliaceus
membrane structures, with two opposing membranes separated by approxi- Desmoglein 1
mately 20 nm, that form links with the actin skeleton.8 They are 0.2–0.5 μm Endemic pemphigus
in diameter and can be found as isolated cell junctions or in association with Desmocollin 3 Atypical pemphigus
tight junctions and desmosomes. Adherens junctions are expressed early in
skin development and contribute to epithelial assembly, adhesion, barrier for- Atypical pemphigus
Desmocollin 1
mation, cell motility and changes in cell shape. They may also spatially co-
IgA pemphigus
ordinate signaling molecules and polarity cues as well as serving as docking (sub-corneal type)
sites for vesicle release. Adherens junctions contain two basic adhesive units:
the nectin-afadin complex and the classical cadherin complex.9,10 The nectins Fig. 1.49
form a structural link to the actin cytoskeleton via afadin (also known as Immunobullous diseases of desmosomes: intraepidermal blistering can arise
AF-6) and may be important in the initial formation of adherens junctions. through autoantibody disruption of four separate desmosomal proteins which leads
The cadherins form a complex with the catenins (α-, β-, and p120 catenin) to different clinical variants of pemphigus.
and help mediate adhesion and signaling. Cell signaling via β-catenin can acti-
vate several pathways linked to morphogenesis and cell fate determination. connexons (homotypic or heterotypic) to form a gap junction. To date, 13
Inherited gene mutations of the adherens junction proteins plakoglobin different human connexins have been described. The formation and stabil-
and P-cadherin have been reported. Plakoglobin mutations result in Naxos ity of gap junctions can be regulated by protein kinase C, Src kinase, cal-
disease (woolly hair, keratoderma, cardiomyopathy).3 P-cadherin mutations cium concentration, calmodulin, adenosine 3′,5′-cyclic monophosphate
underlie autosomal recessive hypotrichosis with juvenile macular dystrophy (cAMP) and local pH.14 The connexins are classified into three groups (α,
as well as ectodermal dysplasia-ectrodactyly-macular dystrophy (EEM) syn- β and γ) according to their gene structure, overall gene homology and spe-
drome, in which there is hypotrichosis, macular degeneration, hypodontia cific sequence motifs.15 Apart from the connexins, vertebrates also contain
and limb defects, including ectrodactyly, syndactyly and camptodactyly.11,12 another class of gap junction proteins, the pannexins, which are related to the
Gap junctions represent clusters of intercellular channels, known as innexins found in nonchordate animals. The function of gap junctions is to
connexons, which form connections between the cytoplasm of adjacent allow sharing of low molecular mass metabolites (<1000 Da) and exchange of
keratinocytes (and other cells).13 Formation of a connexon involves assembly ions between neighboring cells. Gap junction communication is essential for
of six connexin subunits within the Golgi network. This complex is then cell synchronization, differentiation, cell growth and metabolic coordination
transported to the plasma membrane where connexons associate with other of avascular organs, including epidermis.14
Pilosebaceous units 15
Deafness with unusual Deafness with e ndocuticle, exocuticle and ‘a’ layer.1 Around the cuticle is the inner root
hyperkeratosis and oral erosions Clouston-like phenotype sheath (IRS), which is composed of three distinct layers of cells that undergo
keratinization: the IRS cuticle, the Huxley layer and the outermost Henle
Hystrix-like-ichthyosis Palmoplantar keratoderma layer.2 Differentiation in the IRS involves the development of trichohyalin
deafness syndrome with deafness granules, with 8–10 nm filaments orientated in the direction of hair growth.
Keratitis-ichthyosis - The IRS moves up the follicle, forming a support for the hair fiber, and
26 Bart-Pumphrey syndrome degenerates above the sebaceous gland. The outermost layer is the outer root
deafness syndrome
sheath (ORS), which is continuous with the epidermis and expresses epithe-
Non-syndromic deafness Vohwinkel’s syndrome lial keratins, K5/K14, K1/K10 and K6/K16 in the upper ORS and K5/K14/
Non-syndromic deafness 30 Clouston’s syndrome K17 in the deeper ORS.
Normal growth of the hair fiber is 300–400 μm/day. Hair growth is gener-
Erythro-keratoderma ated by the high rate of proliferation of progenitor cells in the follicle bulb.
30.3
variabilis
There are three phases of cyclical hair growth: anagen, when growth occurs;
Peripheral neuropathy and Erythro-keratoderma catagen, a regressing phase; and telogen, a resting phase. The follicle re-enters
31 anagen, and the old hair is replaced by a new one.
hearing impairment variabilis
Immediately above the basal layer in the hair bulb, cells undergo a sec-
Non-syndromic deafness Charcot-Marie ondary pathway of ‘trichocyte’ or hair differentiation, and express a fur-
32
tooth disease (X-linked) ther complex group of keratins, the hard keratins.2 Two families of hair
Atrial fibrillation 40 keratins, types I and II, are present in mammals, which have distinctive
Non-syndromic deafness 43 Oculodentodigital dysplasia amino- and carboxy-terminals with high levels of cysteine residues but
lack the extended glycine residues of epidermal keratins. The proteins dif-
Zonular pulverulent
46
fer from epithelial keratins in position on two-dimensional gels but form
cataract-3 acidic and basic groups. There are four major proteins in each family and
Zonular pulverulent
50 several minor proteins, Ha 1–4 and Hb 1–4. Recent cloning of the hair ker-
cataract -1
atin genes, which cluster on chromosomes 12 and 17, has shown an even
Fig. 1.50 greater number of hair keratin genes, HaKRT1–6 (including 3.1 and 3.2)
Genetic disorders of connexins: nine different human connexin molecules are and HbKRT1–6.
associated with different inherited diseases. Mutations in the four low molecular Mutations in hair keratin genes have been found to cause autosomal domi-
weight connexins shown at the top of the diagram are associated with a spectrum nant forms of the human disease monilethrix. More common hair variants,
of skin pathology, as highlighted.
such as curly hair, may be explained by dynamic changes during hair growth.3
Curvature of curly hair is programmed from the very basal area of the follicle
and the bending process is linked to a lack of axial symmetry in the lower
Inherited abnormalities in genes encoding four different connexins (Cx26, part of the bulb, affecting the connective tissue sheath, ORS, IRS and the hair
30, 30.3 and 31) have been detected in several forms of keratoderma and/or shaft cuticle.
hearing loss (Fig. 1.50). Nondermatologic disorders can also arise from muta- Sebaceous glands usually develop as lateral protrusions from the outer
tions in some higher molecular weight connexins (Cx32, 40, 43, 46 and 50). root sheath of hair follicles, but at certain sites, such as the eyelids, lips, are-
Tight junctions contribute to skin barrier integrity and maintaining cell olae, nipples and labia minora, they appear to arise independently and drain
polarity, although in simple epithelia they are major regulators of perme- directly onto the skin's surface (Figs 1.51 and 1.52). They are widespread in
ability.8 An important function is to regulate the paracellular flux of water- distribution, being found everywhere on the body except on the palms and
soluble molecules between adjacent cells.16 The main structural proteins of soles. They are particularly abundant on the face and scalp, in the midline
tight junctions are the claudins, of which there are approximately 24 sub- of the back and about the perineum, and are concentrated around the ori-
types, as well as the IgG-like family of junctional adhesion molecules (JAMs) fices of the body (Fig. 1.53). Those of the eyelid are known as the glands
and the occludin group of proteins. The principal claudins in the epidermis
are claudin 1 and 4. These transmembranous proteins can bind to the intrac-
ellular zonula occudens proteins ZO-1, ZO-2, ZO-3 which interact with the
actin cytoskeleton.8,17
Clinically, abnormalities in tight junction proteins can result in skin, kid-
ney, ear and liver disease. Inherited gene mutations in claudin 1 have been
reported in one pedigree with diffuse ichthyosis, hypotrichosis, scarring
alopecia and sclerosing cholangitis.18
Pilosebaceous units
There are four classes of pilosebaceous unit: terminal on the scalp and beard;
apopilosebaceous in axilla and groin; vellus on the majority of skin; and
sebaceous on the chest, back and face. The dermal papilla is located at the
base of the hair follicle and is associated with a rich extracellular matrix.
Around the papilla are germinative (matrix) cells that have a very high rate
of division, and give rise to spindle-shaped central cortex cells of the hair
fiber, and the single outer layer of flattened overlapping cuticle cells. A cen-
tral medulla is seen in some hairs, with regularly stacked condensed cells
interspersed with air spaces or low-density cores. The cortical cells are filled
with keratin intermediate filaments orientated along the long axis of the Fig. 1.51
cell, interspersed with a dense interfilamentous protein matrix. The cuticu- Sebaceous glands: on the inner aspect of the labia these appear as tiny yellow
lar cells are morphologically distinct, with flattened outward-facing cells, papules (Fordyce spots). By courtesy of S.M. Neill, MD, Institute of Dermatology,
with three layers inside the cuticle of condensed, flattened protein granules: London, UK.
Fig. 1.52 Fig. 1.54

Normal vulva: sebaceous glands are conspicuous, but arise independently of a hair Nose: multiple sebaceous glands are evident.
follicle and open directly onto the surface epithelium.
Fig. 1.55
Sebaceous lobule: germinative cells are basophilic and flattened. With maturation
the cells acquire their characteristic ‘bubbly’ cytoplasm.
Fig. 1.53
Nose: sebaceous glands are particularly numerous at this site.
of Zeis and the meibomian glands. Sebaceous glands within the areolae are
known as Montgomery's tubercles. The largest sebaceous glands are associ-
ated with small vellus hairs in specialized pilosebaceous units known as seba-
ceous f ollicles (facial pores).
Sebaceous glands consist of several lipid-containing lobules, usually con-
nected to a hair follicle (Fig. 1.54). Each lobule is composed of an outer
layer of small cuboidal or flattened basophilic germinative cells, from which
arises the inner zone of lipid-laden vacuolated cells with characteristic cren-
ated nuclei (Fig. 1.55). The secretions drain into the sebaceous duct, which
joins the hair follicle at the level of the infundibulum (Fig. 1.56). The duct is
lined by keratinizing stratified squamous epithelium and is continuous with
the external root sheath. The glands are holocrine because their secretions
depend on complete degeneration of the acini, with release of all the cells'
lipid contents to become sebum.
Immunohistochemically, the sebaceous cells label strongly for EMA but
they do not express CEA or low molecular weight keratin (CAM 5.2) or
S-100 protein (Fig. 1.57). Ultrastructurally, the mature sebaceous gland
shows gradual accumulation of variably sized, nonmembrane-bound, lipid Fig. 1.56
inclusions in differentiating cells. Numerous mitochondria, ribosomes and Sebaceous duct: this is lined by keratinizing stratified squamous epithelium; it is
membrane-bound vesicles may also be evident. As the cells mature before continuous with the external root sheath.
Eccrine glands 17
Histologically, eccrine sweat glands are divided into four subunits: a highly
vascularized coiled secretory gland, a coiled dermal duct, a straight dermal
duct, and a coiled intraepidermal duct (the acrosyringium) (Fig. 1.59). The
secretory coil is located in the lower dermis, and the duct extends through
the dermis and opens directly onto the skin surface (Figs 1.60, 1.61). The
active sweat glands are present most densely on the sole, forehead and palm,
somewhat less on the back of the hand, still less on the lumber region, and
the lateral and extensor surfaces of the extremities, and least on the trunk
and the flexor and medial surfaces of the extremities. The uncoiled dimen-
sion of the secretory portion of the gland is approximately 30–50 μm in diam-
eter and 2–5 mm in length. The size of the adult secretory coil ranges 1–8 ×
10−3 mm3. The secretory component lies in the lower reaches of the reticular
Fig. 1.57
Sebaceous gland: the epithelial cells normally strongly express EMA.
Fig. 1.58
Sebaceous gland: in this field from the center of a sebaceous lobule, the cytoplasm
is completely distended with lipid droplets. Germinative cells are evident in the
right-lower quadrant.
their disintegration, the lipid droplets completely fill the cytoplasm and com-
press the centrally located nucleus (Fig. 1.58).
The secretion of sebaceous glands is sebum, an exceedingly compli-
cated lipid mixture that includes triglycerides (57%), wax esters (26%) and
squalene (12%). Its function includes waterproofing, control of epidermal
water loss, and a protective function, inhibiting the growth of fungi and bac-
teria. Secreted sebum undergoes significant changes due to the presence of
Propionibacterium acnes (triglyceride hydrolysis) within the pilosebaceous Fig. 1.59
Eccrine gland: (A) palmar
canal and Staphylococcus epidermidis (cholesterol ester formation) on the
skin showing numerous
perifollicular skin. Skin surface lipid is composed of a mixture of sebum and eccrine glands located in
epidermal lipids. the deep reticular dermis
and subcutaneous fat,
(B) the secretory unit is in
Eccrine glands the lower field. Sections
through the coiled duct
Human sweat glands are generally divided into two types: eccrine and apo- are evident in the upper
crine.1 The eccrine gland is the primary gland responsible for thermoregula- field. The epithelium of
tory sweating in humans.2 Eccrine sweat glands are distributed over nearly the duct is more darkly
the entire body surface. The number of sweat glands in humans varies greatly, B stained than that of the
ranging from 1.6 to 4.0 million. glandular component.
(see below). Sometimes the secretory lobules show striking clear cell change
due to glycogen accumulation (Fig. 1.62). The myoepithelial cells contract
in response to cholinergic stimuli. They have spindled cell morphology and
are distributed in a spiral, parallel array along the long axis of the secretory
tubule. On the basis of their expression of keratin filaments, they appear to
be of ectodermal rather than mesenchymal derivation. They do not label for
vimentin. Myoepithelial cells therefore develop from the epithelial cells of the
tip of the secretory coil and not, as might be expected, from adjacent mesen-
chymal cells. The dermal duct components consist of a double layer of cuboi-
dal basophilic cells. The duct is not merely a conduit, but has a biologically
active function, modifying the composition of eccrine secretion and, particu-
larly, the reabsorption of water. The intraepidermal portion of the sweat duct
opens directly onto the surface of the skin. A myoepithelial layer is absent.
The secretory unit is strongly labeled by CAM 5.2 (both cytoplasmic and
membranous) and Ber-EP4 and there is luminal accentuation (Fig. 1.63). The
ductal component is completely negative. EMA can be detected along the
luminal aspect of the secretory unit and outlining the intercellular canaliculi.
It is also present around the luminal border of the duct, and is often present
in large quantities within the lumen. CEA is present in a similar distribution
to EMA although secretory labeling tends to be rather focal and somewhat
weaker while the ductal lumen is more strongly outlined. The myoepithelial
Fig. 1.60
Eccrine gland: high-power
view of eccrine straight
duct.
Fig. 1.62
Eccrine gland: excessive glycogen has resulted in vacuolated epithelium.
Fig. 1.61
Eccrine gland: most
superficially, the duct
coils through the stratum
corneum.
dermis or around the interface between the dermis and subcutaneous fat and
is surrounded by a thick basement membrane and loose connective tissue
often rich in mucin. It embodies an outer discontinuous layer of contractile
myoepithelial cells and an inner layer of secretory cells comprising two cell
types: large clear pyramidal cells, which appear to be responsible for water
secretion, and smaller, darkly staining mucopolysaccharide-containing cells
(probably secreting a glycoprotein), which are much less commonly seen. Fig. 1.63
Between adjacent cells are canaliculi, which open into the lumen of the tubule Eccrine gland: immunohistochemistry.
Apocrine glands 19
cells can be identified by antibodies to S-100 protein, desmin and smooth

muscle actin. The eccrine glands show strong activity for the enzymes
amylophosphorylase, leucine aminopeptidase, succinic dehydrogenase and
cytochrome oxidase.3 Weak or no activity is seen for NADH diaphorase,
esterase and acid phosphatase.
With electron microscopy, the serous cells are characterized by abundant
intracytoplasmic glycogen granules and numerous mitochondria (Figs 1.64,
1.65). Adjacent cell membranes, which show marked interdigitations, may
separate to form microvilli-lined intercellular canaliculi. The mucous cells
contain numerous electron-dense lipid droplets and lysozymes. Myoepithelial
cells are present at the periphery of the secretory coil within the eccrine basal
lamina (lamina densa) and contain abundant myofilaments with characteris-
tic dense bodies. The sweat duct lumen is bordered by conspicuous microvilli
(Fig. 1.66). The cytoplasm contains numerous clear vesicles. Tonofilaments
are characteristically orientated in a circumferential manner deep to the
plasma membrane, the so-called cuticle of light microscopy. This is particu-
larly well developed in the acrosyringium.
Human perspiration is classified into two types: insensible perspiration A B
and active sweating. Insensible perspiration involves water loss from the
Fig. 1.66
Eccrine gland: (A) lumen of the eccrine dermal duct lined by conspicuous microvilli,
(B) high-power view of eccrine dermal duct showing microvilli and circumferentially
orientated tonofilaments.
respiratory passages, the skin, and gaseous exchanges in the lungs. Heat,
exercise and carbon dioxide can all induce active sweating in human beings.
Active sweating may be classified into two types: thermal and mental/emo-
tional. Thermal sweating plays an important role in keeping the body's tem-
perature constant and involves the whole body surface.4 The secretory nerve
fibers innervated in human sweat glands are sympathetic, which appear to be
cholinergic in character as sweating is produced by pilocarpine and stopped
by atropine.5 Vasoactive intestinal peptide (VIP) coexisting in the cholinergic
nerve fibers has been suggested as a candidate neurotransmitter that may con-
trol the blood circulation of the sweat glands. Acetylcholine is the primary
neurotransmitter released from cholinergic sudomotor nerves and binds to
muscarinic receptors on the eccrine sweat gland, although sweating can also
occur via exogenous administration of α- or β-adrenergic agonists. The ini-
tial fluid released from the secretory cells is isotonic and similar to plasma
although it is devoid of proteins. As the fluid travels up the duct towards the
surface of the skin, sodium and chloride are reabsorbed, resulting in sweat
Fig. 1.64 on the surface being hypotonic relative to plasma.6 When the rate of sweat
Eccrine gland: low-power electron micrograph showing the lumen in the upper-right production increases, however, for example during exercise, ion reabsorption
quadrant, granular mucous-secreting cells and serous cells. mechanisms can be overwhelmed due to the large quantity of sweat secreted
into the duct, resulting in higher ion losses. The sodium content in sweat on
the skin's surface, therefore, is greatly influenced by sweat rate.
Apocrine glands
Apart from eccrine glands, the skin also contains apocrine sweat glands.1,2
Apocrine glands have a low secretory output, and hence no significant role in
thermoregulation. Apocrine glands are found predominantly in the anogeni-
tal and axillary regions, but are also located in the external auditory meatus
(ceruminous glands), the eyelid (Moll's gland), and within the areola. They
are derived from the epidermis, and develop as an outgrowth of the follicu-
lar epithelium. They first appear during the fourth to fifth month of gesta-
tion. Their function in humans is unknown, but in other mammals they are
responsible for scent production and have importance in sexual attraction.
As with sebaceous glands, they are smaller in childhood, becoming larger and
functionally active at puberty. The secretions of the ceruminous glands are
believed to lubricate, clean and protect the external ear from bacterial and
fungal infections.
A B
Apocrine glands include two distinct components: a complex secretory
Fig. 1.65 element situated in the lower reticular dermis or subcutaneous fat, and
Eccrine gland: (left) high-power view of clear cell showing conspicuous a tubular duct linking the gland with the pilosebaceous follicle at a site
mitochondria and numerous electron-dense glycogen granules, (right) high-power above the sebaceous duct. Microscopically, the secretory portion comprises
view of secretory granules in a dark cell. an outer discontinuous layer of myoepithelial cells and an inner layer of
cuboidal to columnar eosinophilic cells (Figs 1.67, 1.68). Although a histo-

logical artifact, secretory droplets, which appear to be pinched off from the
superficial aspect of the columnar cells (decapitation secretion), can be seen
on light microscopy. The duct portion is formed by a double layer of cuboi-
dal epithelium. It is morphologically indistinguishable from the eccrine
duct. The inner layer of the secretory portion contains a single columnar
secretory cell type containing numerous large dense granules located at the
apical aspect, which contribute to the lipid-rich secretion produced. The
inner layer is also surrounded by a fenestrated layer of myoepithelial cells
but the lumen may be larger in diameter than that present in eccrine tissue
The apocrine excretory duct does not have any known reabsorptive func-
tion and consists of a double layer of cuboidal cells that merge distally with
the epithelium of the hair follicle, resulting in emptying of the secretion into
the hair follicle.
Immunohistochemically, the secretory unit shows very strong labeling
with the antibody CAM 5.2 (both cytoplasmic and membranous), and there
is luminal accentuation. The apocrine duct is negative (Fig. 1.69). EMA labels
the cytoplasm of the secretory cells, and is accentuated along the luminal
border. It is also present along the luminal aspect of the apocrine duct. With
CEA, there is faint, focal staining of the secretory epithelium. The luminal Fig. 1.69
Apocrine gland: immunohistochemistry (CAM 5.2 and EMA).
aspect of the duct is strongly outlined. Cytoplasmic granules express epider-

mal growth factor. The myoepithelial cells of the secretory unit are reactive
for S-100 protein and smooth muscle actin (Fig. 1.70). The apocrine secre-
tory epithelium strongly expresses the enzymes NADH diaphorase, esterase,
acid phosphatase and β-glucuronidase. There is weak or absent reactivity for
amylophosphorylase, leucine aminopeptidase, succinic dehydrogenase and
cytochrome oxidase. The apocrine gland also can be stained with cationic
colloidal gold at pH 2.0.3
Ultrastructure of the apocrine reveals cuboidal to columnar secretory cells
containing numerous osmiophilic secretory vacuoles. Mitochondria are pres-
ent in large numbers. While some show obvious double cristae, others are so
electron dense that the internal structure is obscured. The Golgi is conspicu-
ous. The luminal border is lined by prominent microvilli (Fig. 1.71).
The mechanism of apocrine secretion and control of apocrine glands is
uncertain, but there is adrenergic sympathetic innervation, and secretion is
provoked by external stimuli such as excitement or fear. The unpleasant odor
of apocrine secretion, which is odorless in itself, is due to breakdown prod-
ucts produced by cutaneous bacterial flora.
Fig. 1.67 A third type of intermediate sweat gland, the apo-eccrine gland, has
Apocrine gland: this specimen from normal axillary skin shows apocrine secretory also been described in axillary skin but its existence is not universally
lobules in the subcutaneous fat. Ducts are present in the upper right of the field. accepted.
Fig. 1.68
Apocrine gland: lobules are lined by tall columnar cells with intensely eosinophilic Fig. 1.70
cytoplasm. ‘Decapitation secretion’ is conspicuous. Apocrine gland: immunohistochemistry (S-100 protein and SMA).
Dermal–epidermal junction 21
Basal keratinocyte
Keratin filaments
Hemidesmosomal inner plaque
Hemidesmosomal outer plaque

Cell membrane
Sub-basal dense plate
Lamina lucida
Anchoring filaments
Lamina densa
Anchoring fibrils
Fig. 1.71
Apocrine gland: close-up view showing microvilli and decapitation secretion.
Papillary dermis
Dermal–epidermal junction Fig. 1.73

Schematic representation of a hemidesmosome-anchoring filament-anchoring
The interface between the lower part of epidermis and the top layer of dermis
fibril complex at the dermal–epidermal junction. A continuum of adhesive proteins
consists of a complex network of interacting macromolecules that form the extends from the keratin tonofilaments within basal keratinocytes through to
cutaneous basement membrane zone (BMZ) (Figs 1.72, Fig. 1.73).1 Many of dermal collagen. This complex represents the main adhesion unit at the dermal–
these components are glycoproteins and thus the BMZ can be recognized his- epidermal junction.
tologically as staining positive with PAS staining (Fig. 1.74). Ultrastructural
examination of the BMZ by transmission electron microscopy shows two
layers with different optical densities (Fig. 1.75).2 The upper layer, the lam-
ina lucida, is a low electron density region of 30–40 nm in breadth which is
directly subjacent to the plasma membranes of basal keratinocytes. Below the
lamina lucida is the lamina densa, an electron-dense region, 30–50 nm across,
which interacts with the extracellular matrix of the upper dermis. Within
the cutaneous BMZ distinct adhesion complexes are evident. Extending from
Keratins
5 & 14
Plectin
230-kDa
BP Ag
α6β4
integrin Type XVII Fig. 1.74
collagen The basement membrane region stains strongly with periodic acid-Schiff.
Laminin-332
Type IV inside the basal keratinocytes, through the lamina lucida and lamina densa,
collagen and into the superficial dermis are ultrastructurally recognizable attachment
structures. The components of these adhesion units are the hemidesmosomes,
anchoring filaments and anchoring fibrils.3 The importance of these struc-
Type VII tural complexes in securing adhesion of the epidermis to the underlying der-
collagen mis is highlighted by both inherited and acquired subepidermal blistering skin
diseases (Figs 1.76, Fig. 1.77). The precise role of individual proteins in adhe-
sion is demonstrated by the group of inherited skin blistering diseases, epi-
dermolysis bullosa, in which components in the hemidesmosomal structures,
Fig. 1.72 anchoring filaments, or anchoring fibrils are genetically defective or absent.4
The macromolecular components of the dermal–epidermal junction centered on This leads to fragility at the dermal–epidermal junction as a result of minor
a hemidesmosome-anchoring filament-anchoring fibril complex. Protein–protein trauma.
interactions between these molecules secure adhesion between the epidermis and The hemidesmosomes extend from the intracellular compartment of the
the subjacent dermis. basal keratinocytes to the cell membrane adjacent to the lamina lucida in
Keratins
5 & 14
Bullous
pemphigoid
Bullous Plectin
pemphigoid-like 230-kDa
BP Ag Mucous
membrane
Bullous α6β4 pemphigoid
pemphigoid-like integrin Type XVII
Mucous
collagen Laminin-332 membrane
pemphigoid
Fig. 1.75
Transmission electron microscopy of the dermal–epidermal junction. Bar = 200 nm.
EB acquisita Type VII
Bullous SLE collagen
Keratins
EB simplex
5 & 14 Fig. 1.77
Recessive Acquired disorders of hemidesmosomal proteins. Autoantibodies directed against
EB simplex EB simplex components of the hemidesmosome-anchoring filament-anchoring fibril complex
EB simplex with give rise to specific subepidermal autoimmune blistering diseases.
Plectin
muscular dystrophy 230-kDa
BP Ag
EB simplex with Non-Herlitz
pyloric atresia junctional EB structure of laminins contains both globular and rodlike segments which con-
α6β4 tribute to interactions with other extracellular matrix molecules, as well as
integrin Type XVII
Herlitz & cell attachment and spreading, and cellular differentiation. The critical role
Junctional EB with collagen of laminin 332 in providing integrity to the cutaneous BMZ is evident from
Laminin-332 non-Herlitz
pyloric atresia
junctional EB findings that mutations in any of the three polypeptide subunits (the α3, β3,
or γ2 chains) can result in junctional forms of epidermolysis bullosa.
The major component of the lamina densa is type IV collagen, which in
skin is mainly composed of the α1 and α2 chains.7 Type IV collagen is assem-
bled to form a complex hexagonal arrangement which allows high flexibility
Dominant and to the BMZ and facilitates interactions with other collagenous and noncollag-
Type VII
recessive
collagen enous proteins (Fig. 1.79). Other BMZ components at the dermal–epidermal
dystrophic EB
junction include the glycoprotein nidogen (previously known as entactin)
which interacts with type IV collagen either alone or as part of a laminin-
nidogen complex. Also present are the heparan sulfate proteoglycans, which
are highly negatively charged and hydrophilic and capable of interacting with
Fig. 1.76 a number of basement membrane components and thus contribute to the
Genetic disorders of hemidesmosomal proteins. Mutations in components of the architectural organization of the BMZ.8
hemidesmosome-anchoring filament-anchoring fibril network give rise to specific
Anchoring fibrils are ultrastructurally recognizable fibrillar structures
variants of epidermolysis bullosa (EB).
which extend from the lower part of lamina densa to the upper reticular der-
mis. The main component of anchoring fibrils is type VII collagen (Fig. 1.80).9
Individual type VII collagen molecules are ≈450 nm long and by complexing
the upper portion of the dermal–epidermal basement membrane. The inner
as antiparallel dimmers and aggregating laterally, they forms loops which are
plaques of hemidesmosomes serve as attachment sites for keratin filaments
traversed by interstitial dermal collagens (types I, III and V) to adhere the
while the outer plaques associate with anchoring filaments that traverse the
BMZ to the underlying dermis.10 Type VII collagen is synthesized by both
lamina lucida. Subjacent to the hemidesmosomal outer plaques in the lamina
dermal fibroblasts and epidermal keratinocytes. Also inserting into the lam-
lucida are the sub-basal dense plates which contribute to the structural orga-
ina densa at the dermal–epidermal junction are elastic microfibrils, contain-
nization of the attachment complex. Intracellular hemidesmosomal proteins
ing proteins such as fibrillin. Fibrillin-containing microfibrils may exist as a
include the 230-kD bullous pemphigoid antigen 1 and the 500-kD plectin
fibrillar mantle surrounding an elastin core or be found independently as elas-
protein. Transmembranous hemidesmosomal proteins comprise the 180-kD
tin-free microfibrils. The latter, located beneath the lamina densa, are known
bullous pemphigoid antigen (also known as type XVII collagen), and the α6
as the dermal microfibril bundles (Fig. 1.81)
and β4 integrin molecules.5 The hemidesmosomes are associated with anchor-
ing filaments in the lamina lucida, thread-like structures 3–4 nm in diameter
that span the lamina lucida to the lamina densa. Dermal collagen
Located at the lamina lucida–lamina densa interface are the laminins.
The major laminin within the cutaneous BMZ is laminin 332, previously The major extracellular matrix component in the dermis is collagen.
known as laminin 5 (Fig. 1.78). In addition, laminin 111 (laminin 1), laminin Currently, 29 distinct collagens have been identified in vertebrate tissues
311 (laminin 6), laminin 321 (laminin 7) and laminin 511 (laminin 10) are and each is designated a Roman numeral in the chronological order of its
also integral components of the dermal–epidermal junction.6 The cruciform discovery. At least eight different collagens are found in human skin. All collagen
Dermal collagen 23
α3
β3 γ2
Fig. 1.78
Laminin-332 is a major
adhesion protein at the dermal–
epidermal junction: (A) the
protein is composed of three
polypeptide chains: α3, β3, and
γ2; (B) Laminin-322 identified by
B immunofluorescence in a sample
A
of split skin.
molecules consist of three subunit polypeptides which can either be iden-

tical in homotrimers or can consist of two or even three genetically differ-
ent polypeptides in heterotrimeric molecules. Since the different subunits
are all distinct gene products, there are well over 40 different genes in the
human genome that encode the different subunit polypeptides.1 Collagens
demonstrate considerable tissue specificity and are synthesized by a number
of different cell types, including dermal fibroblasts, keratinocytes, vascular
endothelial cells, and smooth muscle cells. A characteristic feature of col-
lagen is the presence of hydroxyproline and hydroxylysine residues, amino
acids that are post-translationally synthesized by hydroxylation of proline
and lysine residues, respectively. These hydroxylation reactions take place in
the rough endoplasmic reticulum by prolyl and lysyl hydroxylases, respec-
tively, enzymes that require ascorbic acid, molecular oxygen and ferrous iron
as cofactors. The hydroxylation of prolyl residues is necessary for stabili-
zation of the triple-helical conformation at physiologic temperatures, and
hydroxylysyl residues are required for formation of stable covalent cross-
links. In the rough endoplasmic reticulum, trimeric molecules are formed
and following the prolyl hydroxylation reactions, triple helices are generated
which are then secreted through Golgi vesicles into the extracellular space.
Here, parts of the noncollagenous peptide extensions are cleaved by specific
proteases, and the collagen molecules undergo supramolecular organization.
To acquire fibrillar strength, the fibers are then covalently linked together by
specific intra- and intermolecular cross-links. The most common forms of
cross-links in type I collagen are derived from lysine and hydroxylysine resi-
dues, and in some collagens there are also cysteine-derived disulfide bonds.
Fig. 1.80
Normal skin: the anchoring fibrils are composed predominantly of type VII collagen
as shown in this immunogold electron microscopic preparation.
On the basis of their fiber architecture in tissues, collagens can be divided

into different classes. Types I, II, III, V and IX align into large fibrils and
are designated as fibril-forming collagens. Type IV is arranged in an inter-
lacing network within the basement membranes, while type VI is a distinct
microfibril-forming collagen and type VII collagen forms anchoring fibrils.
FACIT collagens (fibril-associated collagens with interrupted triple-heli-
ces), include types IX, XII, XIV, XIX, XX, and XXI.2 Many of the FACIT
collagens associate with larger collagen fibers and act as molecular bridges
stabilizing the organization of the extracellular matrices.
Fig. 1.79 Type I collagen, the most abundant form of collagen, is the predomi-
Basement membrane: basement membrane staining with type IV collagen. nant collagen in human dermis, accounting for approximately 80% of total
Fig. 1.82
Normal skin of forearm:
Fig. 1.81 in the papillary dermis
Normal skin: this view the collagen fibers are
shows a well-formed fine and sometimes have
dermal microfibril bundle a vertical orientation.
(arrowed). Masson's trichrome.
c ollagen. Type I collagen associates with type III collagen to form broad,
extracellular fibers in the dermis. Mutations in the type I and III collagens or
in their processing enzymes can result in connective tissue abnormalities seen
in different forms of the Ehlers-Danlos syndrome, and mutations in the type
I collagen gene lead to osteogenesis imperfecta.3
Type III collagen accounts for about 10% of the total collagen in adult der-
mis, although it is the predominant dermal collagen in the fetus. It predomi-
nates in vascular connective tissues, the gastrointestinal tract, and the uterus,
and mutations in the type III collagen gene occur in the vascular type of the
Ehlers-Danlos syndrome.
Type V collagen is present in most connective tissues, including the der-
mis, where it represents less than 5% of the total collagen. Type V collagen is
located on the surface of large collagen fibers in the dermis, and its function
is to regulate their lateral growth. A lack of type V collagen leads to vari-
able collagen fiber diameters and an irregular fiber contour in cross-section.
Such fibers are seen in autosomal dominant forms of Ehlers-Danlos syndrome
associated with mutations in the type V collagen gene.
Mature collagen fibers are relatively inert and can exist in tissues under
normal physiologic conditions for long periods. However, there is some
continuous turnover of collagen that involves a number of enzymes of Fig. 1.83
the matrix metalloproteinases (MMP) family. These proteinase families Normal skin of back: broad bundles of collagen typify the reticular dermis.
include the collagenases, gelatinases, stromelysins, matrilysins, and the Masson's trichrome.
membrane-type MMPs.4 The MMPs are synthesized and secreted as inert
proenzymes which become activated proteolytically by removal of the
approximately 64 nm (Fig. 1.84). The cross-striations are seen because of
propeptide. The MMPs are zinc metalloenzymes and require calcium for
the longitudinal overlap of individual collagen molecules, which occurs dur-
their activity. The MMPs also have specific small molecular weight pep-
ing assembly of the mature fibril. Fibrous long-spacing collagen is a vari-
tide inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs).
ant with a periodicity of 90–120 nm (Fig. 1.85). It is characteristically seen
These proteins stoichiometrically complex with MMPs to prevent colla-
in peripheral nerve and central nervous system tumors. Collagen bundles
gen degradation. In normal human skin, a number of MMPs are syn-
exhibit anisotropy and are therefore birefringent when viewed with polar-
thesized and secreted by fibroblasts and keratinocytes. The expression of
ized light (Fig. 1.86).
these enzymes is enhanced in various pathologic states, including inva-
sion and metastasis of cutaneous malignancies, as well as during dermal
wound healing. Dermal elastic tissue
Within the papillary dermis, collagen fibers are fine and often verti-
cally orientated whereas reticular dermal collagen consists of broad, thick The elastic fiber network provides resilience and elasticity to the skin.1 Elastic
bundles generally arranged parallel to the surface epithelium (Figs 1.82, fibers are a relatively minor component in normal sun-protected adult skin, com-
1.83). When longitudinal sections of collagen are examined by transmis- prising less than 2–4% of the total dry weight of the dermis. The configuration
sion electron microscopy they show cross-striations with a periodicity of of elastic fibers in the reticular dermis consists of horizontally orientated fibers
Dermal elastic tissue 25
which interconnect (Fig. 1.87).2 Extending from these into the papillary dermis
is a network of vertical extensions of relatively fine fibrils which consist either
of bundles of microfibrils (oxytalan fibers) or of small amounts of cross-linked
elastin (elaunin fibers) (Fig. 1.88).3 Elastic fibers have two principal compo-
nents: elastin, which is a connective tissue protein that forms the core of the
mature fibers, and the elastin-associated microfibrils which consist of a family
of proteins. Examination by transmission electron microscopy reveals an elas-
tin core that makes up over 90% of the elastic fiber and which is surrounded
by more electron-dense microfibrillar structures (Fig. 1.89).
Elastin is initially synthesized as a precursor polypeptide, tropoelastin,
which consists of approximately 700 amino acids with a molecular mass of
≈70 kD.4 The amino acid composition of tropoelastin is similar to collagen in
that about one-third of the total amino residues consist of glycine but the pri-
mary sequence is different, with domains rich in glycine, valine, and proline,
alternating with lysine- and alanine-rich sequences: a characteristic sequence
motif is the presence of two lysine residues separated by two or three alanine
residues. The lysine residues in tropoelastin are critical for the formation of
covalent cross-links between desmosine and its isomer, isodesmosine, which
appear to be unique to elastin. The first step in formation of these elastin-
Fig. 1.84 specific cross-links is oxidative deamination of three lysine residues to form
Collagen: it is characterized by cross-striations with a periodicity of 64 nm.
Fig. 1.85 Fig. 1.87

Fibrous long-spacing collagen: compare with the adjacent conventional collagen Reticular dermis: the elastic fibers are long and fairly thick and tend to run parallel to
fibers. There is a very different periodicity. the surface epithelium.
Fig. 1.86 Fig. 1.88

Collagen of the reticular dermis: note the birefringence when viewed with polarized Papillary dermis: the elastic fibers are delicate and orientated perpendicular to the
light. Masson's trichrome. epithelial surface. Weigert–van Gieson stain.
Fig. 1.90
Fig. 1.89 Ground substance: an eccrine gland from the sole of the foot shows an abundance
Elastic fiber: this consists of microfibrils embedded in an electron-dense matrix of glycosaminoglycans.
called elastin.
aldehydes, known as allysines. These aldehydes, with additional lysine, fuse enriched in dermal fibroblasts, facilitates the adherence of cells in conjunc-
to form a stable desmosine compound which covalently links two of the tro- tion with other extracellular matrix binding molecules, such as the integrins.3
poelastin polypeptides. Addition of desmosines to other parts of the molecule Proteoglycans also interact with other extracellular matrix molecules besides
progressively converts tropoelastin molecules into an insoluble fiber struc- collagen; notably, chondroitin sulfate and dermatan sulfate bind fibronectin
ture. The oxidative deamination of lysyl residues to corresponding aldehydes and laminin. The largest extracellular GAG, hyaluronic acid, plays an impor-
is catalyzed by a group of enzymes, lysyl oxidases, which require copper for tant role in providing physical and chemical properties to the skin, mediated
their activity. Thus, copper deficiency can lead to reduced lysyl oxydase activin part by its hydrophilicity and viscosity in dilute solutions. Of particular
ity and synthesis of elastic fibers that are not stabilized by sufficient amounts note, hyaluronic acid has an expansive water-binding capacity, providing
of desmosines. In such a situation, the individual tropoelastin polypeptides hydration to normal skin. Indeed, water makes up ≈60% of the weight of
remain soluble and susceptible to non-specific proteolysis, and the elastin-rich normal human skin in vivo. Other properties attributed to large proteogly-
tissues are fragile. The metabolic turnover of elastin is slow, but is increased cans complexes, such as those formed with the versican or basement mem-
in some forms of cutis laxa and cutaneous aging. Elastic fibers are degraded brane proteoglycans, include their ability to serve as ionic filters, regulate salt
by elastases and metalloelastases. and water balance, and provide an elastic cushion.1
The elastin-associated microfibrils consist of tubular structures of ≈10– Except when present in very large amounts, ground substance cannot be
12 nm in diameter. These proteins include fibrillin, the latent transforming easily detected by routine hematoxylin and eosin staining (Fig. 1.90). Cationic
growth factor-β binding family of proteins, and the fibulins. Other compo- dyes, such as Alcian blue at appropriate pH and electrolyte concentration, are
nents comprise the families of microfibril-associated glycoproteins and micro- usually necessary for its demonstration.
fibril-associated proteins (MFAP), the emilins and certain lysyl oxidases. The
importance of the fibrillin is illustrated by mutations resulting in Marfan
syndrome with skeletal abnormalities, aortic dilatation, subluxation of the Fibroblast biology
ocular lens, and cutaneous hyperextensibility.5 Likewise, the significance of
The main cell responsible for the synthesis of collagens, elastic tissue and
certain fibulins is evident from mutations resulting in cutis laxa, manifesting
proteoglycan/glycosaminoglycan macromolecules in the dermis is the fibro-
with loose and sagging skin and loss of elastic recoil.
blast.1 In the mid-dermis of postnatal skin, the number of fibroblasts ranges
from 2100 to 4100 per mm3, and the cells have a limited replicative capacity
Ground substance ranging from 50–100 cell divisions. Fibroblasts also play a significant role
in epithelial–mesenchymal interactions, secreting various growth factors and
Proteoglycans form a number of subfamilies defined by a core protein to which cytokines that have a direct effect on epidermal proliferation, differentiation
polymers of unbranched disaccharide units, glycosaminoglycans (GAGs), are and formation of extracellular matrix. The term fibroblast refers to a fully
linked.1 The core proteins can be intracellular, reside on the cell surface, or differentiated, biosynthetically active cell, while the term fibrocyte refers to
be part of the extracellular matrix and the GAGs are highly charged polyan- an inactive cell.
ionic molecules that vary greatly in size. For example, dermal fibroblasts can Myofibroblasts are a specialized form of fibroblast found in granulation
synthesize versican which consists of a core protein with attachment sites for tissue and are involved in wound contraction. They are functionally distinct
12 to 15 GAG side chains. The GAGs in versican are primarily chondroitin from other fibroblasts with ultrastructural, biochemical and physical fea-
sulfate or dermatan sulfate, but versican can also bind hyaluronic acid, result- tures of smooth muscle cells. Moreover, myofibroblasts are characterized
ing in formation of large aggregates. Proteoglycan/GAG complexes have mul- by the presence of intracellular bundles of α smooth muscle actin, which is
tiple functions. For example, the proteoglycans containing heparan sulfate the actin isoform expressed by smooth muscle cells. Currently it is thought
and dermatan sulfate have the ability to bind extracellular matrix compo- that the evolution of myofibroblasts involves a preceding form known as
nents, including various collagens.2 In addition, these proteoglycans bind the protomyofibroblast, although the latter do not always become the fully
several growth factors, cytokines, cell adhesion molecules, and growth fac- differentiated myofibroblast. In contrast to myofibroblasts, protomyofibro-
tor binding proteins, thereby influencing the bioactivity of these molecules. blasts have stress fibers but no α smooth muscle actin filaments. A bio-
They can also serve as antiproteases. In addition to binding to a number synthetically active fibroblast has an abundant cytoplasm, well-developed
of extracellular molecules, proteoglycans also play a role in the adhesion of rough endoplasmic reticulum, and prominent ribosomes attached to the
cells to the extracellular matrix. For example, syndecan-4, which is selectively membrane surfaces.
Cutaneous blood vessels and lymphatics 27
Fibroblasts from different anatomical sites all have similar morphology

but fibroblasts in different sites have their own gene-expression profiles and
Epidermis
characteristic phenotypes, synthesizing extracellular matrix proteins and
cytokines in a site-specific manner.2 Papillary dermis
Dermal fibroblasts have numerous functions, not only in synthesizing and Superficial
depositing extracellular matrix components, but also in proliferation and migra- vascular plexus
tion in response to chemotactic, mitogenic and modulatory cytokines, and also
autocrine and paracrine interactions. Autocrine activity includes the trans-
forming growth factor (TGF)-β-induced synthesis and secretion of connective
tissue growth factor which promotes collagen synthesis as well as fibroblast Reticular dermis
proliferation. Paracrine activity affects keratinocyte growth and differentiation,
specifically through fibroblast secretion of keratinocyte growth factor (KGF),
granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6 and fibro-
Deep
blast growth factor (FGF)-10. Fibroblasts also contribute to basement membrane vascular plexus
formation partly by producing type IV collagen, type VII collagen, laminins and
nidogen, but also through the secretion of cytokines, such as TGF-β, that stimu-
late keratinocytes to produce basement membrane components.
Neovascularization and lymphangiogenesis are also important processes for Subcutaneous fat Fig. 1.91
the maintenance of normal skin homeostasis and wound healing, for which Relationship of the
superficial and deep
fibroblasts have an important paracrine role. Members of the vascular endothe-
vascular plexuses.
lial growth factor (VEGF) family include VEGF-A, -B, -C, and -D, which are
produced by normal human fibroblasts and are important in regulating vascu-
lar and lymphatic endothelial cell proliferation through specific receptors. constituting the external elastic lamina. Small arterioles have an endothelium
There is, however, considerable heterogeneity within fibroblast popula- surrounded by a single layer of smooth muscle. Capillaries consist of a single
tions. For example, fibroblasts isolated from the papillary dermis compared layer of endothelial cells, but may have adjacent pericytes, which have less
to the reticular dermis have higher rate of synthesis of type III collagen and well-developed dense bodies and fewer filaments than smooth muscle cells.
there can be as much as 30-fold differences in the level of fibronectin expres- Endothelial cells and pericytes form tight junctions. Venous capillaries have
sion within individual cells. Fibroblasts from the papillary dermis appear numerous pericytes and a multilayered basement membrane in contrast to
smaller, grow faster and have a longer replicative lifespan.3 When co-cultured arterial vessels where the basement membrane is solitary and homogeneous.
with keratinocytes, papillary dermal fibroblasts produce a more differentiated Each dermal papilla is supplied by a single capillary loop. Endothelial cells
and organized epidermis with complete formation of the dermal–epidermal contain vimentin filaments, Weibel-Palade bodies measuring approximately
junction. Papillary dermal fibroblasts also produce more granulocyte–mac- 0.1 × 3.0 μm (containing factor VIII) and numerous pinocytotic vesicles (Figs
rophage colony-stimulating factor (GM-CSF) and relatively less keratinocyte 1.93, 1.94). Postcapillary venules are larger, but have the same basic struc-
growth factor (KGF) than reticular dermal fibroblasts. In addition, there are ture as capillaries. Their wall is devoid of smooth muscle. The small muscu-
differences in the synthesis of some extracellular matrix components, such lar venules into which the postcapillary venules drain have an intima made
as decorin. While fibroblasts demonstrate certain variability in their gene up of flattened endothelial cells surrounded by a smooth muscle layer one or
expression profiles they are considered fully differentiated cells with relatively two cells thick. They are therefore similar to small arterioles, but with much
little plasticity. Recent observations, however, suggest that fibroblasts can be wider lumina. Veins are composed of an endothelium surrounded by a muscle
induced to become pluripotent stem cells (iPS), essentially indistinguishable coat several layers thick. Typically, an internal elastic lamina is poorly repre-
from the embryonic stem cells, by transduction of cultured fibroblasts with sented. There is usually a thick connective tissue adventitia, but elastic fibers
four transcription factors, Oct4, Sox2, Klf4, and c-myc.4 are absent; only very large muscular veins have elastic tissue (Fig. 1.95).
Also present in the dermis are veil cells, which surround all the microves-
sels and separate them from the adjacent connective tissue. Veil cells are long,
Cutaneous blood vessels and lymphatics thin cells with an attenuated cytoplasm, and they more closely resemble fibro-
blasts than pericytes. They do not have a basement membrane investment and
The skin receives a rich blood supply from perforating vessels within the skele- are located outside the vessel wall.
tal muscle and subcutaneous fat.1 Most of the blood flow is directed toward the The capillary loop in the dermal papilla has an ascending arterial compo-
more metabolically active constituents of the skin, namely the epidermis, hair nent and an intrapapillary segment, which is characterized by a hairpin turn
papillae and the adnexal structures. While the dermal papillae are richly vascu- and a descending venous capillary segment. Capillary loops run perpendicular
larized, no capillaries actually enter the epidermis, which receives its nutrition to the skin surface, except in the nail where they have a parallel orientation.
by diffusion. The subcutaneous vessels give rise to two vascular plexuses linked The dermis is richly supplied with arteriovenous anastomoses. Specialized
by intercommunicating vessels: the deep vascular plexus lies in the region of the shunts (glomus bodies), found primarily in the dermis of the fingertips, con-
interface between the dermis and subcutaneous fat, and the superficial vascu- sist of an arterial segment (Sucquet-Hoyer canal), which connects directly
lar plexus lies in the superficial aspects of the reticular dermis and supplies the to the venous limb (Fig. 1.96). The canal is surrounded by several layers of
papillary dermis with a candelabra-like capillary loop system (Fig. 1.91). Each modified smooth muscle cells (glomus cells) with a particularly rich nerve
loop consists of an ascending arterial limb and a descending venous limb. The supply. Glomus bodies function as sphincters, allowing the capillaries of the
vessels of the dermal papillae comprise terminal arterioles, arterial and venous superficial dermis to be bypassed, therefore increasing the venous return from
capillaries, and postcapillary venules, with the last predominating. Within the the extremities.
deep vascular plexus are small muscular arteries, which give rise to the arteri- Cutaneous blood flow (under hypothalamic control) is of extreme impor-
oles that supply the superficial vascular plexus (Fig. 1.92). tance in thermoregulation. Mediated by the autonomic nervous system, heat
The histology of these plexuses is similar, the difference being one of size loss can be increased or decreased by varying the blood flow to the superficial
rather than structure (arterioles have a diameter of less than 0.3 mm).2 From vascular plexuses. If the environmental temperature exceeds that of the body,
the lumen outwards the arteriole consists of a very thin intima resting against a then the blood flow to the papillary dermis increases. A concomitant increase
conspicuous internal elastic lamina. Next to this is the media, consisting of two in eccrine sweat gland secretion, evaporation of which cools the outer parts
layers of smooth muscle, which constitutes the bulk of the vessel. The adven- of the body, lowers the temperature of the circulating blood and maintains a
titia surrounding the media is composed of loose connective tissue. In small stable core temperature. Temperature control therefore depends on a delicate
muscular arteries (but not arterioles), the adventitia often contains elastic fibers interplay between both vascular and sweat gland functions.
Fig. 1.92
Small muscular artery from the deep vascular plexus from
the lower leg of an elderly man with endarteritis (intimal
thickening): note the thick muscle coat and conspicuous
internal elastic lamina, the latter accentuated by the
Weigert–van Gieson reaction. (A) Hematoxylin and eosin;
A B (B) Weigert–van Gieson.
trunks are very thick and muscular and can be confused with an artery
(Fig. 1.98). The absence of an internal elastic lamina readily allows their
distinction. Vascular endothelial cells may be identified by the monoclo-
nal antibody CD31 or by an anti-von Willebrand factor antibody. Vascular
endothelial growth factor receptor 3 (VEGFR-3) has not lived up to its
promise to be a useful lymphatic endothelial cell marker.5,6 Lymphatic vessel
endothelial hyaluronan receptor 1 (LYVE-1), Prox-1 and podoplanin may
be more useful.7
Nervous system of the skin

The skin may be innervated with around one million afferent nerve fibers.
Most terminate in the face and extremities; relatively few supply the back.
The cutaneous nerves contain axons with cell bodies in the dorsal root gan-
glia. Their diameters range from 0.2 to 20.0 μm. The main nerve trunks enter-
ing the subdermal fatty tissue each divide into smaller bundles. Groups of
myelinated fibers fan out in a horizontal plane to form a branching network
from which fibers ascend, usually accompanying blood vessels, to form a
Fig. 1.93 web of interlacing nerves in the superficial dermis. The cutaneous nerves sup-
Normal dermal capillary: note the lining of endothelial cells surrounded by a pericyte ply the skin appendages and form prominent plexuses around the hair bulbs
cell process and adjacent basal lamina. The lumen contains erythrocytes (E). and the papillary dermis. The afferent receptors consist of free nerve endings,
nerve endings in relation to hair, and encapsulated nerve endings. Free nerve
endings, of both myelinated and nonmyelinated types and with a low conduc-
The dermis also contains an extensive lymphatic system, which is closely tion speed, are mainly responsible for the appreciation of temperature, itch
associated with the vascular plexuses.3 Although largely disregarded except and pain. Hair follicles are supplied by an intricate network of myelinated
for their role in tumor spread, lymphatics are of major importance in fibers, some of which ramify as free nerve endings in the periadnexal fibrous
removing the debris of daily wear and tear including fluid, cells and macro- tissue sheath, while others enter the epidermis to terminate as expansions
molecules (Fig. 1.97). They also represent the primary disposal mechanism in intimate association with Merkel cells in the external root sheath. The
for contaminating microorganisms. Lymphatics have been shown to supply hair disc is a complex structure consisting of basally situated Merkel cells
the major route for epidermal Langerhans cells to reach the regional lymph and an associated myelinated peripheral nerve fiber. Despite the name, it has
node following antigen stimulation. Under normal circumstances these deli- an inconstant association with hair follicles. Hair discs are slowly adapting
cate vessels are collapsed and are difficult to detect. They are supported by mechanoreceptors. Throughout their course the axons of cutaneous nerves
delicate elastic tissue scaffolding and consist of a large thin-walled collapsed are enveloped in Schwann cells but, as they track peripherally, an increas-
vessel lined by attenuated endothelium and characterized by the presence of ing number lack myelin sheaths. Most end in the dermis; some penetrate the
multiple valves. Their presence is much more obvious in obstructive situ- basement membrane, but do not travel far into the epidermis.
ations (e.g., lymphedema or due to the presence of metastases). Dermal Sensory endings are of two main kinds: corpuscular, which embrace non-
lymphatics are loosely aggregated into a superficial and deep plexus, which nervous elements; and ‘free’, which do not. Corpuscular endings can, in turn,
drain into muscularized lymphatic trunks.4 In the lower limbs the lymphatic be subdivided into encapsulated receptors, of which a range occurs in the
Nervous system of the skin 29
A B
Fig. 1.94
(A) Small dermal arteriole: the lumen is compressed to a narrow slitlike space; (B) high-power view of typical Weibel–Palade bodies. These are characteristic of blood vessel
endothelium.
A B
Fig. 1.95
Companion vein to Figure 1.92: note the wide diameter of the lumen in comparison to the relatively thin muscle coat. There is a little elastic tissue but no discernible internal
elastic lamina. (A) Hematoxylin and eosin; (B) Weigert–van Gieson.
dermis, and nonencapsulated, exemplified by Merkel's ‘touch spot’, which Meissner's corpuscles are characteristic of the papillary ridges of glabrous
is epidermal. skin in primates. They have a thick, lamellated capsule, 20–40 μm in diameter
The most striking of the encapsulated receptors is the Pacinian corpuscle. and up to 150 μm long (Fig. 1.100).1 Meissner's corpuscles are involved in the
It is an ovoid structure about 1 mm in length, which is lamellated in cross- appreciation of touch sensation (rapidly adapting mechanoreceptors) and are
section like an onion, and is innervated by a myelinated sensory axon, which found predominantly in the dermal papillae of the hands and feet, the lips,
loses its sheath as it traverses the core (Fig. 1.99). Pacinian corpuscles are and on the front of the forearm. They comprise a perineural-derived lamel-
responsible for the appreciation of deep pressure and vibration and are found lated capsule surrounding a core of cells and nerve fibers, and are supplied by
predominantly in the subcutaneous fat of the palms and soles, dorsal surfaces myelinated and nonmyelinated nerve fibers. They make intimate contact with
of the digits, around the genitalia, and in ligaments and joint capsules. the basal keratinocytes. Meissner's corpuscles have a multiple nerve supply
The Golgi-Mazzoni corpuscle found in the subcutaneous tissue of the and each nerve may also supply multiple corpuscles. Of somewhat different
human finger is similarly laminate but of much simpler organization. Another structure are the terminals first described by Ruffini in human digits, in which
classical receptor is the Krause end bulb, an encapsulated swelling on myeli- several expanded endings branch from a single, myelinated afferent fiber. The
nated fibers situated in the superficial layers of the dermis. endings are directly related to collagen fibrils. ‘Free nerve-endings’, which
Fig. 1.96 Fig. 1.99

Glomus body: note the arterial and venous limbs connected by a vascular channel Pacinian corpuscle: note the characteristic lamellar internal structure.
rich in glomus cells.
Fig. 1.97
Lymphatics: these exceedingly thin-walled channels are normally not visible in the
dermis. They become readily apparent, however, when obstructed, as in this patient
with lymphedema.
Fig. 1.100
Meissner's corpuscle within a dermal papilla: with hematoxylin and eosin staining it
appears as perpendicularly orientated lamellae of Schwann cells.
appear to be derived from nonmyelinated fibers, occur in the superficial der-

mis and in the overlying epidermis.2 Those in the dermis are arranged in a
tuftlike manner and have thus been designated penicillate nerve endings.
Subcutaneous fat
Fat is a major component of the human body. In nonobese males, 10–12% of
body weight is fat, while in females the figure is 15–20%. Eighty per cent of fat
is under the skin; the rest surrounds internal organs. Fat comprises white and
brown adipose tissue, the latter being more common in infants and children
Fig. 1.98 and is characterized by different mitochondrial properties and increased heat
Skin of lower leg: muscular lymphatic trunks can be readily mistaken for arteries. production.1 Historically, fat has been thought to provide insulation, mechani-
An internal elastic lamina is characteristically absent. cal cushioning and an energy store but recent data suggest that it also has an
Subcutaneous fat 31
endocrine function, communicating with the brain via secreted molecules such ediastinum. The brown coloration is due to the high cytochrome con-
m
as leptin to alter energy turnover in the body.2 Adipocytes also have important tent. The brown fat cytoplasm contains numerous, somewhat pleomorphic,
signaling roles in osteogenesis and angiogenesis. Indeed, multipotent stem cells mitochondria. Endoplasmic reticulum and a Golgi apparatus are not usually
have been identified in human fat which are capable of developing into adi- visible. The adipocytes have a bubbly appearance with the nucleus located
pocytes, osteoblasts, myoblasts and chondroblasts. Biological clues to genes, towards the center of the cell (Fig. 1.103).
proteins, hormones and other molecules that influence fat deposition and
distribution are gradually being realized, from both research on rare inher-
ited disorders (such as the lipodystrophies or obesity syndromes) as well as
population studies on more common forms of obesity.3
The subcutaneous fat is divided into lobules by vascular fibrous septa, and
its cells are characterized by the presence of a large single globule of lipid,
which compresses the cytoplasm and nucleus against the plasma membrane
(Fig. 1.101). The adipocyte is large, measuring up to 100 μm in diameter. The
cytoplasm contains numerous mitochondria. Smooth endoplasmic reticulum
is prominent and a Golgi is often conspicuous. Processing for routine histo-
logical preparation dissolves the lipid, but the use of special stains on fro-
zen sections will reveal its presence (Fig. 1.102). The subcutaneous fat may
contain large numbers of mast cells.
Deposits of brown fat may be seen in the newborn and occasionally
in adults, particularly in the interscapular region, the back, thorax and
Fig. 1.102
Adult fat in frozen section stained by the Sudan IV technique.
Fig. 1.101
The lipid contents of fat cells are dissolved during processing using conventional
(paraffin-embedding) techniques. The cells therefore appear empty and have Fig. 1.103
peripheral compressed nuclei. Typical brown fat showing pink granular cytoplasm.
Chapter
Specialized techniques in
2 dermatopathology
Pratistadevi K. Ramdial, Boris C. Bastian, John Goodlad, John A. McGrath and
Alexander Lazar
See
for references and
additional material
Specimen fixation, grossing/put-through, Immunofluorescence 35 Polymerase chain reaction (PCR) 43

processing, embedding and
Electron microscopy 37 Diagnosis of lymphomas 43
sectioning 32
PCR analysis of cutaneous lymphoid infiltrates 44
Diagnosis of inherited skin diseases 37
Routine and ‘special’ stains 33 TCR gene rearrangement in cutaneous
Molecular techniques 39 lymphoproliferations 44
Immunohistochemical techniques 34 IG gene rearrangement in cutaneous
Chromosomal karyotyping 39
Immunohistochemical techniques and Allelic imbalance 39 lymphoproliferations 45
trouble shooting 34 Fluorescence in situ hybridization (FISH) 39
Comparative genomic hybridization (CGH) 42
specimens embedded with the cut surfaces down. The eccentric sectioning
Specimen fixation, grossing/ put-through, ensures that the lesion is not missed. Biopsies less than 4 mm are put through
processing, embedding and sectioning in toto.9,10
Tissue processing refers to a series of steps that effect the removal of
The aim of fixation in dermatopathology is to maintain clear and consistent extractable water from biopsies to ensure sections of optimal diagnostic qual-
morphological features and to preserve tissue in an optimal state suitable for ity.9 These include fixation, dehydration, clearing, infiltration and embedding
a range of staining and ancillary histopathological techniques.1,2 Most fixa- in a support matrix. Use of manual and automated tissue processing achieves
tion methods employed during tissue processing depend on chemical fixa- this goal, including:
tion of tissue in liquid fixatives.3 Tissue fixation may also be accomplished • carousel-type processors,
by physical (heat, microwave, freeze-drying and freeze substitution) and/or • self-contained vacuum tissue processors,
chemical (coagulant and cross-linking) methods.4 The most commonly used • microwave tissue processing.
fixative is 10% neutral-buffered formalin solution. The quality of fixation is In most laboratories, overnight processing runs are the norm. 9
affected by: However, microwave-assisted tissue processing facilitates shorter pro-
• the size of the specimen, cessing times of one to two hours. Dehydrating reagents promote the
• duration and temperature of fixation, removal of unbound water and aqueous fixatives from the tissue.
• pH, Clearing reagents serve as an intermediary between the dehydrating and
• concentration, infiltrating solutions, being miscible with both. Paraffin is the most pop-
• osmolality, ular infiltration and embedding medium, being suitable for the major-
• ionic composition of fixatives and additives contained in the fixative.5 ity of routine and special stains. The important principle to be adhered
Formalin fixation occurs at an approximate rate of 1 mm per hour.4,6,7 to during embedding of skin biopsies is that the orientation of the skin
The volume of the fixative should be at least 10 times the volume of the sample should offer the least resistance to the blade during microtomy.
specimen.7 Large specimens, such as tumors, may require sectioning into Skin biopsies are usually cut in a plane at right angles to the epidermis
5-mm thick slices, covering with fixative soaked gauze or cloth and fixation so that the epidermal surface is sectioned last, minimizing its compres-
overnight.5,7 sion and distortion.
Diagnostic dermatological biopsies may be: Suboptimally processed tissue may result in incomplete tissue sections and
• small incisional (shave, core, punch), expansion or disintegration of sections in the water bath. Incorrectly embed-
• excisional specimens.8 ded tissue may result in poorly orientated incomplete sections. Faulty micro-
Prior to put-through, excisional specimens that require an appraisal of tome mechanisms, loose, dull or damaged blades and inaccurate clearance
margins should be inked. If localization sutures have been inserted by sur- angles may be the causes for:
geons then four-quadrant, four-color painting or two-color painted halves • thick and thin sections,
(Fig. 2.1) may be appropriate. Shave biopsies are used to sample or remove • folds (Fig. 2.2),
lesions, and if of appropriate size, may be divided into sections, bisected or • holes (Fig. 2.3),
trisected and embedded on edge. Edge embedding is critical in a shave exci- • scores (Fig. 2.4),
sion of a lesion such as a small melanoma so that the width and depth of • chatter.10
invasion can then be quantified.8,9 The main purpose of core or punch biop- The presence of calcified areas and suture in skin tissue and nicks in the
sies, which generally measure 2–8 mm in diameter, is to sample large lesions. blade may result in chatter or splitting of sections at right angles to the knife
Biopsies larger than 4 mm in size should be bisected eccentrically and the edge.
Routine and ‘special’ stains 33
A B C D
Fig. 2.1
Gross representation of basal cell carcinoma: (A) with two-color painting of the
inferior surface (B). A 2-mm thick gross sections demonstrating the black and
blue painting at put through (C) and in paraffin blocks (D). By courtesy of Dr. J.
Deonarain, Department of Anatomical Pathology, National Health Laboratory
Service, Durban, South Africa.
Fig. 2.3
Technical artifact: holes in
tissue sections because
tissue sections were cut
too thin.
Fig. 2.2
Technical artifact: folds in tissue sections because of poor water bath floating
technique.
Routine and ‘special’ stains

With the advent of immunohistochemistry, special stains are less commonly
employed, but can still play an important role in highlighting certain tissue
characteristics or for detection of infectious organisms.
Diagnostic sections are usually stained with hematoxylin and eosin (H&E),
the most widely used routine stain.1 The hematoxylin component stains the
nuclei blue-black and the eosin stains the cytoplasmic compartment and con-
nective tissue in variable shades and intensity of pink, orange and red. The
periodic acid-Schiff (PAS) technique is used widely to demonstrate: Fig. 2.4
Technical artifact: score
• glycogen, in tissue section because
• starch, of a damaged microtome
• sialomucin, blade.
• neutral mucin,
• basement membranes,
• α1-antitrypsin, charides are not. Mucicarmine demonstrates acidic epithelial mucins.2 It is
• reticulin, useful for the diagnosis of adenocarcinomas and the mucoid C. neoformans
• Russell bodies of plasma cells, capsule. Alcian blue highlights acidic mucopolysaccharides, staining the muci-
• fungi.2 nous components of dermal mucinoses, granuloma annulare, scleredema of
The PAS technique is therefore employed to demonstrate basement mem- Bushke, lupus erythematosus and metastatic adenocarcinomas. Alcian blue
brane thickening in lupus erythematosus, porphyria cutanea tarda and in demonstrates heterogeneity of staining that is pH based: sialomucins are
some tumors. Glycogen is digested by diastase, while neutral mucopolysac- demonstrated at pH 2.5 and sulfamucins at pH 1.0.3
34 Specialized techniques in dermatopathology
Table 2.1
The more commonly used histochemical stains
Stain Component Outcome
A. Routine
Hematoxylin- Cells, connective Nuclei: blue
eosin tissue Cytoplasm: pink/red
Extracellular matrix:
red/pink
B. Carbohydrates &
glycoconjugates
Periodic acid-Schiff Neutral mucins, glycogen Magenta
PAS-diastase Glycogen, Resistant to
proteoglycans, HA diastase
resistant sialomucin digestion
Alcian blue, pH 2.5 Labile sialomucin Blue
Alcian blue, pH 1.0 Sulfomucin, resistant Blue
sialomucin
Mucicarmine Sialomucin, sulfomucin Pink
Colloidal iron Sialomucin, sulfomucin Blue
Fig. 2.5 HA, proteoglycans
Special stains: Warthin-Starry silver stain demonstrating Donovan bodies. High iron diamine Proteoglycans, Blue
sulfomucin
Toluidine blue Sulfomucin Blue
Hyaluronidase HA Sensitive to HA
While colloidal iron, initially described by Hale for the identification of
acid mucopolysaccharides, is as sensitive as Alcian blue for this purpose, C. Connective tissue
its specificity and selectivity are debatable and background staining may be fibers
problematic.4 However, reduction of pH of the colloidal iron solution and Masson trichrome Collagen Blue or green
Muscle, nerve Red
inclusion of acetic acid washes may reduce this artifact.3–5 The high iron
Verhöeff-van Gieson Elastic fibers Black
diamine stain, in contrast to colloidal iron, stains highly acidic sulfamu- Pinkus acid orcein Elastic Dark brown
cins but does not stain sialomucins or hyaluronic acid.5–7 Connective tissue Silver nitrate Reticulum fibers Black
stains highlight collagen, elastic and reticulin fibers. The trichrome stain, a
D. Infective stains
combination of three dyes, is employed for the differential demonstration
Ziehl Neelsen Acid fast bacilli Red
of muscle, collagen fibers, fibrin and erythrocytes.8 Elastic fibers may stain
Fite-Faraco (weakly) acid fast bacilli Red
with eosin, phloxine, Congo red and PAS stains but are demonstrated well Periodic acid-Schiff Fungi, parasites Magenta
with the Verhöeff method in the diagnosis of scleroderma, anetoderma and Mucicarmine Cryptococcus sp Red
pseudoxanthoma elasticum. Silver stains are useful to demonstrate reticulin Giemsa Leishmania sp, Red
fibers, melanin and the identification of infective agents. While methenamine Donovan bodies Metachromatically
silver and Gomori Grocott methenamine silver stains highlight fungi and purple
bacteria, Warthin-Starry, Dieterle and Steiner silver stains are particularly Methenamine silver Fungi, bacteria Black
useful in the demonstration of spirochetes, B. henselae and Donovan bodies Grocott Fungi Black
(Fig. 2.5). Masson-Fontana silver staining is pivotal to the staining of the methenamine
silver
cell wall of C. neoformans, especially in the identification of capsule-deficient
Warthin Starry silver Spirochetes, bacteria Black
C. neoformans. The role of the more commonly used special stains is sum-
Dieterle and Spirochetes, bacteria Black
marized in Table 2.1. Steiner silver
E. Other
Immunohistochemical techniques Perl's potassium Hemosiderin Blue
ferrocyanide
Since the first practical application of antibodies using the peroxidase labeled Oil red O Lipids Red
antibody method on paraffin-embedded tissues in 1968, immunohistochemis- Scarlet Red Lipids Red
Von Kossa Phosphate (often as Black
try (IHC) has emerged as a powerful supplementary investigation to histomor-
calcium phosphate) Black
phologic assessment.1–3 IHC has widespread dermatopathologic diagnostic,
Alizarin red S Calcium Orange-Red
prognostic, therapeutic and pathogenetic applications, not only in a range of Alkaline Congo Red Amyloid Apple green
neoplastic (Table 2.2), immunobullous and infective disease, but also in the birefringence
distinction between reactive and neoplastic disorders.4–14 Immunohistologic Chloro-acetate Myeloid series Red granules
techniques can be performed manually or in automated platforms. While esterase
automation allows enhanced quality and reproducibility of staining, detailed,
exact IHC protocols are critical in the many laboratories that still perform Key: HA, hyaluronic acid
manual IHC, to achieve optimal, reproducible results.

assess histomorphology with the latter.1 The peroxidase-antiperoxidase
(PAP) technique, was replaced by alkaline phosphatase-antialkaline phos-
Immunohistochemical techniques and phatase (APAAP) techniques and avidin-biotin labeling.1,2 Although the
trouble shooting streptavidin-biotin labeling system gained popularity, the endogenous biotin-
associated background staining under certain circumstances has resulted in
In many centers, IHC is now the most commonly utilized ancillary test for increasing use of labeled polymer-based detection systems, suitable for man-
clinical tissue samples. ual and automated IHC platforms (Fig. 2.6).3
Historically, the introduction of enzymes as labels in IHC overcame dif- The direct conjugation of the primary antibody to the label formed the
ficulties associated with immunofluorescence, including the inability to principle of the initial, traditional direct technique, in which the labeled
Immunofluorescence 35
Table 2.2 animal.1 The secondary antibody binds to the primary antibody with the
Some diagnostic immunohistochemical applications for cutaneous tumors4–13 biotinylated end being available for binding to a third layer. This layer may
Stain Application bind either to enzyme-labeled streptavidin or to a complex of enzyme-labeled
biotin and streptavidin. The enzyme may be horseradish peroxidase or alka-
Epidermal and appendageal neoplasms
line phosphatase. An appropriate chromogen is used for detection. In the per-
AE1/AE3 Pan-keratin. Confirms epithelial lineage oxidase method, peroxidase-oriented chromogens such as diaminobenzidine
CAM 5.2 CKs 8,18. Confirm epithelial lineage. Useful to confirm or 3-amino-9 ethylcarbazole are appropriate. Indole reagents (red), naphthol
glandular neoplasms
fast red (red) or NBT / BCIP (blue) are the chromogens used in the alkaline
MNF 116 CKs 5, 6, 8, 17, 19. Useful in diagnosis of SCC with
single cell infiltration
phosphatase-streptavidin method.1,4
BerEP4 Positive in BCC. Negative in SCC. The presence of endogenous biotin and resultant background staining led
CK 7 Confirmation of mammary and extra-mammary Paget's to the introduction of the increasingly popular polymer-based immunohis-
disease tochemical methods. In the new direct Enhanced Polymer One Step (EPOS)
p63 Distinguish primary cutaneous spindle SCC from technique, approximately 70 enzyme molecules and 10 primary antibodies
mesenchymal spindle cell tumors & primary are conjugated to a dextran ‘backbone’. While the entire IHC procedure is
cutaneous adnexal from metastatic adenocarcinomas completed in one step, the method is limited to highly select manufacturer-
CD10 Trichoepithelioma: positive in stroma and papillae, specific primary antibodies. Other newer polymer detection systems with a
negative in epithelium. BCC: positive in epithelium, dextran backbone to which multiple enzyme molecules may attach are avail-
negative in stroma.
able for manual and automated IHC. These quick, reliable and reproducible
bcl2 Positive in BCC, negative in SCC.
techniques are also characterized by greater sensitivity. Single-, dual-, and
Vascular proliferations triple-color staining with different chromogens is possible.1,2,4,5
CD31 High specificity and good sensitivity for endothelial tumors Background staining is a common difficulty that has multiple predispos-
CD34 High sensitivity but low specificity for endothelial tumors ing causes.6 While monoclonal antibodies reduce non-specific background
Fli-1 Nuclear staining of endothelial tumors staining, not only must antibody concentrates and prediluted preparations be
GLUT 1 Positive in endothelial cells of all juvenile hemangiomas. optimized for usage at the correct dilution in different laboratories (Figs
Usually negative in congenital hemangiomas 2.7 and 2.8), diluent pH is also critical in ensuring the absence of antibody
(rapidly involuting congenital hemangioma and non-
degeneration and resultant background staining. Avidin-biotin detection sys-
involuting congenital hemangioma)
tems and horseradish peroxidase systems may require biotin blocking and
Melanocytic tumors endogenous peroxidase quenching steps to decrease unnecessary background
S-100 protein Most widely used melanocytic marker. It is highly sensitive staining. Polymer-based detection systems can effectively eliminate biotin-
but not as specific as other melanocytic markers induced false-positive staining. While antigen retrieval techniques are criti-
HMB 45 Good specificity but relatively low sensitivity.Tends to cal for antigen unmasking, optimal results require control of the pH and
be negative in spindle cell melanoma. Also positive in temperature of retrieval solutions and controlled enzymatic digestion (Fig.
PEComa. 2.9).7–10 The latter causes excessive background staining when sections are
Melan A/Mart 1 Similar specificity to HMB45. Tends to be negative in exposed to increased digestion time, inappropriate high temperature and
spindle cell melanomas.
inadequate rinsing, causing protein diffusion into or deposition in skin sec-
Ki-67 Higher proliferation index in melanoma (13–35%)
than in nevi (<5%). Useful in the evaluation of some
tions and b ackground staining.
melanocytic tumors, mainly nevoid melanoma Chromogen entrapment, precipitation and contaminants may lead to false-
positive interpretation of an IHC test. Depletion of peroxidase or alkaline
Neuroectodermal and neural tumors phosphatase chromogenic activity, a consequence of the breakdown of chro-
S-100 protein Positive in neuroectodermal, neuronal, nerve sheath, mogens because of the sensitivity to light and heat, results in a background
chondroid tumors, some sweat gland tumors and blush. A similar effect is seen when there is inadequate chromogen rinsing
myoepithelioma or prolonged chromogen time. Filtering of the chromogen is effective in pre-
NSE Merkel cell carcinoma venting chromogen precipitation. Chatter, tears, folds and wrinkles and poor
CK 20 Merkel cell carcinoma adhesion of sections to slides causes entrapment and suboptimal rinsing of
Neurofilament Merkel cell carcinoma chromogen (Fig. 2.10). Skin sections with a thick stratum corneum, dermal
Chromogranin Merkel cell carcinoma calcification, or sclerosis may be prone to these artifacts, requiring meticulous
Synaptophysin Merkel cell carcinoma microtomy to prevent its occurrence. The handling of water baths, tissue sec-
TTF1 Negative in most Merkel cell carcinoma
tions and slides with ungloved hands may cause contamination of sections
with squames.1
Myogenic/myofibroblastic differentiation
False-negative immunostaining may also compromise IHC interpreta-
MSA Tumors of muscle origin
tion. Incomplete deparaffinization causes suboptimal or incomplete staining
Desmin Tumors of muscle origin (smooth muscle and skeletal
because of incomplete tissue penetration by the antibody. Overdigestion of
muscle, rarely and focally in myofibroblastic tumors)
Myogenin Positive in rhabdomyosarcoma tissue sections by proteolytic enzymes can destroy the tissue sections with
SMA Positive in smooth muscle tumors, glomus tumor, attendant loss of antigen for antibody binding. Other causes of false-negative
myopericytoma, dermatomyofibroma immunostaining include:
• incorrect temperature of reagents, including retrieval solutions,
BCC, basal cell carcinoma; SCC, squamous cell carcinoma; SMA, anti-smooth muscle
actin; MSA, muscle specific actin; CK, cytokeratin.
• expired antibodies,
• inappropriate dilutions,
• suboptimal storage of antibodies .1,3
a ntibody reacted directly with the tissue antigen.1 In the two-step indirect
technique, labeled secondary antibody directed against the immunoglobulin
of the animal in which the primary antibody was raised was used to visual- Immunofluorescence
ize an unlabeled primary antibody.4 The labeled streptavidin-biotin (LSAB)
method is a three-step technique. An unconjugated primary monoclonal Immunofluorescent techniques have the potential to define antigen-antibody
or polyclonal antibody, attached to the tissue antigen forms the first layer, interactions at a subcellular level.1 This interaction requires the irreversible
creating an antigen-antibody complex. The second layer is formed by a bioti- binding of a readily identifiable label for its recognition.1,2 Fluorochromes
nylated secondary antibody raised against the same species of the primary such as rhodamine or fluorescein are labels that can absorb radiation in the
P Antigen
Biotin
B
P Peroxidase
P B B P
P B P Primary
P
Antibody
Secondary
Antibody
P
Secondary Antibody on
a polymer backbone Fig. 2.6
Immunohistochemical techniques:
(A) direct, (B) indirect (C)
streptavidin biotin (D) polymer
chain. By courtesy of Dr. J.
Ag Ag Ag Ag Ag Deonarain, Department of
Direct method Indirect method Avidin-biotin method Polymer chain two step direct method Anatomical Pathology, National
Health Laboratory Service, Durban,
A B C D South Africa.
Fig. 2.7 Fig. 2.9

Technical artifact: poor tissue fixation resulting in incomplete sections, Technical artifact p53 stain: wrinkling and background staining of tissue sections
fragmentation and suboptimal AE1/AE3 stained section. because of erroneously high temperature heat-assisted microwave antigen retrieval
exposure of sections in EDTA buffer (pH 8.0).
Fig. 2.8 Fig. 2.10

Technical artifact: suboptimal antibody concentration of CD3 antibody resulting in Technical artifact: HHV8 stained sections demonstrating chromogen entrapment in
background staining. stratum corneum.
Diagnosis of inherited skin diseases 37
form of ultraviolet or visible light.1–5 Direct and indirect immunofluorescence between the dermatopathologist and molecular laboratory is absolutely criti-
(IMF) techniques demonstrate a range of tissue antigens of dermatopatho- cal for efficient use of molecular techniques.
logic importance, including the diagnosis of infectious and autoimmune blis- Analysis of the inherited skin blistering disorder known collectively as epi-
tering disorders.3 In the direct IMF technique, antibody is conjugated directly dermolysis bullosa (EB) discussed in detail in Chapter 4 demonstrates the
with a fluorochrome and is used to detect an antigen in a tissue section using complex, multifaceted approach to diagnosis required in such cases. EB has
ultraviolet light microscopy.1–3 In the indirect IMF technique, patient serum been shown to result from mutations in genes encoding at least 11 different
(containing the antibodies) interacts with a tissue section containing the anti- structural proteins at or close to the dermal–epidermal junction (Fig. 2.11).1
gen. Antibody to a human immunoglobulin, conjugated to a fluorochrome, is Clinically, the different types of EB are characterized by widely differing
applied thereafter.1–7 The successful demonstration of the antigen requires the prognoses, from death in early infancy to blistering that may become milder
antigen to remain sufficiently insoluble in situ. Skin biopsies for direct immu- in later life.2 The clinical presentation in neonates, however, can be confusing
nofluorescence can be transported fresh on saline-soaked gauze in a container to dermatologists and pediatricians because of the overlapping features (Fig.
on ice, or in a transport medium such as Michel medium.8 The transport 2.12). In these circumstances, skin biopsy, usually a superficial shave biopsy
medium must be maintained at a pH of 7.0 to 7.2.1,3,5 The main uses for IMF since the key region is the dermal–epidermal junction, can provide critical
in dermatopathology are in the interpretation of the autoimmune blistering
diseases, lupus erythematosus, and vasculitis.6,7 In general, immunofluores-
cence has the following advantages over immunohistochemistry:
• more sensitive detection of antigen. Keratins
• use of special fixation that preserves ‘difficult’ antigens. 5 & 14
EB simplex
Electron microscopy EB simplex

with muscular Plectin
Electron microscopy is less utilized than in the past. Immunohistochemical 230-kDa
dystrophy
BP Ag
approaches are preferred in those instances where they are a reasonable
Non-Herlitz
substitute. junctional EB
Junctional
Transmission electron microscopy offers better resolution than light α6β4
EB with Type XVII
microscopy.1 To optimize this, tissue has to be embedded in extremely rigid integrin Herlitz &
pyloric atresia collagen
material to allow sectioning at 80 nm. In most circumstances, hydrophobic Laminin-332 non-Herlitz
epoxy resins are preferred. When a specimen is removed for ultrastructural junctional EB
examination, it must be fixed in a suitable fixative immediately. The volume
of the fixative should be 10 times the sample size. The final specimen size is
1 mm2.1 Fixation is affected by:
• pH,
Dominant and
• osmolarity, recessive
Type VII
• ionic composition of buffer, dystrophic EB
collagen
• fixative concentration,
• temperature,
• duration of fixation.
Primary fixation in an aldehyde, usually gluteraldehyde, and secondary
Fig. 2.11
fixation in osmium tetroxide are standard procedures. Advances in immu-
Basement membrane region: protein components at the dermal–epidermal junction
nohistochemistry have decreased the dependence on electron microscopy for and the subtypes of EB that result from mutations in the genes encoding these
ultrastructural confirmation of cell lineage. Notwithstanding, dermatologic proteins.
ultrastructural investigations are important in the diagnosis of:
• undifferentiated tumors,
• immunobullous disease,
• cerebral autosomal dominant arteriopathy with subcortical infarcts and
leucoencephalopathy (CADSIL),
• amyloidosis,
• metabolic storage diseases.2–7
Intercellular junctions, Weibel-Palade bodies, melanosomes, and premelano-
somes may help in the diagnosis of carcinomas, endothelial tumors, and mel-
anocytic tumors, respectively.3 In CADSIL, extracellular, electron-dense granular B
material is present in an indentation in vascular smooth muscle cells.5,6 Amyloid
is identifiable as randomly arranged, extracellular, nonbranching fibrils of inde-
terminate length and 7–10 nm diameter.7 Transmission electron microscopy
remains a valuable tool in the ongoing evaluation of the structure of normal and
pathological human cell and tissue components and infective agents.8–10
Diagnosis of inherited skin diseases

An efficient approach to genetic testing often relies on initial traditional his-
A C
tologic characterization of skin biopsies.
Recent advances in molecular genetics and gene sequencing have led to
Fig. 2.12
many inherited skin diseases being diagnosed or confirmed by clinical molec- Epidermolysis bullosa: clinical appearances of neonates with different forms of
ular biologists rather than dermatopathologists. Analysis of skin biopsies still inherited EB. All three cases have similar blisters and erosions but their respective
remains vital for the accurate diagnosis of several genodermatoses, and often prognoses differ considerably; (A) Severe, generalized recessive dystrophic EB; (B)
provides a guide for subsequent molecular analyses. Examination of the skin Dowling-Meara EB simplex; (C) Herlitz junctional EB. Skin biopsy is fundamental to
biopsy informs the selection of additional molecular testing. Communication establishing the subtype of severe forms of EB.
A B
Fig. 2.13 Fig. 2.15

Optimal skin biopsy for diagnosing EB: following local anesthesia, the normal- Specific antibody probes to subtype inherited EB: (A) immunostaining of normal
appearing skin is gently rubbed, and then a superficial shave biopsy is taken. The control skin with an antibody to type VII collagen shows bright linear labeling at the
skin sample can then be subdivided for immunolabeling of frozen sections as well dermal–epidermal junction; (B) in contrast, the complete absence of labeling in skin
as being processed for transmission electron microscopy. from an individual with EB (case illustrated in Fig. 2.12a) indicates a diagnosis of severe,
generalized recessive dystrophic EB. (Bar = 50 μm.)
diagnostic and prognostic information. Typically, nonblistered skin from any antibodies can be used either to determine the level of cleavage in the
body site is sampled. Just before the biopsy is taken, the skin is rubbed gently skin (antigen mapping) or to see if there is a reduction or absence of
in an attempt to induce fresh microsplits at the dermal–epidermal junction, to immunostaining for a particular antigen.4 Figure 2.14 , for example,
facilitate the microscopic subtyping of EB (Fig. 2.13). demonstrates labeling using an antibody against type IV collagen in skin
The most informative investigation is immunolabeling of the der- from the neonate illustrated in Figure 2.12a . In this example, labeling
mal–epidermal junction using a panel of basement membrane anti- maps to the roof of the split. This indicates that the lamina densa is in
bodies. Skin biopsies can be transported in Michel's medium to a the blister roof and that there is a sublamina densa plane of blister for-
diagnostic laboratory at ambient temperature: this fixative is extremely mation. These findings support a diagnosis of dystrophic EB. This diag-
useful since basement membrane zone immunoreactivity is main- nosis can be refined by immunolabeling with an antibody to type VII
tained for at least 6 months. 3 For the immunolabeling, frozen skin collagen, as shown in ( Fig. 2.15 ). In normal skin there is bright, linear
sections are used rather than formalin-fixed paraffin-embedded mate- labeling at the dermal–epidermal junction; however, in the skin from the
rial because the antigenic epitopes of several transmembranous pro- neonate shown in Figure 2.12a , there is a complete absence of type VII
teins may be lost in routine skin processing. The basement membrane collagen immunoreactivity. All other antibodies show normal reactivity
Fig. 2.14
Antigen mapping to diagnose the subtype of inherited EB: this picture shows
immunolabeling of rubbed skin from an individual with EB (case illustrated in Fig. 2.16
Fig. 2.12a) with an anti-type IV collagen antibody. Rubbing the skin induces microsplits Transmission electron microscopy of skin in Dowling-Meara EB simplex (case
at the dermal–epidermal junction (asterisk). The type IV collagen reactivity maps to the illustrated in Fig. 2.12b): within the basal keratinocyte cytoplasm the keratin
roof of the dermal–epidermal junction (arrows). This indicates a sub-lamina densa plane filaments are condensed and form clumps and there is cytolysis that occurs just
of cleavage and establishes a diagnosis of dystrophic EB. (Bar = 25 μm.) above the dermal–epidermal junction. (Bar = 1 μm.)
Molecular techniques 39
at the dermal–epidermal junction. These findings therefore establish a

diagnosis of severe, generalized recessive dystrophic EB. Reduced or Molecular techniques
absent immunolabeling with specific basement membrane antibodies is
an extremely useful and rapid means of diagnosing recessive forms of Chromosomal karyotyping
EB. For example, skin from the neonate shown in Figure 2.12c demon-
This technique can be used as an initial screen to demonstrate gross chromo-
strated a lack of reactivity against laminin-332 but normal immunos-
somal aberrations associated with certain tumors. Most skin tumors are small
taining for all other antibodies. These findings establish a diagnosis of
and thus tissue is generally not set aside for karyotype analysis.
Herlitz junctional EB.
Chromosomal karyotyping is the historical gold standard for detecting
The development of a panel of basement membrane antibodies, most of
chromosomal aberrations in neoplastic tissue (Fig. 2.17). Fresh tumor tissue is
which are commercially available, has led to decreased emphasis on transmis-
required to grow the cells and the cytogenetic preparations and interpretation
sion electron microscopy as a diagnostic tool in EB.5 Ultrastructural analysis,
require skilled personnel. Nonetheless, this technique provides an open, unbi-
however, can be useful in confirming the plane of cleavage and in establish-
ased look at all of the chromosomes of a particular tumor. Total chromosomal
ing the diagnosis of certain dominant forms of EB. Skin from the neonate
gains and losses and also translocations between chromosomes can be demon-
illustrated in Figure 2.12b, for example, shows normal intensity basement
strated. Some of these chromosomal translocations are virtually diagnostic of
membrane zone reactivity for all diagnostic probes but transmission electron
certain tumors, particularly soft tissue and hematopoietic tumors.1 Other chro-
microscopy (Fig. 2.16) identifies discrete clumps of tonofilament and basal
mosomal changes can be suggestive of certain tumor types. While most trans-
keratinocyte cytolysis, characteristic of the Dowling-Meara variant of EB
locations are now confirmed by the other molecular methods described below,
simplex. For recessive forms of EB, however, immunolabeling of basement
traditional chromosomal karyotyping retains a role as an initial examination
membrane proteins has become the most important diagnostic approach.6,7
of the chromosomal complement of a neoplasm and an important tool for dis-
Reduced or absent staining for a particular protein provides a rapid diagnosis
covery of new chromosomal aberrations.2 Indeed, over time, the discovery of
as well as a means of identifying the encoding gene (or genes) in which the
chromosomal translocations within specific tumor types is proportional to the
underlying pathogenic mutations are present. Thus the skin biopsy findings,
number of cases karyotyped.3 Additional methodologies discussed below such
both histologic and immunohistochemical, provide a direct guide to molecu-
as spectral karyotyping (SKY) or multiplexed fluorescence in situ hybridiza-
lar screening tests, most of which are PCR-based, as discussed below. This
tion (mFISH) can aid in the interpretation of complex karyotypes.
molecular information can then be used for genetic counseling, carrier screen-
ing, and DNA-based prenatal testing, if indicated.
While the details of the initial analysis change in the diagnostic work-
Allelic imbalance
up of various inherited skin diseases, in many cases, preliminary histologic Gains or losses of specific regions of DNA, often containing particular genes
and other testing is performed in an attempt to determine which molecular of interest, can provide diagnostic insight.
diagnostic test is most relevant. This is important, as such testing is difficult An allele is a variant of a particular genetic locus or region of DNA such
and expensive and thus selection of which gene to examine is important for as a gene. Detection of allelic imbalance or loss of heterozygosity (LOH) is a
efficient diagnostic work-up. method that can detect the presence of deletions or gains of specific alleles in
Fig. 2.17
Genetics of clear cell sarcoma: (A) this complicated karyotype shows derivative chromosomes 12 (blue box) and 22 (orange box). While recurrent translocation-associated
karyotypes are initially simple, they can become more complex with tumor progression. (B) The mechanism of chromosomal translocation involves breaks in chromosomes
12 and 22 that recombine to produce novel derivative chromosomes 12 and 22. The active fusion gene (EWSR1-ATF1) is produced on der(22). The fusion genes can be
produced by a variety of breakpoints within the introns of the involved genes making multiple exon combinations (C). This complicates the design of PCR-based detection
methods, as does substitution of the CREB1 gene for ATF1 on occasion.
paraffin-embedded material.4 This usually corresponds to regions of a particu-

lar gene(s) of interest. For this approach, PCR is used to amplify small genomic
fragments that carry common polymorphisms and thus have a high likelihood
of being present in two different variants (alleles) in an individual. Ideally, these
variants are of different size so that they can easily be detected on an electro-
phoretic gel; DNA sequencing can be used if this is not possible. Only if two
different alleles in the normal tissue of a patient are present is this technique
informative. Imbalance (loss of one allele) is implied if one detects only one
of the alleles in the tumor tissue. More detailed analysis can distinguish those
which are true losses. Sites of recurrent losses are typically areas that harbor
tumor suppressor genes. This method can detect losses that would not be dem-
onstrated in a traditional chromosomal karyotype analysis and can be readily
adapted to formalin-fixed, paraffin-embedded (FFPE) tissue. The limitations of
LOH analysis include that it is sensitive to contamination by normal (stromal)
cells that can make it difficult to decide whether an allele is lost. Another draw-
back is its inability to determine whether the imbalance is caused by the loss of
one marker or by a copy number increase of the other marker.
Fluorescence in situ hybridization (FISH)

FISH uses specific probes to determine the number of copies of a specific
region of DNA that are present or whether a particular locus has been rear-
ranged as part of a chromosomal translocation.
FISH utilizes fluorescently labeled probes that are complementary to and
thus specifically hybridize a specific region of genomic DNA, allowing it to
be visualized.5,6 The labeled probe and the target genomic DNA, which can be
metaphase spreads, interphase nuclei (Fig. 2.18), or nuclei in formalin-fixed,
paraffin-embedded tissue sections (Fig. 2.19), are denatured and brought
into contact for several hours to days. Given appropriate hybridization con- Fig. 2.18
ditions, the labeled probes will anneal with the corresponding sequence Four-color FISH to two interface nuclei and metaphase chromosomes: the upper
portion shows two interface nuclei with the hybridization signals for the four
in the target DNA. This is easiest if probes are targeted to chromosomal
colors detectable as discrete spots. In the metaphase spread underneath, the
regions that are rich in repetitive sequences such as the centromeres. In these
hybridization signals can be seen to map to chromosome 6p (purple), 6 centromere
regions the probe can hybridize multiple times, resulting in hybridization (light blue), 6q (yellow), and chromosome 11q13 (green).
signals that are large and easy to detect. However, these regions typically do
not contain any functional genes, and while increases in chromosome copy
number can be recognized, no direct information on the copy number of a
specific cancer gene or locus can be obtained. Human cancers, including
melanoma, frequently have aberrations that involve only fragments of the
chromosome. The detection of these types of aberrations requires probes
targeted to unique, i.e., non-repetitive, sequences of DNA. Unique sequence
probes give smaller hybridization signals and can be more difficult to detect.
However, by using larger probe sizes of 100–300 kb, detection of unique
sequences is possible in paraffin sections (see Fig. 2.17). The advantage of
FISH is that it can detect cells with aberrations in the presence of signifi-
cant numbers of normal cells, provided that the neoplastic cells can be mor-
phologically identified in the hybridized section. Combinations of FISH and
immunofluorescence have been developed to assist in the identification of
the target cell population, but the compromises that have to be made to
accommodate antigen preservation by maintaining acceptable hybridization
Fig. 2.19
efficiency restrict its application for routine use in paraffin-embedded tissue. FISH to tissue sections of a melanoma (left panel) and nevus (right panel): the
Detection of heterozygous deletions is more difficult with FISH in tissue sec- panels show 400-fold magnifications of two nests of melanocytes with the nuclei
tions, because truncation of nuclei in tissue sections cut at normal thickness stained in blue. The green probe for chromosome 11q13 shows amplification in the
results in random loss of hybridization signals. Similarly, increased ploidy of melanoma as evident by a marked copy number increase compared to the purple
the neoplastic tumor cell population can simulate a gain of the target locus. signals representing chromosome 6p. By contrast, the melanocytes of the nevus in
These problems can be compensated by simultaneously hybridizing multiple, the right panel do not show significant differences for these two loci.
differentially labeled, probes to several loci in the genome and by analyzing a
larger number of cells. Comparing a probed locus to a centromeric probe on the flanking probes are fluorescently labeled in two different colors such as
the same chromosome in an alternate color can also compensate for cell ane- green and red, and when they are in close proximity in an intact chromo-
uploidy. A common example of this technique is comparison of the hybrid- some, the spectral overlap leads to two yellow signals, one for each normal
ization signals for the HER2 locus on 17q with centromere 17. This allows chromosome. In a cell with a rearrangement of a gene such as EWSR1 at
one to detect and distinguish both increased copy number of chromosome 22q12 in clear cell sarcoma, nuclei are seen with one intact chromosome 22
17 and specific amplification of the HER2 locus. with EWSR1 producing a yellow signal. In addition, the centromeric probe is
FISH using probes that flank a potential breakpoint associated with a chro- retained on the derivative (rearranged) 22 chromosome while the telomeric
mosomal translocation can be used to demonstrate rearrangement of that probe is transferred to the recipient chromosome (12 in the case of clear cell
locus (Fig. 2.20). This can be diagnostically helpful in certain hematopoi- sarcoma) leading to separate red and green signals in the nucleus. This method
etic malignancies with recurrent translocations, e.g., large cell anaplastic lym- only indicates that a locus is rearranged, not the identity of the chromosomal
phoma and some soft tissue tumors that can involve the skin.7,8 In this method, partner and gene. Thus caution must be used in interpretation as different
Molecular techniques 41
der(22) d(22)
22 22
d(12)
12 R
der(12) 22
Y Y
Probe Y G
22
R
R
EWSR1 ATF1
Active breakpoint
ATF1 I
Probes Probe
G Y G
Y Y G
R EWSR1 ATF1 EWSR1 G
(q12) Silent breakpoint
R Y
A B
Fig. 2.20
Break-apart fluorescent in situ hybridization (FISH) technique: the 12;22 translocation associated with clear cell sarcoma is depicted; (A) when the EWSR1 locus is intact, the
probes hybridize to the centromeric (red) and telomeric (green) regions flanking the gene. The spectral overlap of the two signals in juxtaposition produce a yellow signal.
Thus in cell lacking rearrangement of this locus, two yellow signals are present, representing the two copies of chromosome 22 lacking rearrangement (right); (B) When
rearrangement occurs, such as the balanced translocation with chromosome 12 depicted here, the centromeric probe (red) is retained by the derivative chromosome
22 while the green probe is transferred to the derivative chromosome 12. Thus in the nuclei one yellow signal indicates the intact chromosome 22 while the derivative 12
and 22 chromosomes segregate freely as single green and red signals, respectively (right).
Desmoplastic small
round cell tumor
WT1 NR4A3(TEC) Extraskeletal myxoid

11p13 9q22 chondrosarcoma
Myxoid CHOP/DDIT3 EWSR1

posarcoma 12q13 22q12
Angiomatoid
ATF1 ETS family Ewing
fibrous / PNET
12q13 FLI1 11q24 sarcoma
histiocytoma
ERG 21q22
FUS/TLS
FEV 2q36
Clear cell sarcoma 16p11 Acute myeloid leukemia
(EWSR1-ATF1) CREB1
ETV1 7p22 Fig. 2.21
ETV4 17q12 (FUS-ERG) Multiple translocations involve EWSR1 and the
(EWSR1-CREB1) 2q32
ZSG 22q12 Ewing homologous gene, FUS: both EWSR1 and FUS
(FUS-ATF1) CREB3L2 / PNET
7q33 sarcoma can often substitute for one another and both are
involved in balanced translocations with multiple
CREB3L1 genes resulting in a variety of neoplasms. Since
11p11 FISH only indicates that a single locus, such as
EWSR1, is re-arranged and nothing about the fusion
partner, results must be interpreted carefully within
the clinical and morphologic context of a tested
Low grade
case. Sometimes techniques such as RT-PCR must
fibromyxoid sarcoma
be used to verify the fusion partner.
translocations seen in different neoplasms can be associated with the same

probed locus. For instance, EWSR1 is rearranged in clear cell sarcoma, Ewing nuclei have to be counted. The latter restriction has been partially overcome
sarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histio- by the development of computer-based counting algorithms.9
cytoma, and some cases of myxoid liposarcoma (Fig. 2.21). Careful correla- In situ hybridization can also employ chromogenic probes such that
tion with the clinical and histologic features can help avoid confusion in these light microscopy can be used to visualize signals (termed CISH). This
situations. method is useful for detecting amplification of a genetic locus and tech-
The disadvantage of FISH is that it can only look at a few loci at a time, nically can be utilized in a break-apart probe strategy to detect trans-
and that analysis is time-consuming because signals in a large number of locations, but in practice this latter application can be very difficult to
interpret. Probably the most common use for CISH is in direct detection
of nucleic acids associated with infections in cells such as human papil-
lomavirus (HPV) or Epstein-Barr virus. In HPV, this technique can be use
to type the virus and determine whether it is high risk (e.g., 16 and 18)
or low risk (6 and 11). In this application, ISH is used to demonstrate the
presence of viral DNA that is not present in a cell until infection occurs.
Modifications of this technique can be used to detect messenger RNA in
tissue sections as well.
In situ hybridization, fluorescent or chromogenic, is best used to
demonstrate:
• amplification of a specific gene,
• rearrangement of a specific gene,
• presence of ‘foreign’ (infection-related) DNA or RNA.
Comparative genomic hybridization (CGH)

Comparative genomic hybridization can be used to demonstrate gains and
losses of DNA through the entire genome of a tumor sample. While this is
mainly a research tool at this time, its application has lead to important dis-
coveries that have been translated into focused genetic tests.
CGH demonstrates for the entire genome:
• regions of chromosomal loss (often containing tumor suppressor genes),
• regions of chromosomal gains (often containing oncogenes),
• overall patterns of gains and losses (rather than just a few focused
regions).
As originally described, CGH detects and maps DNA sequence copy num- Fig. 2.22
ber variation throughout the entire genome onto a cytogenetic map supplied Comparative genomic hybridization (CGH) on a metaphase chromosome spread
by metaphase chromosomes (Fig. 2.22).10 CGH can be regarded as a varia- (upper panels) and a microarray (lower panels): the regions of the chromosomes
tion of FISH in which the entire genome of a sample such as DNA from a skin (upper panel) that appear red are affected by deletions, whereas the regions that
tumor is used as a hybridization probe. The tumor is freed from contaminat- appear green are affected by gains or amplifications (bright green). Yellow indicates
ing normal cells by manual dissection, the DNA extracted, and labeled with a an area with normal DNA complement-no gain or loss. The lower panel on the right
fluorochrome (green, for example). In addition, a reference probe of normal shows a DNA microarray with approximately 2500 targets printed as triplicates
genomic DNA from a healthy donor is labeled with a different fluorochrome spots. Triplets that appear green indicate gains whereas those that appear red
indicate loss. The array targets are not printed in order of their genomic position
(red, for example). Equal amounts of the green- and red-labeled DNA are
which can help control for technical variations. The precise genomic location of
mixed and hybridized onto a substrate, which represents the entire human the DNA copy number changes detected by the measurement only becomes
genome. Originally, these were metaphase spreads of normal human chro- apparent after plotting the average ratios of red to green fluorescence intensities
mosomes prepared from lymphocytes of a healthy donor that represented a corresponding to their genomic position as illustrated in Figure 2.23
cytogenetic map. More recently, this substrate has been replaced by manu-
factured microarrays composed of nucleotide probes that are printed at high
density on a solid surface.11 Depending on the number and lengths of these
nucleotide probes, the entire genome can be represented on an array. By using
smaller probes, higher resolution of genetic gains and losses can be achieved.
During the hybridization, the red- and green-labeled DNA populations com-
pete for binding to corresponding regional microarray targets. For each
array target (or region of a chromosome in the original protocol) the ratio
of red and green fluorescence intensity ratio is determined. A ratio of 1 indi-
cates a balanced situation at this locus, i.e., no gain or loss in the tumor (see
Fig. 2.23). In the presence of deletions in the tumor genome, less green probe
will be available to hybridize to the corresponding targets, which will result
in a decreased green to red fluorescence intensity ratio (< 1). In the presence
Fig. 2.23
of increased copies, the corresponding targets still show a green to red fluo-
DNA copy number changes as detected by array CGH of an acral melanoma: the
rescence intensity ratio greater than 1. The ratio of red and green fluores- graph shows the log2 of the ratio of the fluorescence intensity ratios of tumor
cence intensity can be used to quantify the copy number change. A ratio of to reference DNA plotted according to their genomic position on the x-axis. The
1 indicates normal copy number, a ratio < 1 indicates a loss, and a ratio > 1 numbers at the top and at the bottom indicate the chromosomes. A log2 ratio of
indicates a gain. Gains with a high ratio that only affect portions of a chro- zero corresponds to normal copy number. As can be seen, multiple contiguous
mosomal arm are called amplifications. They arise from multiple independent chromosomal regions showed losses and gains. The arrow corresponds to an
events (chromosomal breakage and fusions) that accumulate under positive amplification of chromosome 11q13 interval containing the gene that encodes
selection, typically because the genomic region present in the amplicon con- cyclin D1.
tained an oncogene, i.e., a gene that provided a growth advantage to the
tumor cells with increased copies of the gene. analysis of solid tumors. Compared to conventional cytogenetic analysis,
The full experimental protocol for CGH is slightly more complex than CGH does not require culture of cells for karyotypic analysis, which brings
outlined above. A third, unlabeled DNA population is needed to ascertain the major advantage that CGH can be performed on archival tissue. It is
that repetitive regions that are scattered throughout the genome do not cross- important to note that the DNA copy number measurement obtained with
hybridize and interfere with the measurement. This blocking DNA is highly CGH represents an average of the entire cell population from which the DNA
enriched for repetitive regions and suppresses unwanted cross-hybridization was extracted. For this reason, only the copy number alterations present in
between repetitive regions in the labeled DNA populations and the chro- a substantial portion of the cells are detected by the method. Depending on
mosomes which serve as substrate. CGH has revolutionized the cytogenetic the type of aberration – amplifications can be detected most easily – the copy
Diagnosis of lymphomas 43
number change needs to be present in about 30% to 50% of the cells in

order to be identifiable. Alterations affecting only a minority of cells remain
undetected. A further limitation is that CGH only detects genomic aberra-
tions that result in DNA copy number changes. Balanced translocations and
Primer Primer Primer Primer
point mutations are not detected. Copy number neutral rearrangements that
arise through chromosomal recombination and LOH (see above) are also not EWSR1 ATF1
detectable by CGH. More recent implementations that use oligonucleotides EWSR1 / ATF1 Fusion
to determine single nucleotide polymorphisms (SNPs) allow the genome-wide
simultaneous assessment of DNA copy number and LOH in unfixed tumor
tissue.12,13 However, these methods are still being optimized to allow broad
applicability to routinely fixed tissue. No Amplification Amplification
Polymerase chain reaction (PCR)

1 2
In the diagnostic setting, PCR is used primarily to acquire sufficient DNA for
analysis by sequencing or other methods, primarily to demonstrate a muta-
tion or other genetic change or the presence of a specific gene or messenger Type 2
RNA. EWSR1-ATF1
PCR is an extremely flexible technique and can be adapted to: fusion amplicon
• detect mutations (base pair substitutions, insertions and deletions) in
genes,
• demonstrate novel fusion transcripts (gene fusions), Fig. 2.24
Use of reverse transcription-polymerase chain reaction (RT-PCR) to detect fusion
• demonstrate clonality,
transcripts: this technique uses reverse transcription to convert RNA to cDNA that
• demonstrate loss of heterozygosity (loss of one allele), can then be amplified by PCR. This step is necessary as the breakpoints in the
• detect DNA or RNA associated with infectious organisms, usually large intronic regions of genomic DNA within a gene are essentially random,
• detect the levels of expression of messenger RNA. making it extremely difficult to amplify such large regions to identify the breakpoints
The ability to specifically amplify and detect any segment of DNA in the using genomic DNA as the template. When the gene is transcribed to RNA, the
human genome has opened many diagnostic doors. In this technique, a pair introns are removed during splicing and introns are directly juxtaposed
of short sequences of DNA (called primers) that hybridize to two sequences (Fig. 2.11c) allowing more ready detection of the novel juxtaposition of exons from
of genomic DNA (or RNA reverse transcribed to DNA) are designed to two different genes. When primers are designed for the exons of each of the two
amplify a specific region of DNA. Using a DNA polymerase that is stable genes involved in a translocation, amplification only occurs of the cDNA of the fusion
at high temperatures, a series of annealing, extending, and melting/denatur- transcript as these introns would not be adjacent in normal tissue. This product
ing cycles amplifies the DNA between the two probes. This technique can be will have a specific size and can be detected on a gel, but direct DNA sequencing
or other methods should be used to confirm its identity. Amplification of normal
used on nucleic acids extracted from formalin-fixed, paraffin-embedded tis-
housekeeping gene transcripts are used to ensure the quality of the cDNA.
sue, although probes must be designed to amplify shorter segments of DNA
since the starting material has been cross-linked and fragmented from the
formalin treatment. A variety of techniques based on PCR can be used to
amplify DNA and then determine its sequence. Direct sequencing of genomic
was not valuable, at least in part because of the presence of nodal nevi which
DNA allows detection of point mutations in cancer, such as BRAF or NRAS
would also be detected by this technique. While widely used in the research
in melanoma.14 Generally, one can detect a mutation in 1 in 5 cells with this
arena, other diagnostic approaches based on detection of gene expression will
technique. More sensitive techniques such as pyrosequencing can reduce this
likely evolve with time.
to 1 in 10 or 20 cells by analysis for a precise mutation. Finally, allele-specific
It is often advantageous to have multiple methodologies for detecting vari-
PCR can be used to detect a known point mutation in as little as 1 in 50
ous molecular defects, as they are used in different situations and provide
or 100 cells. This technique has applications such as detecting KIT D816V
slightly different information. Figure 2.25 depicts this for the translocation
mutation in mastocytosis in skin where the neoplastic cells may be sparse
present in clear cell sarcoma.
relative to the surrounding normal tissue.15 Insertions and deletions in genes
can also be detected, usually by Sanger sequencing.8
Reverse transcribing RNA to DNA can allow specific detection of fusion Diagnosis of lymphomas
genes produced by chromosomal translocations such as seen in clear cell
sarcoma or dermatofibrosarcoma protuberans.16,17 This technique is partic- The diagnosis and subclassification of lymphomas has transformed dramati-
ularly valuable as there is no amplification product in the absence of tumor cally in the last three decades. Prior to this, the classifications in general use
as the translocations are not seen in normal tissue or other tumors (see were based purely on the morphological features of the neoplastic lympho-
Fig. 2.24). Because the two genes involved in a translocation event may cytes.1,2 However, modern classification systems also utilize all available immu-
have breaks at multiple introns (the noncoding region of DNA between the nophenotypic, genetic, and clinical information to group cases together for
protein encoding exon segments), multiple primer pairs may be necessary to the purposes of treatment and prognostication.3–7 Immunohistochemical and
detect all of the possible translocation types. Also, since multiple genes can molecular techniques therefore form an integral part of the diagnostic process,
be involved, for instance clear cell sarcoma can contain either an EWSR1- and are routinely employed in the assessment of suspect cutaneous lymphop-
ATF1 or EWSR1-CREB1 fusion, additional primer sets will be required for roliferations in order to discriminate reactive from neoplastic processes, and
detection of these as well (see Fig. 17.11c).18,19 In hematopoietic malignan- to subclassify the latter once identified. A battery of antibodies and molecular
cies, detection of fusion transcripts can be used to detect minimal residual techniques are now available to the practicing pathologist. 8–14
disease in the peripheral blood or marrow to measure tumor DNA as a sur- This section focuses specifically on amplications of the polymerase chain
rogate of tumor load to assess response to therapy or allow early detection reaction (PCR) to diagnostic hematopathology, the molecular technique in
of recurrence. This approach may be applied to solid tumors in the future. most common usage, for the detection of antigen receptor gene rearrange-
PCR can be used to detect normal genes as well. An instance of this in der- ment. The relevant immunophenotypic and genetic features of specific
matopathology was the attempt to detect melanocyte-specific RNA (reverse lymphoma subtypes are detailed in Chapter 29. In addition, FISH-based tech-
transcribed to DNA) in sentinel lymph nodes that might have been missed by niques can also be used to demonstrate translocation associated primarily
histology and immunohistochemical screening.20–22 Ultimately, this technique with B-cell lymphomas.
Fig. 2.25
Multiple modalities for detection of recurrent translocations. Traditional karyotypes use metaphase chromosomes spreads to detect translocations and other structural
genetic aberrations using banding (staining) techniques. FISH uses less condensed interphase chromosomes to detect rearrangements or amplifications. RT-PCR can detect
the precise exons involved in a fusion RNA transcript. Each is a valid method for demonstrating chromosomal translocations, but each has applicability to different sample
types and provides different information.
PCR analysis of cutaneous lymphoid

infiltrates
The diagnosis of cutaneous lymphoma relies on a constellation of morpho-
logic, immunophenotypic, and clinical features, and may be difficult, par- * *
ticularly in the early stages. Molecular genetic findings are increasingly
incorporated into the diagnostic process. Often, their role is confirmatory,
demonstrating clonality in a lesion already thought to be lymphomatous on
the basis of pathological findings. However, in a significant proportion of
cases, a definitive diagnosis cannot be reached with certainty on the basis of
histology and immunophenotype. In such instances, the results of molecular
clonality studies may provide sufficient additional information for a diagno-
* *
sis to be assigned and/or to guide patient management. However, PCR analy-
sis of skin biopsies is subject to the same limitations and pitfalls as described
above. Therefore, the results of such studies must always be interpreted with
caution and only following close discussions between the pathologist, molec-
ular biologist, and clinician.
TCR gene rearrangement in cutaneous

lymphoproliferations
Unlike the testing of solid tumors, PCR-based testing of lymphoid infiltrates
can take advantage of TCR receptor gene rearrangements to establish clonal-
ity, although this does not always equate to malignancy.
Clonality studies may be useful in identifying the early stages of myco-
sis fungoides or other cutaneous T-cell lymphomas. Dominant clones can
be demonstrated in the early lesions of mycosis fungoides and in cases of
cutaneous T-cell lymphoma which could not otherwise be identified using
conventional morphology (Fig. 2.26).1–6 They have also been said to facil-
itate discrimination between mycosis fungoides and inflammatory derma-
toses, and simulators of mycosis fungoides such as actinic reticuloid.3–8 PCR
is also useful in identifying the underlying disease in erythroderma when it is
due to cutaneous T-cell lymphoma, rather than inflammatory processes such
as eczema, contact dermatitis, drug reactions, pityriasis rubra pilaris, pso-
A B
riasis, and pemphigus foliaceus.5,9–12 In addition, there are certain variants
and malignant mimics of cutaneous T-cell lymphoma, in which absence of a Fig. 2.26
clonal TCR gene rearrangement helps confirm the diagnosis. These include Mycosis fungoides: TCR gene rearrangement (photo of gel). Red astrixes indicate
extranodal NK/T-cell lymphoma of nasal type, CD4+/CD56+ hematodermic dominant clonal T-cell gene rearrangement shown as discrete bands rather than a
neoplasm and leukemia cutis. smear demonstrating numerous clones and non-rearranged receptors.
Diagnosis of lymphomas 45
However, clonality does not always equate with a diagnosis of malignant

lymphoma. Monoclonal TCR gene rearrangements have been demonstrated Constant Variable Disulphide Heavy Light
domain domain chain chain
in otherwise typically benign dermatoses. These include: bonds
• discoid lupus erythematosus,

• lichen planus,
• lichen sclerosus.13–15
Bona fide T-cell clones may also be found in examples of cutaneous T-cell
pseudolymphoma, particularly those associated with reversible hypersensitivity
drug reactions, and in some instances the same clone has been demonstrated
in biopsies from the same patient taken at different sites.15–19 There is also a
group of disorders which generally run a benign clinical course, but can be
associated with progression to cutaneous T-cell lymphoma, usually mycosis
fungoides but occasionally cutaneous anaplastic large cell lymphoma or some
other form of cutaneous T-cell lymphoma. These include:
• pigmented purpuric dermatosis,
• pityriasis lichenoides chronica,
• pityriasis lichenoides et varioliformis acuta, Fig. 2.27
Structure of Ig. The two
• lymphomatoid papulosis.20–34 epitope binding sites are
A variable, but often high, incidence of monoclonality is found when series of formed primarily by the
these conditions are analyzed by PCR for the TCRG and/or TCRB gene, and the two variable domains.
same clone is usually found in follow-up biopsies when lymphoma ensues.18,25,32–39
Another similar group comprises cutaneous T-cell lymphoproliferative dis- cases using PCR techniques designed to detect IG gene rearrangements as part
orders that are currently thought to represent very indolent or prelymphoma- of the routine diagnostic work-up (Figs 2.27 and 2.28).1–4 However, even
tous forms of recognized subtypes of cutaneous T-cell lymphomas including: using BIOMED-2 protocols, there may be a significant false-negative rate.
• large plaque parapsoriasis,15,19,40 This is particularly the case if the only primers used are for the framework
• idiopathic follicular mucinosis,15,41 regions on the IG heavy chain gene, one study detecting clonality in only 67%
• syringolymphoid hyperplasia with alopecia,42–44 of primary cutaneous B-cell lymphomas.4 This is likely to be due to the rela-
• hypopigmented mycosis fungoides.45 tively high proportion of lymphomas of germinal center, or postgerminal cen-
These are thought to be related to variants of mycosis fungoides. Idiopathic ter origin encountered in the skin, since these are associated with high levels
erythroderma has similarities to Sezary syndrome46 and atypical lymphocytic of somatic hypermutation. Detection levels increase when assays targeting IG
lobular panniculitis to subcutaneous panniculitis-like T-cell lymphoma.47,48 light chains, including the Kde, are introduced.2
These entities are typically monoclonal and share many characteristics with Clonality assays are not a reliable way of differentiating B-cutaneous lym-
the lymphomas to which they are putatively related. However, they lack full phoid hyperplasia from cutaneous B-cell lymphoma. Monoclonal immuno-
morphologic and/or phenotypic evidence of lymphoma, and although most globulin gene rearrangements have been demonstrated in lesions designated
run a recalcitrant course resistant to topical therapy, and some progress to B-cutaneous hyperplasia (or synonyms thereof), even when less sensitive
overt malignant lymphoma, most have an innocuous clinical outcome. Southern blotting techniques have been used.5–9 However, in series quoting
It has been proposed that the following be encompassed under the rubric high levels of monoclonal B-CLH, relatively few cases progress to overt lym-
of ‘cutaneous T-cell lymphoid dyscrasia’49: phoma.5,7,8 These lesions may therefore be analogous to the cutaneous T-cell
• idiopathic pigmented purpuric dermatosis, dyscrasias described above, in that they may run a protracted but ultimately
• pityriasis lichenoides, benign clinical course, only rarely progressing to overt malignancy.
• large plaque parapsoriasis,
• idiopathic follicular mucinosis,
• syringolymphoid hyperplasia with alopecia,
• hypopigmented mycosis fungoides,
• idiopathic clonal erythroderma,
• atypical lymphocytic lobular panniculitis.
The concept is similar to that of monoclonal gammopathy of uncertain sig-
nificance, already well established for plasma cell dyscrasias.46 ‘Cutaneous T-cell
lymphoid dyscrasia’ is used to convey the limited but real malignant potential
of these monoclonal and oligoclonal lymphoproliferations, and is preferred by
the authors to terms such as ‘premycotic’, because evolution to overt cutaneous
T-cell lymphoma is uncommon. It is hypothesized that T-cell clones develop as
a result of chronic antigenic stimulation. Acquisition of genetic abnormalities
by an expanded clone results in an ability for autonomous growth. This is ini-
tially held in check by the host immune cells, and only when these are overcome
does the fully malignant clone emerge. Entities that occasionally harbor clonal
populations of T cells, but have no malignant potential (such as drug-induced
pseudolymphoma), are excluded from this category.
IG gene rearrangement in cutaneous

lymphoproliferations
Fig. 2.28
A number of variant gene rearrangements often involve the promoters of
B-cell lymphoma: Ig gene rearrangement
immunoglobulin genes to drive the expression of oncogene critical to lym- (photo of gel). The upper bands arrowed in
phomagenesis. The current World Health Organization (WHO) classification lanes two and three indicate non-rearranged
scheme relies on these molecular results for precise classification. IG with the astrix in lane two indicates a
The clonal nature of cutaneous B-cell infiltrates in both primary and sec- polyclonal IG population. The lower band in
ondary cutaneous B-cell lymphomas can be confirmed in a high percentage of lane three shows a dominant IG clone.
Chapter
3 Disorders of keratinization
Dieter Metze
See
for references and
additional material
Ichthyosis 46 Lichen spinulosus 66 Marginal papular acrokeratoderma 82

Ichthyosis vulgaris 46 Phrynoderma 67 Huriez syndrome 82
X-linked recessive ichthyosis 49 Keratosis pilaris 67 Vohwinkel's syndrome 83
Syndromes with steroid sulfatase Keratosis pilaris atrophicans 68 Loricrin keratoderma 84
deficiency 50 Clouston's syndrome 84
Acquired ichthyosis-like conditions 69
Multiple sulfatase deficiency 50 Olmsted syndrome 85
Pityriasis rotunda 70
Refsum syndrome 50 Papillon-Lefèvre syndrome 86
Autosomal recessive lamellar ichthyoses 51 Erythrokeratodermas 71 Naxos syndrome 87
Harlequin ichthyosis 54 Erythrokeratoderma variabilis 71 McGrath syndrome 87
Autosomal dominant lamellar ichthyosis 55 Progressive symmetric erythrokeratodermia 73 Pachyonychia congenita type I 88
Congenital bullous ichthyosiform Keratitis-ichthyosis-deafness Pachyonychia congenita type II 88
erythroderma 55 syndrome 73 Tyrosinemia type II 89
Ichthyosis bullosa of Siemens 58 Hystrix-like ichthyosis with deafness 74 Carvajal Huerta syndrome 89
Linear epidermolytic epidermal nevus 59 Howell-Evans syndrome 90
Palmoplantar keratoderma 75 Schöpf-Schulz-Passarge syndrome 91
Epidermolytic acanthoma 59
Keratosis palmoplantaris diffusa
Focal epidermolytic hyperkeratosis 60
Vörner-Unna-Thost 76 Acquired palmoplantar keratoderma and
Peeling skin syndrome 60
Epidermolytic hyperkeratosis with polycyclic internal malignancy 91
Ichthyosis hystrix Curth-Macklin 60
psoriasiform plaques 77 Keratoderma climactericum 91
Congenital reticular ichthyosiform
Diffuse nonepidermolytic palmoplantar Clavus 91
erythroderma 61
keratoderma 77 Callus 91
Comèl-Netherton's syndrome 61
Progressive palmoplantar keratoderma 78 Acrokeratosis verruciformis of Hopf 91
Sjögren-Larsson syndrome 63
Keratolytic winter erythema 78 Porokeratosis 92
Conradi-Hünermann-Happle syndrome 65
Mal de Meleda 79 Hyperkeratosis lenticularis perstans 95
Other congenital ichthyotic Keratosis palmoplantaris areata Granular parakeratosis 96
syndromes 65 et striata 80 Circumscribed palmar or plantar
Follicular ichthyosis 66 Keratosis palmoplantaris nummularis 80 hypokeratosis 96
Ichthyosis follicularis with alopecia and Punctate palmoplantar keratoderma 81
photophobia 66 Keratosis punctata of the palmar creases 81
• Congenital ichthyoses present with collodion membrane or ichthyosiform

Ichthyosis erythroderma at birth or manifest within 4 weeks.
• Variants in which the skin lesions are but one facet of a more sinister
The term ichthyosis (Gr. ichthys, fish) is applied to a number of heterogenous systemic illness (syndromic ichthyosis).
genetic disorders characterized by permanent and generalized abnormal kera- The development of a diffuse ichthyosis-like scaling during life should not
tinization.1,2 The clinical features range from mild involvement, often passed be confused with ichthyotic skin disorders. These acquired ichthyosis-like
off as ‘dry skin’ (xerosis), through to severe widespread scaly lesions causing (ichthyosiform) skin conditions can be caused by different underlying dis-
much discomfort and social embarrassment (Fig. 3.1). The scales are often eases (see below). 4
shed as clusters rather than as single cells as is the norm.1 The pathogenesis of
the ichthyoses is very complex but ultimately depends upon two distinct final
common pathways: one relates to retention of corneocytes (e.g., ichthyosis
Ichthyosis vulgaris
vulgaris, recessive X-linked ichthyosis), the other involves epidermal hyper-
proliferation (e.g., congenital ichthyosiform erythroderma, bullous ichthyo- Clinical features
sis, Sjögren-Larsson syndrome and Refsum's disease).3 This relatively common disorder (incidence of 1:250 to 1:1000 births) has
Ichthyotic skin disorders are classified into the following groups3a an autosomal dominant mode of inheritance.1,2 It may present initially as
(Tables 3.1, 3.2): keratosis pilaris (follicular hyperkeratosis) on the arms, buttocks and thighs.
• Noncongenital ichthyoses develop 4 weeks after birth and spare flexures, The disease is usually fairly mild and becomes apparent within the first few
palms and soles. months or years of life. It affects the sexes equally and presents as dryness
Ichthyosis 47
Fig. 3.1
(A, B) Severe generalized ichthyosis: this was an
A B incidental finding at postmortem. Ichthyosis can be very
disfiguring and a considerable social disadvantage.
Table 3.1 those on the face and scalp. The rims of the ears are often scaly.3 There is sea-
Non-congenital ichthyoses sonal variation, with improvement of the condition in the summer months,
Isolated (nonsyndromic With associated symptoms particularly in humid climates.2 The palms and soles show increased palmar
ichthyosis) (syndromic ichthyosis) and plantar markings in contradistinction to sex-linked ichthyosis and may
Autosomal dominant ichthyosis Syndromes with steroid sulfatase also show mild hyperkeratosis.3 An association with keratosis punctata of
vulgaris deficiency the palms and soles has also been documented.4 Chapping of the hands and
feet can be a problem.5 There is no evidence of hair, nail, or teeth involve-
Recessive X-linked ichthyosis Multiple sulfatase deficiency
ment. There is an increased incidence of atopic disorders.5 Serum lipids are
Refsum's disease
normal.3
Table 3.2 Pathogenesis and histological features

Congenital ichthyoses Ichthyosis vulgaris is characterized by deficiency of profilaggrin, a major con-
stituent of the keratohyalin granules.6,7 Flaky tail mice, which represent an ani-
Isolated (nonsyndromic With associated symptoms
mal model of ichthyosis vulgaris, produce defective profilaggrin with resultant
ichthyosis) (syndromic ichthyosis)
absence of filaggrin.8 Ultrastructurally, the keratohyalin granules are reduced,
Autosomal recessive lamellar Comèl-Netherton's syndrome
spongy or crumbly and associated with decreased amounts of filaggrin.9 The
ichthyoses (nonbullous congenital Sjögren-Larsson syndrome
clinical severity of ichthyosis vulgaris correlates with the reduction of keratohy-
ichthyosiform erythroderma)
alin granules, which reflects a defective epidermal synthesis of filaggrin. Using
Harlequin ichthyosis Conradi-Hünermann-Happle fluorescein-labeled filaggrin antibodies demonstrates the severity of the defect
syndrome (chondrodysplasia (H. Traupe and V. Oji, unpublished observation). Filaggrin aggregates keratin
puncta type 2)
intermediate filaments in the lower stratum corneum and is subsequently prote-
Autosomal dominant lamellar Ichthyosis prematurity syndrome olyzed to form free amino acids including urocanic and pyrrolidone carboxylic
ichthyosis acids critical as water-binding compounds in the stratum corneum.
Bullous congenital ichthyosiform Gaucher syndrome, Type 2 Linkage analysis of the epidermal differentiation complex on chromosome
erythroderma Dorfman-Chanarin syndrome 1q21 has identified mutations in the gene encoding filaggrin. Parents with one
Ichthyosis bullosa of Siemens Trichothiodystrophy heterozygous filaggrin mutation may be asymptomatic, whereas affected off-
spring with two mutations often show classic ichthyosis vulgaris.10 Since the
Peeling skin syndrome Ichthyosis follicularis with atrichia filaggrin gene is a major susceptibility gene for atopic dermatitis, mutations
ichthyosis hystrix Curth-Macklin and photophobia
have also been shown in atopic dermatitis.11
Congenital reticular ichthyosiform Ichthyosis vulgaris is characterized by mild to moderate orthohyperkera-
erythroderma tosis associated with a hyperplastic, atrophic or normal epidermis. The key
feature is a thin or absent granular cell layer (Fig. 3.3).12,13 Regional vari-
ation in the thickness and/or presence of the granular cell layer may be a
(xerosis) and slight to moderate fine scaling, particularly involving the exten- feature and therefore it is best to take the biopsy from a site of maximal scal-
sor surfaces of arms and legs and characteristically sparing the flexures (Fig. ing. The lesions of keratosis pilaris show dilated follicles containing large
3.2). The light-gray scales vary in quality from thick adherent shiny plates keratin plugs. In the upper dermis a mild perivascular lymphocytic infiltrate
to simply dusty accumulations which, when scratched, leave a mark just as may be present. When ichthyosis vulgaris is associated with atopic dermatitis,
when one touches a dusty surface. The truncal lesions tend to be thicker than parakeratosis and other signs of a spongiotic dermatitis can be found.
Differential diagnosis
The histologic differential diagnosis includes other diseases character-
ized by orthohyperkeratosis and a reduced or absent stratum granulosum
(Table 3.3)
Table 3.3
Histologic patterns in ichthyotic skin disorders
Orthohyperkeratosis & stratum granulosum reduced or absent

Ichthyosis vulgaris (w/o atopic dermatitis)
Acquired ichthyosis-like condition
Refsum syndrome
Dorfman syndrome
Trichothiodystrophy syndrome
Fig. 3.2 Conradi-Hünermann-Happle syndrome
Ichthyosis vulgaris: Orthohyperkeratosis & stratum granulosum well developed
abdominal involvement
XR-ichthyosis
is most noticeable in this
AR-lamellar ichthyosis
patient. Sparing of the
Harlequin ichthyosis
flexures is characteristic
Acquired ichthyosis-like condition
of this variant of
(Lichen simplex chonicus)
ichthyosis. By courtesy
of W.A.D. Griffiths, MD, Hyperkeratosis with ortho- and parakeratosis and stratum granulosum
Institute of Dermatology, prominent
London, UK. AD-lamellar ichthyosis
Sjögren-Larsson syndrome
Inflammatory skin disease
Epidermolytic hyperkeratosis
Bullous ichthyotic erythroderma Brocq
Annular epidermolytic ichthyosis
Ichthyosis bullosa Siemens
Epidermal nevi
Epidermolytic acanthoma/leukoplakia
Epidermolytic palmoplantar keratoses
Incidental finding
Perinuclear vacuoles and binucleated keratinocytes
With parakeratosis:
Congenital reticular
Ichthyosiform erythroderma
With orthokeratosis:
Ichthyosis hystrix Curth-Macklin
A Differential diagnosis:
Epidermolytic ichthyoses (Keratin clumps !)
Follicular hyperkeratosis
Keratosis pilaris, lichen spinulosus, phrynoderma
Keratosis pilaris atrophicans
Ichthyosis vulgaris with follicular keratosis
Lamellar ichthyosis
Ichthyosis follicularis with alopecia and photophobia
Congenital atrichia
HID-, KID syndrome
Hereditary mucoepithelial dysplasia
Pachyonychia congenita
Ectodermal dysplasias
Darier's disease
Pityriasis rubra pilaris
Psoriasis-like features
Psoriasis vulgaris
Dermatophytosis
Comèl-Netherton's syndrome
B Annular epidermolytic ichthyosis
CHILD syndrome
Fig. 3.3 Papillon-Lefèvre syndrome
(A, B) Ichthyosis vulgaris: there is hyperkeratosis. The granular cell layer is absent.
Ichthyosis 49
X-linked recessive ichthyosis

Clinical features
Also known as steroid sulfatase deficiency and ichthyosis nigricans, this
X-linked, recessively inherited disorder has an incidence of 1:6000 male
births.1–3 The disease is exceedingly rarely expressed in females.4 Cutaneous
lesions tend to be more conspicuous and severe than in the autosomal dom-
inant variant.2 The scales are large and dark and are seen particularly on
the trunk, the extensor surface of the extremities, the scalp, the preauricular
region, and the neck (Figs 3.4–3.7).2 Mild Involvement of the flexures is also
present (Fig. 3.8).1 However, differentiation from ichthyosis vulgaris can be
difficult as some patients present with fine, light scales and the flexures may
be spared. The palms and soles are usually unaffected and keratosis pilaris is
not a feature. Involvement of the trunk and neck often gives the skin a dirty
appearance. Lesions may improve or disappear in warm weather.2 The hair,
nails, and teeth are not affected.
Corneal opacities due to comma-shaped deposits in the posterior capsule
of Descemet's membrane or corneal stroma, visible with slit-lamp exami-
nation (Fig 3.9), are characteristic and may be detected in female carriers.5 Fig. 3.5
Inadequate cervical dilatation may lead to prolonged delivery of affected Sex-linked ichthyosis: the scale is coarser than that seen in ichthyosis vulgaris.
male newborns. Undescended testes and hypogonadism can be a feature in By courtesy of the Institute of Dermatology, London, UK.
as many as 25% of affected patients.6–8 Rarely, testicular cancer has been
documented.6
Pathogenesis and histological features

The disease is associated with a deficiency of the microsomal enzyme, ste-
roid sulfatase/STS (sterol sulfate sulfohydrolase/arylsulphatase C).9 This is a
membrane-bound enzyme, which hydrolyses the 3-β-sulfate esters of choles-
terol and the sulfated steroid hormones.10 Absence of this enzyme is associ-
ated with persistence of the sulfate moiety on a number of sulfated steroid
hormones and cholesterol sulfate.3
X-linked recessive ichthyosis is characterized by a raised serum choles-
terol sulfate.10 The corneocytes contain excess cholesterol 3-sulfate and
diminished free sterol.11 Steroid sulfatase deficiency possibly results there-
fore in persistence of the lipid contents of the membrane-coating granules
and hence increased or persistent adhesion between adjacent keratin plates
in the stratum corneum. Beyond that, increased amounts of cholesterol sul-
fate may inhibit the epidermal serine protease activity, which results in reten-
tion of corneodesmosomes leading to less shedding of scales and retention
hyperkeratosis. Steroid sulfatase deficiency can be detected using the patient's
Fig. 3.6
Sex-linked ichthyosis: the scales are large and disfiguring. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.
eripheral leukocytes and cultured skin fibroblasts. Diagnosis may also be

p
affected by lipoprotein electrophoresis, which shows increased mobility of
low density and very low density beta-lipoproteins in addition to the steroid
sulfatase deficiency.12,13
The gene locus for recessive X-linked ichthyosis is within the Xp22.3
region of the X chromosome.14–16 Recently, indirect genotypic analysis using
polymorphic DNA markers closely linked to the STS gene has been shown
to be a reliable method of detection of the carrier status.14,17 Complete dele-
tions of structural STS gene have been reported in 90% of patients with
X-linked ichthyosis;14,16–19 the other 10% show partial deletions or point
mutations.1 Carrier status can also be confirmed by fluorescent in situ
hybridization (FISH) analysis.19 Recently, rapid diagnosis and differentia-
tion from ichthyosis vulgaris using polymerase chain reaction (PCR) has
been documented.20 Other important genes are located close to the steroid
sulfatase gene.
Fig. 3.4 Lesions show non-specific features of compact hyperkeratosis and slight
Sex-linked ichthyosis: there is severe involvement. Note the large, dark confluent acanthosis associated with a granular cell layer, which may be normal
scales. or increased in thickness (Fig. 3.10).21,22 Keratohyalin granules show no
Fig. 3.7
Sex-linked ichthyosis:
in this example the
scales appear dirty. This
can be an extremely
embarrassing condition.
By courtesy of the
Institute of Dermatology,
London, UK.
Fig. 3.9
(A) Sex-linked ichthyosis: characteristic linear opacities at the level of Descemet's
membrane. Slit-lamp photograph. (B) Same lesion viewed by specular microscopy.
By courtesy of R.J. Buckley, MD, Moorfield's Eye Hospital, London, UK.
Syndromes with steroid sulfatase

deficiency
A number of other important genes are located close to the steroid sulfatase gene.
If a deletion is larger, it may include some of these genes, producing a contigu-
ous gene syndrome.1 Two closely linked genes are those for Kallmann syndrome
(hypogonadotropic hypogonadism and anosmia) and X-linked recessive chon-
drodysplasia punctata.2 Possible linkage to a gene for hypertrophic pyloric steno-
sis has also been described.2 Thus patients may present with the skin changes of
X-linked recessive ichthyosis but with a whole spectrum of other problems.2
Fig. 3.8
Sex-linked ichthyosis: Multiple sulfatase deficiency
involvement of the
flexures is sometimes a
Multiple sulfatase deficiency is a severe neuropediatric disorder inherited as an
feature of this variant. By autosomal recessive. Patients develop normally for the first several years and
courtesy of the Institute then begin to show striking loss of mental capacity and motor abilities. They
of Dermatology, London, usually die before puberty. The ichthyosis is typically mild and the least of
UK. their problems. In multiple sulfatase deficiency patients the ichthyosis is simi-
lar to but usually less severe than in X-linked recessive ichthyosis. Therefore,
ichthyosis in a child with unexplained neurological symptoms should always
prompt measurement of steroid sulfatase levels.1
abnormality. Follicular plugging is not a feature. Paradoxically, biopsies of
thicker scales can show massive orthohyperkeratosis with reduction of the
granular layer and a thin epidermis, causing confusion with ichthyosis vul-
Refsum syndrome
garis. A discrete lymphocytic perivascular inflammatory cell infiltrate may
be evident. Clinical features
Ultrastructural features include a high number of transitional cells and an Refsum syndrome (hereditary motor and sensory neuropathy type 4, here-
abnormal persistence of desmosomal disks in the horny layer while keratohy- dopathica atactica polyneuritiformis, phytanic acid deficiency) is a rare type
alin granules are normal. An increased melanosome transfer accounts for the of an autosomal recessive syndromic ichthyosis.1 The skin changes appear
dark appareance of the scales.23 in childhood and are similar to those seen in ichthyosis vulgaris including
Ichthyosis 51
The more severe noneyrthrodermic phenotype of lamellar ichthyosis has an

estimated prevalence of 1:200 000–300 000. The infant is often born encased
in a thick ‘collodion’ plate-like shell of keratin (Figs 3.11, 3.12), and while
the term ‘collodion baby’ is most often applied to cases of lamellar ichthyosis,
similar appearances are sometimes found in a number of other disorders such
as autosomal dominant lamellar ichthyosis, Netherton's syndrome, Sjögren-
Larsson syndrome, trichothiodystrophy, and infantile cerebral Gaucher
syndrome.3,4 Hence, colloidon baby is a clinical description but not a dis-
ease. Within a few days the shell is shed to reveal a mild erythroderma with
Fig. 3.11
Autosomal recessive
lamellar ichthyosis: the
collodion membrane
is best seen on the
forehead. There is scaling
and erythema on the
trunk. By courtesy of
B
R.A. Marsden, MD,
St George's Hospital,
Fig. 3.10 London, UK.
(A, B) Sex-linked ichthyosis: there is hyperkeratosis and mild acanthosis. The
granular cell layer is normal.
hyperlinear palms. Due to lipid storage, melanocytic nevi may show a yellow
hue. Associated symptoms include loss of vision from retinitis pigmentosa,
in which night blindness is often the first problem, anosmia, cardiac arrhyth-
mias, and a whole spectrum of neurological problems including bilateral
sensorineural deafness, cerebellar ataxia, and peripheral polyneuropathies.2

Refsum syndrome is generally caused by a mutation in a gene encoding
perioxisomal phytanol-CoA hydroxylase, although it can also be caused by
specific mutations in the peroxisomal receptor gene PEX7.3,4 Peroxisomes are
involved in the metabolism of bile acid and cholesterol biosynthesis. Elevated
levels of phytanic acid in plasma and tissue are diagnostic. Low-phytol diet
is mandatory.5
Routine histology of a skin biopsy does not differ from ichthyosis vulgaris.
When a biopsy is fixed in alcohol and a Sudan stain performed, lipid drop-
lets are found in the keratinocytes, in particular in biopsies from melanocytic
nevi. The same inclusions can be shown by ultrastructural examination.6 Fig. 3.12
Autosomal recessive
lamellar ichthyosis: note
Autosomal recessive lamellar ichthyoses the erythema. The skin
is shiny, taut, and shows
Clinical features fissuring around the
anterior aspect of the
Autosomal recessive lamellar ichthyoses include a group of mostly mono- ankle. By courtesy of D.
genetic disorders presenting at birth with generalized hyperkeratosis and Atherton, MD, Children's
scaling (ichthyosis congenita). The clinical presentation varies considerably Hospital at Great Ormond
in severity and clinical course.1–5 Street, London, UK.
g eneralized scaling (Fig. 3.13). In nonerythrodermic phenotype of lamellar described including ichthyosis, keratinization, hyper- and parakeratosis, and
ichthyosis the scales are large, dark and platelike and cover the entire body papilla development. The teeth are not affected.3
including the palms, soles, scalp, and flexures.5–8 Fissuring of the hands and In contrast, other individuals show a more pronounced erythroderma
feet occurs and the skin around the joints may become verrucous. There is with fine, white scaling (non-bullous congenital ichthyosiform erythroderma,
often associated difficulty with sweating, and hyperpyrexia may be a feature.7 NCIE). A collodion membrane is often present at birth.1 After shedding, the
There is nail dystrophy, hair involvement (scarring alopecia), severe ectro- infant typically presents with an intense generalized erythroderma.2 While
pion (up to 80% of patients) and eclabium are characteristic (Fig. 3.14). The platelike scales may be seen on the extensor surfaces of the legs, the scalp,
ectropion is of the cicatricial type and develops as a consequence of exces- face, upper extremities and trunk are covered with fine white scaling (Figs
sive dryness and associated contracture of the anterior lamella of the eye- 3.15–3.20).8 Mild ectropion and eclabium may be complications and palmo-
lid. Complications include corneal ulceration, vascularization, and corneal plantar keratoderma is often more severe than in noneyrthrodermic forms of
scarring with eventual blindness.9 Primary conjunctival lesions have also been AR-lamellar ichthyosis.3 Exceptionally, congenital ichthyosiform erythroderma
has been associated with retinitis pigmentosa.10 There is an increased risk of
developing skin cancer including basal and squamous cell carcinoma.11
Fig. 3.13
Autosomal recessive
lamellar ichthyosis:
note the widespread
Fig. 3.15
and prominent large
Nonbullous congenital
dark brown scales. By
ichthyosiform
courtesy of D. Atherton,
erythroderma: there is
MD, Children's Hospital
intense erythema and fine
at Great Ormond Street,
scaling is also present.
London, UK.
The scalp hair is sparse
and the eyebrows are
absent. By courtesy of
D. Atherton, MD, Children's
Hospital at Great Ormond
Street, London, UK.
Fig. 3.14
Autosomal recessive
lamellar ichthyosis: in
this infant, there is gross
ectropion and eclabion.
By courtesy of D. Atherton, Fig. 3.16
MD, Children's Hospital Nonbullous congenital ichthyosiform erythroderma: there is marked erythema with
at Great Ormond Street, severe scaling. Blistering is not seen in this variant of ichthyosis. By courtesy of
London, UK. D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK.
Ichthyosis 53
Fig. 3.17 Fig. 3.19

Nonbullous congenital ichthyosiform erythroderma: there is intensive erythema and Nonbullous congenital ichthyosiform erythroderma: the scales are large, thick and
fine scaling. By courtesy of the Institute of Dermatology, London, UK. white. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.20
Nonbullous congenital ichthyosiform erythroderma: there is severe palmar
involvement and constriction bands are evident. By courtesy of the Institute of
Dermatology, London, UK.
Other variants of transglutaminase mutations are characterized by dis-

tinct clinical features. In self-healing collodion baby the transglutaminase-1
mutation is pressure-sensitive so that while in utero the enzyme cannot
Fig. 3.18 function properly, it resumes normal function after birth. About 10% of
Nonbullous congenital ichthyosiform erythroderma: there is generalized platelike collodion babies fall into this group.19 In bathing suit ichthyosis (BSI) the
scaling. By courtesy of the Institute of Dermatology, London, UK. mutation in transglutaminase-1 appears to be temperature sensitive so that
the face and extremities are almost completely spared apart from skin areas
overlaying blood vesssls. Digital thermography has validated a striking cor-
Pathogenesis and histological features relation between warmer body areas and the presence of scaling, suggesting
The most common cause of lamellar ichthyosis is transglutaminase-1 deficiency a decisive influence of the skin temperature. In situ TGase testing in skin
which accounts for 30–40% of cases. Mutations in the transglutaminase-1gene of BSI patients has also demonstrated a marked decrease of enzyme activity
result in markedly diminished or lost enzyme activity and/or protein. In some when the temperature is increased from 25 to 37 degrees Celsius.20
cases, this enzyme is present but there is little detectable activity, and in other The second most common mutation in lamellar ichthyosis can be found
clinically similar cases, transglutaminase-1 levels appear to be normal.12–17 in the binding cassette protein.21,22 Missense mutations cause lamellar ich-
Since conventional enzyme assays and mutational analyses are tedious, an thyosis while deletions are responsible for the far more dramatic harlequin
assay for the rapid screening of transglutaminase-1 activity using covalent fetus.23 Mutations in either transglutaminase-1 or the lipoxygenases are most
incorporation of biotinylated substrate peptides into skin cryostat sections often responsible for the nonbullous congenital ichthyosiform erythroderma
has been developed.18 Coupled with immunohistochemical assays using phenotype. The ichthyin mutation also usually produces nonbullous con-
transglutaminase-1 antibodies, this allows rapid identification of those cases genital ichthyosiform erythroderma (Table 3.4).24–28 Attempts to refine the
caused by alterations in this enzyme.18 classification of non erythrodermic and erythrodermic phenotypes by the use
Table 3.4
Types of autosomal recessive lamellar ichthyosis (LI)
Type Locus Gene Protein Defect

LI 1 14q11 TGM1 Transglutaminase-1 Impaired cross-linking of proteins and
lipids to the cornified cell envelope
LI 2 2q34 ABCA12 ATP binding cassette Abnormal lamellar body function and
lipid trafficking
LI 3 / LI 4 19p12-q12 FLJ39501 Cytochrome P450 family protein Epidermal lipid metabolism
LI 5 17p13 ALOX12B 12R-lipoxygenase Epidermal lipid metabolism
ALOXE3 Lipoxygenase-3
LI 6 5q33 ICHYN Ichthyin Transmembrane protein
of clinical, biochemical, and ultrastructural observations have so far failed to is occasionally a feature.4 Dilatation and tortuosity of the dermal capillaries is
yield a consistent scheme.29–31 This difficulty is illustrated by the fact that the sometimes evident. Follicular hyperkeratosis may occasionally be seen.
same transglutaminase-1 mutation can give rise to different phenotypes.31 Ultrastructural studies show a variety of features including defective devel-
Histologically, the epidermis in autosomal recessive lamellar ichthyosis opment of the cornified cell envelopes and electron-dense debris adjacent to
shows marked hyperkeratosis (which may be extreme in the collodion baby) the plasma membranes, cholesterol clefts, lipid vacuoles, increased numbers
and mild acanthosis with a normal or thickened granular cell layer (Fig. 3.21). of small and dysmorphic lamellar bodies, elongated membrane structures,
The hyperkeratosis is much less marked in erythrodermic than in noneryth- or membrane packages.32–34 Prenatal diagnosis of lamellar ichthyosis can be
rodermic forms. Epidermal papillomatosis associated with a psoriasiform achieved by fetoscopy and biopsy.35
appearance has also been documented. A perivascular lymphocytic infiltrate
Clinical features
Harlequin ichthyosis (harlequin fetus, ichthyosis fetalis, ichthyosis congenita
gravis) is an extreme and rapidly fatal subtype, where babies are born with
a fissured ‘armor-plated’ skin (Fig. 3.22).1–4 Ectropion and eclabium are fre-
quent complications, and the ears and nose are often malformed.2 Harlequin
fetus has a very high mortality due to respiratory and feeding difficulties
accompanied by excessive fluid loss.3 Sometimes, treatment by retinoids and
intensive care is successful. Long-term survivors, following shedding of the
scales, develop a severe erythroderma reminiscent of nonbullous ichthyosi-
form erythroderma.5 Fortunately, antenatal diagnosis is possible.6,7

This very rare form of ichthyosis is due to an apparently dramatic loss of
function of the lamellar bodies, which results from nonsense mutations in
the ABCA12 gene. Less severe missense mutations cause a variant of lamellar
ichthyosis. This indicates that a severely truncated protein is the molecular
cause of Harlequin ichthyosis.8 The ATP-binding cassette (ABC) transporter
A
family encompasses a variety of membrane proteins involved in the energy-
dependent transport across membranes. In the epidermis, ABCA12 may have
an important function for the lamellar bodies, through exocytosis traffic of
lipids or proteases across the apical keratinocyte membrane.
The lesions are characterized by massive hyperkeratosis (sometimes
with lipid deposits) associated with a normal or absent granular cell layer
(Fig. 3.23). The hair follicles are usually affected first, during the second tri-
mester.2,7 Parakeratosis may also sometimes be evident.9 Acanthosis is often
marked and papillomatosis is sometimes a feature. A sparse mixed inflamma-
tory cell infiltrate can be present in the superficial dermis.7
Ultrastructurally, the harlequin fetus has recently been shown to be associated
with deficient or morphologically abnormal lamellar bodies (including concen
trically lamellated forms) and deficient intercellular lipid lamellae within the
stratum corneum.1,2,9 Small vesicles, devoid of internal lamellation, may be pres-
ent in the granular cell layer (and retained in the stratum corneum), but show no
association with the keratinocyte cell membranes as is typical of normal lamel-
lar bodies.1,9 Recent immunohistochemical evidence suggests that these vesicles
represent abnormal lamellar bodies characterized by an inability to discharge
B their lipid contents into the intercellular space. Keratin and filaggrin expression
have also been shown to be defective.2 In the harlequin fetus, the keratinocytes
Fig. 3.21 may display the hyperproliferative keratins K6 and K16 and show an inability to
Autosomal recessive lamellar ichthyosis: (A) there is very marked hyperkeratosis convert profilaggrin to filaggrin.2 The results of ultrastructural and biochemical
and the epidermis shows papillomatosis; (B) high-power view. analyses suggest that the harlequin fetus is a heterogeneous condition.
Ichthyosis 55
Fig. 3.22
(A, B) Harlequin ichthyosis: the most extreme form
of congenital ichthyosis. There is an exceedingly high
A B mortality. The scales are very thick and are often referred to
as armor-plating.
Histologically, there is an acanthosis, papillomatosis, and compact ortho-

hyperkeratosis with focal parakeratosis that, paradoxically, is associated with
a thickened stratum granulosum (Fig. 3.24).2
Electron microscopy shows a high number of transitional cells and a
spongy appearance of the keratohyaline granules.2
The differential diagnosis includes lichen simplex chronicus which, however,
differs by the presence of inflammatory changes and fibrosis of the papillary
dermis (see Table 3.3).
Congenital bullous ichthyosiform

erythroderma
Clinical features
Congenital bullous ichthyosiform erythroderma (also known as epidermo-
lytic hyperkeratosis, bullous ichthyosis, bullous ichthyosiform erythroderma of
Brocq) is a very rare disease (incidence of 1:300 000 births) and, although some-
Fig. 3.23 times inherited by an autosomal dominant mode, it more often appears to arise
Harlequin ichthyosis: there is massive hyperkeratosis associated with a by spontaneous mutation. At birth the infant may show marked hyperkerato-
conspicuous granular cell layer and a papillomatous epithelium. The dilated spaces sis, erythroderma, or even present as a collodion baby. Although the scales are
in the stratum corneum represent dilated ostial of eccrine ducts. By courtesy of soon lost, leaving a generalized moist, tender erythroderma, re-epithelialization
M.M. Black, MD, Institute of Dermatology, London, UK. leads to further scale production followed by the development of widespread
blistering (Fig. 3.25) which heals without scarring. As the patient becomes
Autosomal dominant lamellar ichthyosis older, the erythema and blistering become less apparent and, later, the disease is
complicated by the development of verrucous hyperkeratosis, especially in the
flexures (Figs 3.26–3.31). In some cases, the scales have been said to assume
Clinical features a porcupine quill-like appearance (ichthyosis hystrix) and scalp involvement
Autosomal dominant lamellar ichthyosis is characterized by generalized scal- may simulate tinea capitis.1 The nape, axilla, groin, and flexural folds are sites
ing with palmoplantar keratoderma.1 Patients may present as a collodion of predilection. Occasional blisters still arise, often in summertime and at sites
baby. They are later covered by diffuse dark-gray scales that involve all areas of pressure. In patients with keratin 1 but not with keratin 10 mutations, pal-
of the body but are most prominent on the extensor surfaces. Backs of the moplantar keratoderma is often present. Nail dystrophy may sometimes be a
hands and feet are characterized by lichenification. There may be massive feature. The patients suffer from an offensive body odor. Congenital bullous
plantar hyperkeratosis with thick, yellow scales. The palms are usually only ichthyosiform erythroderma is associated with considerable morbidity and sig-
minimally involved and show accentuated markings.1 nificant mortality due to sepsis, fluid loss, and electrolyte imbalance.1
A nevoid variant in which the lesions follow Blaschko's lines is also rec-
Pathogenesis and histological features ognized.2 In the past, such lesions may have been mistaken for epidermal
This disorder appears to be genetically and clinically heterogeneous and of nevi showing epidermolytic hyperkeratosis. Due to the possibility of gonadal
variable penetrance. Its genetic defect has not been identified. Biochemically, mutations, children of affected patients with the nevoid variant may develop
an abnormal lipid profile has been detected in the scales.2 generalized congenital bullous ichthyosiform erythroderma
Fig. 3.26
Congenital bullous
ichthyosiform
erythroderma:
Hyperkeratosis and scales
follow re-epithelialization
of widespread blistering.
Fig 3.24
(A, B) Autosomal dominant lamellar ichthyosis: in this example there is marked
compact hyperkeratosis. The granular cell layer is prominent and there is focal
parakeratosis.
Fig. 3.27
Congenital bullous
ichthyosiform
erythroderma: adult
showing very generalized
scaling, particularly
severe on the legs. By
courtesy of the Institute
of Dermatology, London,
UK.

There is considerable evidence in the recent literature confirming that con-
genital bullous ichthyosiform erythroderma represents a genetic disorder of
Fig. 3.25 keratin expression associated with hyperproliferation of the epidermis.5,6 In
Congenital bullous ichthyosiform erythroderma: close-up view of an infant showing the skin, basal keratinocytes predominantly express keratin 5 and 14, while
intense erythema and blistering. By courtesy of M. Liang, MD, The Children's suprabasal cells switch to the expression of keratin 1 and 10. Keratin mono-
Hospital, Boston, USA. mers form obligate heterodimers in pairs of acidic (type I) and basic (type
II) keratins, which assemble into keratin intermediate filaments building a
An annular variant has also been described. Patients may have mild eryth- cytoskeleton for the structural stability and flexibility of epidermal cells.
roderma and blisters at birth, but the characteristic feature is the presence of Transgenic mouse studies using a truncated human keratin 10 gene have
many annular gray hyperkeratotic plaques with a peripheral erythematous been shown to result in the pathobiological and biochemical phenotype of
border. 3,4 epidermolytic hyperkeratosis.7 Epidermolytic hyperkeratosis shows linkage
Ichthyosis 57
Fig. 3.28
Congenital bullous Fig. 3.30
ichthyosiform Congenital bullous
erythroderma: same ichthyosiform
patient as Figure erythroderma: blistering
3.27, showing elbow may sometimes be seen
involvement. By courtesy in adulthood. By courtesy
of the Institute of of the Institute of
Dermatology, London, UK. Dermatology, London, UK.
Fig. 3.31
Fig. 3.29 Congenital bullous
Congenital bullous ichthyosiform erythroderma: the hands are particularly affected. ichthyosiform
By courtesy of the Institute of Dermatology, London, UK. erythroderma: adult
showing very severe
verrucous flexural scaling.
By courtesy of R.A.J.
to the keratin gene cluster either on chromosome 12q11–13 (type II keratin) Eady, MD, Institute of
or chromosome 17q21-q22 (type I keratin).8–10 Direct sequencing of keratin Dermatology, London, UK.
1 and 10 genes has identified point mutations in a number of affected fami-
lies.11–17 Most mutations are missense and clustered at the ends of the central
helical rod domains. Keratin 1 mutations are associated with severe pal-
moplantar hyperkeratosis while keratin 10 mutations are not because kera- formation may be present. There is massive orthohyperkeratosis, papillo-
tin 10 is physiologically substituted by keratin 9 on palmoplantar skin.15 matosis, and acanthosis. The granular cell layer is prominent and contains
Mutations in the keratin 1 or 10 gene exhibiting mosaicism explain the coarse and irregular keratoyhaline granules (Fig. 3.32).
nevoid variant of congenital bullous ichthyosiform erythroderma.18,19 The By immunohistochemistry, epidermolytic hyperkeratosis shows a normal
annular variant shows minor mutations in keratin 1 or 10 genes on distinct distribution pattern of keratins 5/14 and 1/10, but in addition there is over-
keratin domains.4 expression of keratin 14 in the suprabasal epithelium accompanied by quite
The histological features are known as epidermolytic hyperkeratosis or marked labeling of the upper epithelial layers by keratin 16, as would be
granular degeneration and are very striking.20,21 Suprabasal keratinocytes expected in a hyperproliferative state.5,22
appear vacuolated and typically contain distinct eosinophilic intracytoplas- Ultrastructural studies have shown that the intracytoplasmic inclusions
mic inclusions. The cell borders are ill defined and intraepidermal blister seen on light microscopy are composed of abnormally aggregated keratin
Fig. 3.33
Congenital bullous
ichthyosiform
erythroderma: striking
perinuclear keratin
clumping is evident.
By courtesy of R.A.J.
Eady, MD, Institute of
Dermatology, London,
A UK.
Ichthyosis bullosa of Siemens

Clinical features
Ichthyosis bullosa of Siemens is inherited as an autosomal dominant. The
condition, which is milder than congenital bullous ichthyosiform eryth-
roderma, presents at birth with blistering subsequently replaced by dark
lichenified hyperkeratosis of the limbs, predominantly affecting the flexures
and shins (Fig. 3.34).1,2 The skin remains fragile and blisters on mild trauma,
giving rise to characteristic superficial peeling with a molting-like appearance
(Mauserung phenomenon) (Fig. 3.35).2,3 Symptoms usually improve with
age. Erythroderma is typically absent. Rarely, pustulation and hypertrichosis
may be additional features.3,4 There is considerable clinical overlap between
ichthyosis bullosa of Siemens and congenital bullous ichthyosiform
erythroderma, and their distinction can best be achieved by molecular genetic
B analysis.
Fig. 3.32
Congenital bullous ichthyosiform erythroderma: (A) there is massive hyperkeratosis
and acanthosis. The epidermis shows conspicuous superficial vacuolation which has
resulted in vesiculation, (B) there is intracellular edema, and irregular eosinophilic
granules (representing dense abnormal aggregates of keratin filaments) are present
in the superficial layers of the epidermis.
filaments. Since large areas of the cytoplasm lack a regular keratin skeleton,
the suprabasal keratinocytes appear vacuolated and contain irregular kera-
toyhaline granules. Impairment of desmosome-keratin complexes accounts
for the fragility of the epidermis (Fig. 3.33).18 These ultrastructural changes
may form the basis of prenatal diagnosis including amniotic fluid squame
analysis.20,21
Immunoelectron microscopy has identified that the keratin clumps are
composed of keratins 1 and 10.22
Epidermolytic hyperkeratosis is a histopathologic pattern that is seen in
many conditions including ichthyosis bullosa of Siemens, epidermal nevus,
epidermolytic keratoderma, epidermolytic acanthoma, and epidermolytic
leukoplakia (see Table 3.3). It may also represent an incidental finding in
seborrheic keratosis, actinic keratosis, in situ squamous cell carcinoma, inva-
sive squamous cell carcinoma, melanocytic nevi, and epidermal and pilar Fig. 3.34
Bullous ichthyosis
cysts.23 Epidermolytic hyperkeratosis may also be seen in normal and par-
Siemens: flexural
ticularly actinically damaged skin. In such incidental lesions, the changes are hyperkeratosis with early
limited to the epidermis overlying just one or two dermal papillae in contrast blister formation.
to the much more extensive involvement of the other conditions mentioned By courtesy of W.A.D.
above. Therefore, accurate clinical information is necessary to avoid diagnos- Griffiths, MD, Institute of
tic confusion. Dermatology, London, UK.
Ichthyosis 59
Fig. 3.35
Bullous ichthyosis Siemens: marked hyperkeratosis is present over the knees.
By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.

Bullous ichthyosis is associated with a point mutation in the keratin 2e gene
on chromosome 12q11-q13.4–9 Since this keratin is not expressed on volar
skin, palmoplantar keratoderma does not develop.
Histologically and by electron microscopy, the features are indistinguish-
able from congenital bullous ichthyosiform erythroderma except that they
are milder and the vacuolation of the keratinocytes and cytoplasmic inclu-
sions are restricted to the more superficial prickle and granular cell layers
as opposed to involving almost the entire epidermis as is typical of the latter
condition. Subcorneal separation may be evident.10
B
Linear epidermolytic epidermal nevus Fig. 3.36

Linear verrucous epidermal nevi occasionally show the features of epi- Linear epidermolytic epidermal nevus: (A) low-power view showing massive
dermolytic hyperkeratosis (Fig 3.36). Some patients with such a lesion, hyperkeratosis and papillomatosis (B) high-power view showing epidermolytic
hyperkeratosis.
although by no means all, in reality suffer from the nevoid variant of con-
genital bullous ichthyosiform erythroderma.1–4 It is therefore important that
patients with apparent epidermolytic epidermal nevi are offered genetic
counseling.
Epidermolytic acanthoma
Clinical features
Isolated epidermolytic acanthoma (also termed disseminated epidermolytic
acanthoma) is an acquired lesion that presents as a verrucous papule or
plaque approximately 1.0 cm in diameter and sometimes resembles a viral
wart, nevus or seborrheic keratosis.1–3 Lesions may present at any site, but
the scrotum, head, neck, and leg are particularly affected.2,3 Although usually
solitary, occasional patients may present with multiple localized or dissemi-
nated lesions.4–8 Variants affecting the mucosae of the oral cavity and female
genital tract have also been documented.9,10 Caucasians and the Japanese are
predominantly affected.3
Pathogenesis and histological features Fig. 3.37

Although not proven, it has been suggested that epidermolytic acanthoma Epidermolytic acanthoma: the lesion is papillomatous with massive hyperkeratosis.
develops as a consequence of keratin 1 and 10 gene mutation.3 There is a superficial perivascular chronic inflammatory cell infiltrate.
The lesion is characterized by hyperkeratosis, parakeratosis, acanthosis,
and papillomatosis (Fig. 3.37).1,2 The upper prickle cell and granular cell lay- Epidermolytic acanthoma displays diminished expression of keratins
ers show features of epidermolytic hyperkeratosis (i.e., marked vacuolation 1 and 10 and increased expression of the hyperproliferative keratins 6
of the keratinocytes with eosinophilic keratin inclusions) (Fig. 3.38). and 16.3
Fig. 3.38 Fig. 3.39

Epidermolytic acanthoma: there is superficial cytoplasmic vacuolation and Peeling skin syndrome: Erythematous lesions show peeling of the skin leaving
eosinophilic inclusions are conspicuous. superficially denuded red patches. By courtesy of H.Traupe MD and V.Oji MD,
Department of Dermatology, Munster, Germany.
Identical histological changes are seen in congenital bullous ichthyosiform
erythroderma, linear epidermolytic epidermal nevus, epidermolytic palmo-
plantar keratoderma, and in focal epidermolytic hyperkeratosis (see Table
3.3). Clinical information is usually necessary to avoid diagnostic confusion.
Focal epidermolytic hyperkeratosis

Focal epidermolytic hyperkeratosis (incidental epidermolytic hyperkeratosis)
represents a non-specific finding of epidermolytic hyperkeratosis in the epi-
dermis overlying or adjacent to an unrelated lesion. It is very common and
has been described, for example, in seborrheic keratoses, overlying scars and
fibrous histiocytoma, in banal and dysplastic nevi, actinic keratosis, squamous
cell carcinoma in situ, and melanoma. It may also be seen in normal skin. 1–5
Peeling skin syndrome

Clinical features
Peeling skin syndrome (familial continual skin peeling, keratolysis exfoliativa Fig. 3.40
congenitale) is characterized by a spontaneous, lifelong peeling of the stratum Peeling skin syndrome:
corneum without bleeding or pain.1–6 The mode of inheritance is autosomal The skin of the backs
of hand and feet shows
recessive.1 Three types can be distinguished:
reddish scaly patches. By
• In type A a generalized continued shedding or peeling of the entire skin courtesy of H.Traupe MD
without signs of inflammation or other symptoms is present from birth and V Oji MD, Department
or develops during childhood (Fig. 3.39).2 of Dermatology, Munster,
• Type B appears, resembles and is characterized by isolated erythematous Germany
lesions which then peel, leaving burning superficially denuded red
patches with a peripheral collarette.3 Only recently a mutation of
corneodesmosin has been identified.3a
• In type C (acral peeling skin syndrome), involvement is confined to the backs Ichthyosis hystrix Curth-Macklin
of the hand and feet (Fig. 3.40).4,5 A homozygous missense mutation in the
gene of transglutaminase-5 has been identified in two unrelated families.6 Clinical features
‘Ichthyosis hystrix’ is a descriptive name for cornification disorders with spiny
Histological features and dark hyperkeratosis. Ichthyosis hystrix Curth-Macklin is characterised
• In type A, histology shows a plane of separation either within the lower by generalized verrucous plaques, involving the entire trunk, the flexural sur-
part of an otherwise normal horny layer or above the granular cell faces of the extremities and the palms and soles. The autosomal dominant
layer. Ultrastructural analysis reveals an intracellular splitting within the disorder sometimes resembles bullous ichthyosiform erythroderma, but there
corneocytes.2 is no clinical or histological evidence for blistering. 1–3
• In type B, the epidermis is psoriasiform with an absent or reduced
granular cell layer and marked parakeratosis. The split occurs at the level Pathogenesis and histological features
of the granular cell layer.3 Recent evidence suggests that in ichthyosis hystrix Curth-Macklin a mutation
• In type C peeling skin syndrome, the horny layer is detached from the in a keratin gene affecting the variable tail domain (V2) of keratin 1 results
stratum granulosum (Fig. 3.41).4,5 in a failure in keratin intermediate filament bundling and retraction of the
Ichthyosis 61
Fig. 3.41
Peeling skin syndrome: the biopsy is taken from the edge of the lesion. Note that
the stratum corneum is clearly separated from the underlying epidermis.
cytoskeleton from the nucleus.2 This is the first in vivo evidence for the crucial
role of a keratin tail domain in supramolecular keratin intermediate filament
organization and barrier formation.2
Histologically, the epidermis is acanthotic and orthohyperkeratotic. The
suprabasal keratinocytes are vacuolated and a few of them appear binucleated.
In contrast to epidermolytic hyperkeratosis, eosinophilic intracytoplasmic
inclusions are not present.4
The significant ultrastructural observation in ichthyosis hystrix Curth-
Macklin is the presence of perinuclear concentric shells of tonofilaments. In
contrast to keratin mutations of the rod domain in epidermolytic hyperkera-
tosis, aggregations and clumping of keratin filaments are absent.4
Congenital reticular ichthyosiform B

erythroderma
Fig. 3.42
Ichthyosis variegata: (A) there is hyperkeratosis and well-developed psoriasiform
Clinical features hyperplasia; (B) there is parakeratosis with prominent nuclei. Note the cytoplasmic
Congenital reticular ichthyosiform erythroderma is a rare inherited disorder vacuolation. Eosinophilic intracytoplasmic inclusions are absent.
of keratinization.1 Since only sporadic cases have been recognized, the mode of
inheritance is unknown. Most of the patients have been female. The patients an apoptotic mode of cell death.9 Uptake and processing of melanosomes is
are born with congenital ichthyosiform erythroderma. During childhood the irregular. The basic genetic defect in congenital reticular ichthyosiform eryth-
integument clears gradually so that enlarging patches of normal skin appear roderma is due to dominant mutations is keratin 10 that causes mislocalisa-
to be enclosed by erythrokeratotic and hyperpigmented areas in a reticular tion to the nucleolus and disruption of the keratin filament network.9,10
arrangement. Because of this clinical appearance the genodermatosis has also
been termed ichthyosis ‘en confettis’ or, more precisely, ichthyosis variegata.2–8 Differential diagnosis
Associated features are hypertrichosis, and palmoplantar hyperkerato-
The absence of keratin clumping clearly distinguishes congenital reticular
sis, and, in single cases, hypogonadism, growth retardation, hepatomegaly,
ichthyosiform erythroderma from keratinization disorders characterized by
keratoacanthoma or squamous cell carcinoma.1,5,7
epidermolytic hyperkeratosis. Ichthyosis hystrix Curth-Macklin shares the
intraepidermal formation of binucleate, vacuolated keratinocytes but lacks
parakeratosis and shows formation of perinuclear shells of tonofibrils (see
Histologically, the epidermis is pale staining and there is psoriasiform hyper- Table 3.3).
plasia. The horny layer is thickened and parakeratotic. The parakeratotic
corneocytes have enlarged nuclei. The keratinocytes of the upper layers show
prominent perinuclear vacuolation and contain few keratohyalin granules.
Comèl-Netherton's syndrome
Their cell borders are well defined and intracytoplasmic eosinophilic granules
are absent. Some of the vacuolated keratinocytes are binucleate (Fig. 3.42). Clinical features
The dermal vessels are dilated, and there is a sparse perivascular inflamma- Comèl-Netherton's syndrome (Netherton's syndrome, ichthyosis linearis cir-
tory cell infiltrate with scattered melanophages. cumflexa) is a rare genodermatosis inherited as an autosomal recessive. It
While keratin 2e is missing, the other epidermal keratins are regularly is characterized by the triad of congenital ichthyosiform erythroderma, hair
expressed. At the ultrastructural level the arrangement of the keratin skeleton shaft anomalies, and a severe atopic diathesis with high IgE blood levels and
is highly disturbed. Immuno-electron microscopy reveals complete absence eosinophilia.1 It is believed to affect approximately 1:200 000 of the pop-
of keratin filaments in the perinuclear cytoplasm.1–3 The number of transi- ulation.2 Generally, the congenital ichthyosiform erythroderma gradually
tional cells is increased and nick end labeling (TUNEL) for DNA fragmenta- evolves into a milder ichthyosis linearis circumflexa which is characterized
tion shows strong labeling of the parakeratotic corneocytes consistent with by an erythematous, scaly rash predominantly affecting the trunk and limbs.3
It is composed of polycyclic, migratory, annular and serpiginous lesions Patients with Netherton's syndrome may in addition suffer from life
with characteristic two parallel lines of scale at the periphery, the so-called threatening neonatal dehydration with hypernatremia, failure to thrive, and
double-edged scale (Figs 3.43–3.45). In infancy, erythema and scaling may recurrent skin infections often caused by Staphylococcus aureus,4,8,9 amino-
be widespread, but later the face is often predominantly affected (particularly aciduria,5 mental retardation,5,7 and immune defects.1,5 An impaired epider-
marked around the mouth and eyes), along with the perineum,4 and as such mal barrier is a potential risk for increased and even toxic absorption of
the eruption can be mistaken for acrodermatitis enteropathica (Fig. 3.46).1 topical medications.
Later the scalp, face, and eyebrows may show a yellowish scaling.5 Ichthyosis
linearis circumflexa is typically nonpruritic,5 and the nails and teeth are not Pathogenesis and histological features
involved.3 Rarely, infants may also show palmoplantar hyperkeratosis.6 Netherton's syndrome results from mutations in the SPINK5 gene which
Comèl-Netherton's syndrome is often misdiagnosed as seborrheic dermatitis, has been localized to 5q32.10,11 Nonsense, frameshift deletions and inser-
atopic dermatitis, and psoriasis vulgaris. tions and splice site defects resulting in premature termination codons and
Trichorrhexis invaginata (due to a transient and repeated defect of ker-
atinization, with resultant hair shaft intussusception)7 presents clinically as
coarse and lusterless hair, which is short, brittle, and fragile (Fig. 3.46). Pili
torti and trichorrhexis may also be evident (Fig. 3.47).5
Fig. 3.45
Fig. 3.43 Comèl-Netherton's
Comèl-Netherton's syndrome: ichthyosis linearis circumflexa. Note the serpiginous syndrome: there is
lesions with characteristic double border. By courtesy of M. Judge, MD, Institute prominent involvement of
of Dermatology, London, UK. the trunk and limbs.
Fig. 3.44
Comèl-Netherton's syndrome: (A) hyperkeratotic lesions
may sometimes be prominent; (B) note the focal loss of the A B
polycyclic pattern.
Ichthyosis 63
Fig. 3.46
Comèl-Netherton's syndrome: (A) there is profound
erythema with scaling; (B) the hair is dull and appears short
and thin. The eyebrows are deficient. (A) By courtesy of M.
Judge, MD, Institute of Dermatology, London, UK,
A B (B) By courtesy of A. Griffiths, MD, Institute of
Sudan black positive and are thought to represent an influx of serum exu-
dates resulting from the accompanying dermal inflammation.4 Similar ‘inclu-
sions’ have been described in psoriasis and atopic eczema16 and as such they
are not specific. Rarely, the parakeratotic scale may be associated with the
presence of Munro microabscesses.6 Biopsies from the center of the lesion
shows the features of atopic dermatitis.
Electron microscopy reveals reduced numbers of lamellar bodies in kera-
tinocytes and the presence of lysosomal inclusion bodies with intercellular
amorphous deposits in the horny layer.14,16
Immunohistochemistry can demonstrate the absence of LEKTI antigen
and is highly specific.17
The histologic distinction from psoriasis vulgaris may be histologically
extremely difficult (if not impossible) in the absence of clinical information.
Other genodermatoses, dermatophytosis, and inflammatory skin diseases
with a psoriasiform-like pattern must be differentiated (see Table 3.3). Atopic
dermatitis is another important differential diagnosis.
Fig. 3.47
Comèl-Netherton's
syndrome: bamboo hair
(trichorrhexis invaginata). Clinical features
By courtesy of M. This autosomal recessive inherited disorder combines the features of ichthyo-
Judge, MD, Institute of
sis, spastic bi- or quadriplegia and mental retardation.1–5 It is rare, with an
incidence of 0.4 per 100 000 of the population.4 Although the disease may
UK.
be encountered worldwide, the prevalence is particularly high in Northern
Sweden.2
a defective serine protease inhibitor, i.e., Lympho-Epithelial Kazal Type The ichthyosis, which develops in the first year of life with a diffuse scal-
Inhibitor (LEKTI), have been identified.11–13 The lack of LEKTI consequently ing, affects the entire body with the exception of the central face and is typi-
leads to a hyperactivity of the proteases involved in the desquamation pro- cally intensely pruritic (Fig. 3.49).3,5 Later, the skin has a brownish-yellow
cess or inflammatory response (kallikreins) and accounts for the ichthyotic color and shows a cobblestone-like lichenification.4 Hyperkeratosis around
and inflammatory skin phenotype, which is associated with an extremely the umbilicus is said to be characteristic.5 Erythroderma is not a feature and
impaired epidermal barrier. the hair, nails, and sweat glands are unaffected.3,4 The diagnosis should be
For diagnostic features, the biopsy must be taken from skin just preced- especially considered in preterm babies with congenital ichthyosis.5
ing the lesion's scaly margin (Fig. 3.48).14,15 In this region the epidermis may The spasticity, which presents in early childhood, predominantly affects
show psoriasiform hyperplasia with associated spongiosis. There is a thick the legs and is often associated with contractures. The majority of patients are
adherent parakeratotic scale. Small, dark, round or oval granules can be iden- wheelchair bound.4 Kyphoscoliosis may also be present.3 Mental retardation
tified within the stratum granulosum. These are diastase-resistant, PAS and is typically present but is not invariable.1 Epilepsy is sometimes a feature.3
Visual acuity is often impaired and photophobia is a frequent complaint.

Macular degeneration associated with crystal deposition is characteristic
(Fig. 3.50).6

Sjögren-Larsson syndrome results from deficiency of microsomal fatty alde-
hyde dehydrogenase (FALDH).7 The gene has been mapped to 17p11.2 and
multiple mutations including missense mutations, deletions, and insertions
have been identified.8–10 The abnormal level of free fatty alcohols in cultured
fibroblasts, direct testing of FALDH activity, or the presence of LTB4 metabo-
lites in urine can provide biochemical screening and/or confirmation of the
clinical diagnosis, prior to molecular mutation analysis of the FALDH gene.5
Epidermal hyperproliferation has been demonstrated in Sjögren-Larsson
syndrome.11
Histologically, there is papillomatosis, acanthosis, and basket-weave hyperk-
eratosis with scattered mild parakeratosis and occasional follicular hyperkeratosis
(Fig. 3.51).12 The granular cell layer may be slightly thickened. A light lymphohis-
tiocytic infiltrate is sometimes present around the superficial dermal vasculature.
Ultrastructurally, there are lamellar inclusions in the prickle and granular
cell layers.12 Lipid inclusions are not a feature.
A
Fig. 3.48
Comèl-Netherton's syndrome: (A) scanning view showing a detached Fig. 3.50
thickened stratum corneum and psoriasiform hyperplasia; (B) note the marked Sjögren-Larsson syndrome: characteristic macular crystals. By courtesy of
parakeratosis. M. Willemsen, MD, University Medical Center, Nijmegen, Belgium.
Fig. 3.49 Fig. 3.51

Sjögren-Larsson syndrome: there is severe scaling and the skin has a yellowish- Sjögren-Larsson syndrome: there is hyperkeratosis, hypergranulosis and mild
brown color. By courtesy of M. Willemsen, MD, University Medical Center, papillomatosis. A light superficial perivascular lymphocytic infiltrate is present. By
Nijmegen, Belgium. courtesy of M. Willemsen, MD, University Medical Center, Nijmegen, Belgium.
Other congenital ichthyotic syndromes 65
Conradi-Hünermann-Happle syndrome
Clinical features
Conradi-Hünermann-Happle syndrome is an X-linked dominant congeni-
tal ichthyosis with associated chondrodysplasia punctata. It is lethal in the
majority of male embryos. Chondrodysplasia punctata is defined as a stippled
calcification of the epiphyses. There are several forms but only the type
2 variant presents with severe ichthyosiform erythroderma. Later the
erythema clears and a whorled scaling following the lines of Blaschko persists
(Fig. 3.52).1,2
Associated symptoms are scarring alopecia, follicular atrophoderma,
localized hypo-and/or hyperpigmentation, sectorial cataracts, and skeletal
dysplasia, which leads to asymmetric shortening of the long bones or severe
kyphoscoliosis. Due to the individual differences in X-inactivation, expression
of the disease is rather variable even within families.1,2

Biochemical analyses using gas chromatography-mass spectrometry show Conradi-Hönermann-Happle syndrome: there is hyperkeratosis and acanthosis.
elevated plasma levels of 8-dehydrocholesterol and 8(9)-cholesterol, result-
ing from a block of a key enzyme in sterol metabolism, namely the 8–7 ste-
rol isomerase. This enzyme is encoded by the emopamil-binding protein
gene, which shows heterozygous mutations in Conradi-Hünermann-Happle
syndrome.3
The histologic features resemble those of ichthyosis vulgaris (Fig. 3.53).
There is hyperplasia of the epidermis, orthohyperkeratosis, a reduced stra-
tum granulosum, and dilated hair infundibula with follicular plugs. As a
pathognomonic finding in newborns, von-Kossa staining demonstrates cal-
cium deposits in the corneocytes which allows for discrimination of other
ichthyoses that share the feature of a reduced stratum granulosum (Fig. 3.54)
(see Table 3.3). At a later age the calcification is difficult to detect histologi-
cally but electron microscopy may reveal cytoplasmic vacuoles and electron-
dense calcium crystals in the granular cell layer.4
Other congenital ichthyotic syndromes

A
Many syndromes can be associated with congenital ichthyosis. In ichthyosis
prematurity syndrome there is associated polyhydramnios and the premature
neonates may suffer from transient asphyxia. The infants have a thick cheesy
Fig. 3.54
Conradi-Hönermann-Happle syndrome: (A) the granular cell layer is absent. Note
the basophilic deposits within the thickened stratum corneum, (B) the basophilic
Fig. 3.52 deposits represent calcium as seen in this von Kossa preparation.
Conradi-Hünermann-
Happle syndrome:
membrane which desquamates and then the skin improves within some weeks.
Scaly erythema follow
the whorled lines of
The skin shows compact orthohyperkeratosis and acanthosis. At ultrastruc-
Blaschko. By coutesy of tural level, characteristic masses of lipid membranes in lentiform paranuclear
H Traupe MD, Dept of swellings of granular and horn cells can be demonstrated which has lead to
Dermatology, Munster, the designation ichthyosis congenita type 4.1 A novel locus for the ichthyosis
Germany. prematurity syndrome has been assigned to chromosome 9q33–34.2
Type II or infantile cerebral Gaucher syndrome presents as a collodion

baby. The diagnosis of this fetal metabolic disease can be made by measure-
ment of glucocerebrosidase activity in peripheral blood leukocytes or in
extracts of cultured skin fibroblasts.3
Dorfman-Chanarin syndrome is a triglyceride storage disease with
impaired long-chain fatty acid oxidation resulting in cataract, hepatospleno-
megaly, neurosensorial deafness, myopathy or developmental delay. At birth,
generalized white scaling and a variable degree of erythema are present. The
skin findings resemble congenital ichthyosiform erythroderma although the
stratum granulosum may be thinned. Intracellular lipid vacuoles can be pres-
ent in circulating neutrophils, as well as in a variety of other cells including
keratinocytes. Thus a skin biopsy fixed in alcohol may be useful. Lipid vac-
uoles may also be found in the obligate carrier parents. Refsum syndrome
patients also have epidermal lipid vacuoles, but in Dorfman-Chanarin syn-
drome patients, the phytanic acid levels are normal.4
Trichothiodystrophy represents a heterogeneous group of autosomal
recessive disorders that share brittle hair and an abnormally low hair shaft
sulfur content (decrease of cysteine). Trichoschisis and alternating light and A
dark banding by polarizing microscopy are typical findings.5 At least two
subtypes of trichothiodystrophy are associated with congenital ichthyo-
sis: the acronym IBIDS (‘Tay syndrome’) refers to the clinical findings of
ichthyosis (e.g., collodion membrane), brittle hair, intellectual impairment,
decreased fertility, and short stature. Other features are microcephaly, dys-
plasia of nails, failure to thrive, ‘progeria’-like symptoms, cataracts, and
photosensitivity (» PIBIDS).6 Half of all trichothiodystrophy patients show
an abnormal nucleotide excision repair of UV-damaged DNA.7 Histology of
the ichthyotic skin shows acanthosis with orthohyperkeratosis and a reduced
stratum granulosum.
Follicular ichthyosis
Clinical features
Follicular ichthyosis (ichthyosis follicularis) is a poorly documented condition
in which patients present with horny, follicular lesions which, although
usually generalized, show a predilection for the head and neck (Fig. 3.55).1,2 B
In the report by Hazell and Marks, associated clinical findings included
pseudoacanthosis nigricans affecting the axillae, comedones on the cheeks Fig. 3.55
and fingers, and dental malocclusion.2 Literature subsequent to these two Follicular ichthyosis: (A) there are bilateral follicular lesions; (B) the follicles are plugged
papers has focused on the association of ichthyosis follicularis with alopecia with thornlike scale. By courtesy of the Institute of Dermatology, London, UK.
and photophobia (see below).3
Pathogenesis and histological features Pathogenesis and histological features

The mode of inheritance and pathogenesis of this disorder is unknown
Follicular ichthyosis (ichthyosis follicularis) is an umbrella term or histologic
although autosomal dominant and X-linked recessive forms have been
pattern that is present in many conditions and is defined by follicular ortho-
described. The complete IFAP phenotype seems to be only observed in male
hyperkeratosis with or without hypergranulosis in the infundibulum.
patients. It is therefore thought to be of X-linked recessive inheritance. Female
For differential diagnosis see Table 3.3.
carriers may present with linear ‘lesions of Blaschko’ showing circumscribed
hairless, anhidrotic or ichthyotic areas of skin 2,5,6
Ichthyosis follicularis with alopecia and The follicular lesions are characterized by projecting hyperkeratotic plugs
showing focal parakeratosis and associated hypergranulosis.7 Hair follicles
photophobia are atrophic and lack hair shafts and sebaceous glands (Figs 3.57, 3.58).1
Sweat glands are normal but hyperkeratosis of the acrosyringia may occlude
Clinical features the openings of sweat ducts.5
Ichthyosis follicularis with alopecia (atrichia) and photophobia (IFAP syn- The psoriasiform plaques show hyperkeratosis with parakeratosis, acan-
drome) is an exceedingly rare disorder characterized by the presence of thosis, spongiosis, and a bandlike upper dermal lymphohistiocytic infiltrate.7
non-inflammatory thorn-like (filiform) follicular hyperkeratosis that often
improves during the first year of life (Fig. 3.56). Other features are ichthyosi- Differential diagnosis
form dry skin, generalized complete nonscarring alopecia (with absence of Other forms of atrichia and follicular keratosis should be considered (see
eyelashes and eyebrows), and severe photophobia.1–6 Ocular findings may Table 3.3).
include corneal deformity and opacity with surface vascularization.6 Angular
cheilitis, keratotic psoriasiform plaques on the extensor surfaces of the
extremities, and nail dystrophy with chronic infection may also be present.2,6
Lichen spinulosus
Additional findings including hypohidrosis, recurrent respiratory infections,
skeletal abnormalities, cryptorchidism or progressive deteriorating neuro- Clinical features
logic symptoms such as generalized seizures and cerebellar symptoms have Lichen spinulosus is a rare dermatosis of unknown etiology which par-
been reported.5 ticularly affects the extensor surfaces of the arms and legs, back, chest,
Other congenital ichthyotic syndromes 67
Fig. 3.58
Ichthyosis follicularis with alopecia and photophobia: there is hyperkeratosis
centered on an acrosyringium.
buttocks, face, and neck.1 Occasionally, lesions are generalized. Lesions pres-
ent in the second and third decades as round to oval, 2–6-cm flesh-colored
and sometimes pruritic, symmetric plaques composed of multiple 1–3-mm
thorny, grouped follicular papules which protrude above the surface of the
skin.1–3 The texture has been likened to a nutmeg grater. Males are affected
more often than females. There is no racial predilection.2 Other than a cos-
metic nuisance, the condition is of no clinical significance. Lichen spinulosus
has been described in association with Crohn's disease, human immunodefi-
ciency virus (HIV) infection, and as an adverse drug reaction.4–7
Histological features
Lichen spinulosus is characterized by keratotic plugging of dilated follicular
B infundibula and a perivascular and perifollicular lymphohistiocytic infiltrate.1
Sebaceous glands may be atrophic or absent. Perforating folliculitis-like fea-
Fig. 3.56 tures can be superimposed.
Ichthyosis follicularis with alopecia and photophobia: (A) the skin is dry and
ichthyosiform, (B) on the scalp a non-scarring alopecia with follicular hyperkeratosis Differential diagnosis
is characteristic. By courtesy of H Traupe MD, Dept of Dermatology, Munster, There is considerable histological overlap with keratosis pilaris and the follic-
Germany. ular lesions of pityriasis rubra pilaris. The distinction is best made clinically.
Phrynoderma
Clinical features
Phrynoderma (toad skin) most often develops as a consequence of vitamin A
deficiency.1–4 Other proposed etiological factors include deficiencies of the vita-
min B complex, riboflavin, vitamin C, vitamin E, and essential fatty acids.4 In
Western countries most cases develop as a result of malabsorption.4,5 Patients
present with xerosis, hyperpigmentation and multiple 2–6-mm, red-brown,
dome-shaped papules with a central folliculocentric crater filled with lami-
nated keratinous debris.1,4 The elbows and knees are predominantly affected
but lesions may extend to involve the thighs, upper arms and buttocks.1
The papules consist of a cystically dilated follicular infundibulum filled with
keratinous debris.4
Keratosis pilaris
Clinical features
Fig. 3.57 This fairly common condition, which has an autosomal dominant mode of
Ichthyosis follicularis with alopecia and photophobia: there is marked follicular inheritance, is probably a follicular variant of ichthyosis and, indeed, fre-
atrophy. Note the small arrector pili muscles. quently accompanies ichthyosis vulgaris.1–3 The age at presentation is most
A
A
Fig. 3.59
Keratosis pilaris:
(A) typical follicular
papules and pustules on
the thigh; (B) note the
conspicuous plugged
follicles. (A) By courtesy
Fig. 3.60
of R.A. Marsden, MD,
Keratosis pilaris: (A) there
is follicular dilatation and
London, UK, (B) By
plugging; (B) note the
B courtesy of the Institute of
B atrophy of the infundibular
epithelium.
often in the first two decades with a peak during adolescence.2 Up to 40% Keratosis pilaris atrophicans
of adults may be affected.2 There is no racial predilection. There is an appar-
ent increased incidence in females and lesions present as pruritic small fol- Clinical features
licular keratoses, sometimes containing small distorted hairs. They are most Keratosis pilaris atrophicans combines the features of follicular hyper-
often found on the lateral aspects of the arms and thighs, although the face, keratosis and scarring.1 Although some authors believe this to represent a
trunk, and buttocks may also be affected (Fig. 3.59).2 Seasonal variation, single disease entity, others prefer to subdivideit into a number of categories
with lesions being much more severe in winter, is often documented.2 There is including ulerythema ophryogenes, atrophoderma vermiculata, and keratosis
an increased incidence of atopy.2 follicularis spinulosa decalvans.2 Evidence of different modes of inheritance,
Although keratosis pilaris most often presents as an isolated phenom- clinical differences, and variable associations supports the latter.2
enon, occasionally it may develop in association with systemic disease Ulerythema ophryogenes (keratosis pilaris atrophicans facei, KPAF) pres-
including Hodgkin's lymphoma, vitamins B12 and C deficiency, hypo- ents at birth or in early infancy with follicular papules and surrounding ery-
thyroidism, Cushing's disease, and treatment with adrenocorticotropic thema followed by atrophic scarring affecting the lateral aspect of the eyebrows
hormone.3,4,5 (Fig. 3.61).3–5 The cheeks, forehead, temples, and neck may also be involved
(Fig. 3.62). Later on, the entire eyebrow may be lost. Keratosis pilaris affect-
Histological features ing the extensor aspects of the arms and thighs is also sometimes present.3 The
Keratosis pilaris is characterized by follicular dilatation and keratin plugs, condition is believed to be inherited as an autosomal dominant.
which may contain a single or several distorted hair shafts (Fig. 3.60).4 A It may be associated with a number of other inherited disorders including
mild, non-specific chronic inflammatory cell infiltrate surrounds the dermal Noonan's syndrome, woolly hair, cardiofaciocutaneous syndrome, Cornelia de
blood vessels and sometimes involves the hair follicles themselves. Lange syndrome, Rubinstein-Taybi syndrome, and partial monosomy 18.3,6–12
Acquired ichthyosis-like conditions 69
Fig. 3.61
Ulerythema ophryogenes: there is intense erythema with loss of follicles. The
eyebrow is a commonly affected site. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 3.63
Keratosis pilaris atrophicans: (A) low-power view showing gross follicular
hyperkeratosis and dilatation of the ostium; (B) high-power view. Note the
perifollicular fibrosis.
hyperkeratosis, photophobia, and punctate keratitis.18 In some patients it

is inherited as an X-linked recessive disorder which has been mapped to
Fig. 3.62
Ulerythema ophryogenes:
Xp21.13-p22.2.21,22 X-linked dominant and autosomal dominant variants
the cheek is also have also been proposed.19
frequently involved. By
courtesy of the Institute Pathogenesis and histological features
of Dermatology, London, The pathogenesis of keratosis pilaris atrophicans is unknown although it
UK. involves blockage of the follicular ostium by a keratinous plug.
All variants of keratosis pilaris atrophicans are characterized by follicular
hyperkeratosis with ostial dilatation, atrophy of the sebaceous gland, and a
The association with Noonan's syndrome is of particular importance since
scanty perifollicular or perivascular lymphohistiocytic infiltrate. Comedones
such patients suffer from potentially life-threatening congenital pulmonary
and milia may be found. There is a variable perifollicular fibrosis that extends
stenosis. Ulerythema ophryogenes is also associated with atopy.13
into the reticular dermis (Fig. 3.63).3,11,12,16
Atrophoderma vermiculata (ulerythema acneiforme, atrophoderma ver-
miculatum, atrophoderma reticulata, acne vermoulante, folliculitis ulery-
thema reticulata, folliculitis ulerythematosa, honeycomb atrophy) is an Acquired ichthyosis-like conditions
exceedingly rare form of atrophic keratosis pilaris thought to be inherited as
an autosomal dominant. Patients present with follicular keratoses and pit- Acquired ichthyosis-like or ichthyosiform conditions refer to patients who
ted depressions separated by normal skin (worm-eaten appearance) affect- develop diffuse ichthyosis-like scaling during their life (Table 3.5). The adult
ing the cheeks, ears, and forehead (honeycomb atrophy).2,14–17 The disorder onset renders the term acquired ichthyosis inappropriate. It is an important
presents in patients after 5 years of age.2 Unilateral nevoid variants following paraneoplastic manifestation of a number of malignancies: Hodgkin's lym-
Blaschko's lines have been documented.15–17 phoma is most often encountered, but non-Hodgkin's lymphoma including
Keratosis follicularis spinulosa decalvans is characterized by diffuse mycosis fungoides and a range of carcinomas have all been associated.1–8
atrophic keratosis pilaris associated with scarring alopecia affecting the Ichthyosiform skin changes may also accompany malnutrition, HIV and
scalp.18–20 Other conditions sometimes present include atopy, palmoplantar other infectious diseases, sarcoidosis, collagenoses, celiac disease and other
Table 3.5
Acquired ichthyosis-like conditions
Etiology Diseases
Dry skin None
Paraneoplastic Hodgkin and non-Hodgkin lymphoma
Kaposi sarcoma
Various carcinomas
Infections Leprosy
Tuberculosis
HIV/AIDS
Malnutrition Pellagra
Vitamin A deficiency
Drugs Lipid-lowering agents (statins)
Nicotinic acid
Allopurinol
Cimetidine
Lithium A
Retinoids
Gastrointestinal diseases Crohn's disease
Celiac disease
Gastrectomy
Endocrinopathies Hyperparathyroidism
Hypothyroidism
Miscellaneous Renal insufficiency
Sarcoidosis
Graft-versus-host disease
Dermatomyositis and systemic lupus
erythematosus
Down's syndrome
gastrointestinal diseases, renal insufficiency, hypothyroidism, and graft-

versus-host disease.4,9–15 Ichthyosiform skin changes following administra-
tion of lipid-lowering agents and other various drugs or kava consumption
has been documented.13,14 Dry skin, especially in blacks, leads to the develop- B
ment of lamellar scales on the legs and trunk. The features of acquired ich-
thyosis-like skin conditions most often resemble those of ichthyosis vulgaris Fig. 3.64
both clinically and histologically (Figs 3.64–3.67). Acquired ichthyosis: (A) cutaneous manifestations most often resemble ichthyosis
Clinical differential diagnosis includes xerosis cutis which lacks thick vulgaris; (B) close-up view of the scale. By courtesy of the Institute of Dermatology,
scales, develops at later age, and can be easily treated by fatty emolients. London, UK.
Pityriasis rotunda
Clinical features
Also known as pityriasis circinata, this acquired disorder of keratinization
was originally described in the Japanese.1 It is also not uncommon in South
Africans (Bantu) and West Indian blacks,2,3 but has only rarely been reported in
Caucasians with the exception of a subpopulation of Italians in Sardinia.4–7 Fig. 3.65
Patients present with persistent, very sharply defined, circular or oval areas Acquired ichthyosis:
of hyper- or hypopigmentation associated with a fine scale (Fig. 3.68). Lesions, there is intense erythema
which are usually multiple and frequently numerous, are characteristically non- and scaling. This patient
inflammatory and asymptomatic. Often, they are confluent. They measure 0.5– also suffered from graft-
28 cm in diameter and are particularly located on the trunk and limbs. The sex versus-host disease.
incidence is equal. Lesions are sometimes associated with gradual remission By courtesy of B. Solky,
during the summer months and relapse in winter.6 The maximum incidence is MD, Department of
Dermatology, Brigham
in the third to fifth decades. There is often a family history of ichthyosis vul-
and Women's Hospital
garis.8 It may occasionally be associated with a familial incidence.8,9 and Harvard Medical
Pityriasis rotunda sometimes appears to be a cutaneous marker of severe inter- School, Boston, USA.
nal disease including tuberculosis,1 cancer (particularly hepatoma),10,11 leukemia,12 cir-
rhosis,6 ovarian and uterine disease,13 undernutrition, and favism.8 Pityriasis rotunda
might best be regarded as an acquired circumscribed variant of ichthyosis.12 Increased pigmentation of the basal keratinocytes may be evident. A mild
perivascular chronic inflammatory cell infiltrate is sometimes present in the
Histological features superficial dermis. A superficial fungal infection, for example tinea (pityr-
The histological features are subtle and comprise hyperkeratosis with a dimin- iasis) versicolor, should always be excluded by a PAS reaction or silver
ished or absent granular cell layer and loss of the epidermal ridge pattern. stain.14
Erythrokeratodermas 71
Fig 3.66
Acquired ichthyosis: this patient developed ichthyosis in a background of mycosis Fig. 3.68
fungoides. Low-power view showing marked focally compact hyperkeratosis and Pityriasis rotunda: characteristic lesion showing circumscription, scaling, and
acanthosis. hyperpigmentation. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
transmembrane proteins that form gap junctions and are involved in epider-
mal differentiation.The KID/HID syndrome and Vohwinkel's syndrome are
associated with sensorineural hearing loss. In others, the genetic defect has
yet to be identified.2
Erythrokeratoderma variabilis
Clinical features
This rare ichthyosiform dermatosis generally has an autosomal dominant
mode of inheritance although an autosomal recessive variant has recently
been described.1–5 Lesions usually present soon after birth or during the first
year of life and are of two types, typically present simultaneously:
• Type 1 lesions are symmetrically distributed, discrete figurate, and
often bizarre patches of erythema, which vary in size, shape, number,
and location over periods of hours and days (Fig. 3.69).3 These are
sometimes temperature or stress related.1,6
Fig 3.67 • Type 2 lesions are well-defined, fixed geographical, reddish-yellow-
Acquired ichthyosis: high-power view to emphasize the atypical lymphocyte population brown greasy, hyperkeratotic plaques arising either within the
and atypia. Note the well-developed retraction artifact so typical of this condition. erythematous lesions or, more often, independently (Fig. 3.70). Lesions
are usually asymptomatic although occasionally mild pruritus or burning
sensations are a feature.4
Erythrokeratodermas The condition particularly affects the face, buttocks, and extensor surfaces
of the extremities.7 While cold weather in winter and emotional problems
‘Erythrokeratoderma’ or ‘erythrokeratodermia’ refers to a group of geno- may sometimes exacerbate the condition, the symptoms often improve in the
dermatoses characterized by localized erythematous lesions, hyperkeratotic summer months.4 Erythrokeratoderma variabilis is occasionally associated
plaques, and, infrequently, a mild palmoplantar keratosis.1 Many of these with high estrogen levels and symptoms may worsen with estrogen-contain-
diseases represent connexin mutations (Table 3.6). Connexin genes code for ing oral contraceptive therapy.1,2,4 Hypertrichosis (of vellus hairs) and mild
Table 3.6
Diseases with connexin mutations
Disease Inheritance Locus Gene Protein

Erythrokeratoderma variabilis AD or AR 1q35.1 GJB3 Connexin 31
AD 1q35.1 GJB4 Connexin 30.3
Erythrokeratoderma variabilis with AD 1q35.1 GJB4 Connexin 30.3
erythema gyratum repens-like lesions
Keratitis-ichthyosis-deafness syndrome/Hystrix-like- AD 13q11-12 GJB2 Connexin 26
ichthyosis deafness syndrome (KID/HID Syndrome)
Oculodentodigital dysplasia AD 6q22-24 GJA1 Connexin 43
Vohwinkel keratoderma AD 13q11-12 GJB2 Connexin 26
Hidrotic ectodermal dysplasia of Clouston AD 13q11-12 GJB6 Connexin 30
Fig. 3.69
Erythrokeratoderma variabilis: annular and serpiginous erythematous lesions
showing scaling and the characteristic trailing edge. By courtesy of R.A. Marsden,
MD, St George's Hospital, London, UK.
Fig. 3.71
Erythrokeratoderma variabilis: (A) low-power view showing hyperkeratosis,
acanthosis with an undulating skin surface and a very light superficial perivascular
chronic inflammatory cell infiltrate; (B) high-power view showing marked
parakeratosis overlying a thickened orthokeratotic stratum corneum. Note the
presence of a granular cell layer.
erythrokeratoderma variabilis harbor Cx31 or Cx30.3 mutations.8–11 A subset

Fig. 3.70
of patients with connexin 30.3 mutations manifest with a unique clinical
Erythrokeratoderma
variabilis: in these lesions feature, namely transient erythematous patches with a peculiar, circinate or
there is more pronounced gyrate border reminiscent of erythema gyratum repens, i.e., erythrokerato-
scaling. derma with erythema gyratum repens-like lesions.12
The histopathological features of this disease are not specific, consisting of
orthohyperkeratosis, variable parakeratosis, irregular acanthosis, and papil-
lomatosis with an undulating skin surface (Fig. 3.71).3,13 Dyskeratotic cells
eratoderma of the palms and soles may additionally be evident.3,6 The
k with pyknotic nuclei reminiscent of the grains of Darier have been described
mucous membranes, hair, teeth, and nails are unaffected and there are no in one case.6 The granular cell layer appears normal. A perivascular lympho-
associated systemic manifestations.4 histiocytic inflammatory cell infiltrate may be present in the superficial der-
mis. Pilosebaceous follicles and sweat glands are normal.13
Pathogenesis and histological features Connexin immunohistochemistry discloses an irregular distribution of the
Connexin genes code for proteins that form intercellular channels called gap epidermal gap junction proteins.14
junctions that allow for transport and signaling between neighboring cells Ultrastructural observation have shown an increased number of gap junc-
in the epidermis. In the skin, Cx31 and Cx30.3 are expressed in the stra- tions, some of which display four layers, suggesting a loosened connection of
tum granulosum of the epidermis with a suggested role in late keratinocyte the keratinocyte plasma membrane through the gap junctions.15 Other studies
differentiation.8 have revealed markedly diminished numbers of Odland bodies in the granu-
Initially linked to the RH1 locus on 1p, erythrokeratoderma variabilis lar cell layer.6,14 Conspicuous nonmyelinated nerve fibers and Schwann cells
has been mapped to 1p34-p35, which includes the connexion genes GJB3 have been described in the papillary dermis.6,14 These, however, are not con-
and GJB4.7,8 However, erythrokeratoderma variabilis appears to be hetero- sistent findings.16 Nuclear encirclement by condensed keratin filaments and
geneous since not all individuals that have been clinically diagnosed with keratohyalin has also been recorded.16
Erythrokeratodermas 73
Differential diagnosis mitochondria in the granular cell layer are said to be a helpful ultrastructural
diagnostic pointer.3–5,7
Progressive symmetrical erythrokeratoderma is characterized by symmetrical
distribution and a more fixed or very slow progression of erythema and scaly
plaques. Since mutations in the the loricrin gene have been identified (loricrin ker- Differential diagnosis
atoderma), this condition should no longer be grouped as a connexin disorder. Progressive symmetric erythrokeratodermia can be distinguished from pso-
riasis by the absence of suprapapillary plate thinning, neutrophil infiltration,
Progressive symmetric erythrokeratodermia and Munro microabscesses.2 In addition, the parakeratosis tends to be very
focal and hypergranulosis is usually present.
Clinical features
Also known as erythrokeratodermia progressiva symmetrica or Gottron's
syndrome, this condition is inherited as an autosomal dominant with incom-
Keratitis-ichthyosis-deafness syndrome
plete penetrance, although sporadic cases may also be encountered.1,2 It usu-
ally presents in the first year of life with fixed, symmetrical, and sometimes Clinical features
pruritic, erythematous scaly plaques on the extensor surfaces including Keratitis-ichthyosis-deafness syndrome (KID syndrome, palmoplantar ectoder-
the elbows, knees, buttocks, dorsal surfaces of the feet and hands, and head mal dysplasia type XVI) is a very rare genodermatosis. Spontaneous mutations,
(Fig. 3.72).1–5 The face, chest, and abdomen are typically unaffected.2 The autosomal dominant, and autosomal recessive modes of inheritance have all
plaques gradually extend during the first few years and then become static.3 been documented.1–4 There is an equal sex incidence.5 It may present at birth
Additional features include palmoplantar keratoderma and pseudoainhum as a ‘vernix-like’ covering, which soon progresses to a dry, scaling erythema,
(constriction bands on the fingers and toes). The sex incidence is equal.2 There particularly affecting the face (especially the cheeks) and extremities, including
is clinical overlap with erythrokeratoderma variabilis and indeed patients the palms and soles.1,3,4,6,7 The skin may be thickened and leathery.7,8 Later the
may present with features of both diseases. However, progressive symmetric lesions become verrucous and hyperkeratotic, brownish-yellow, sharply circum-
erythrokeratoderma lacks transient migratory erythema.1 scribed plaques (Fig. 3.73).1 Circumoral furrows may lead to a progeria-like
appearance.9 Follicular keratoses sometimes develop on the head and extremi-
Pathogenesis and histological features ties and a ‘prickly’ spiculated appearance on the backs of the hands is occasion-
A mutation in the loricrin gene on chromosome 1q21 has been identified in ally evident.3,4,8 Palmar and plantar involvement with accentuation of the skin
one family with progressive symmetric erythrokeratoderma.6 Similar muta- markings has been likened to heavily grained leather.10 There does, however,
tions have been reported in the ichthyotic variant of Vohwinkels's syndrome. appear to be some variation in presentation.1 Some patients have therefore been
As a result, more definitive genotype-phenotype correlation within the con- described as being normal at birth, developing dry, scaly skin in later childhood,
nexin gene disorders or other causative genes will have to be established to while others have been reported as ‘red and wizened at birth’.11,12
define symmetrical progressive erythrokeratoderma as a separate entity. Inflammation of the cornea with photophobia is usual and a vascularizing
Histologically, there is marked basket-weave hyperkeratosis with focal keratitis leads to severe visual impairment.8 The end result is destruction of
parakeratosis, hypergranulosis, and psoriasiform hyperplasia.2,3 Paranuclear the cornea by a pannus of vascular or fibrous tissue (keratoconus).1
vacuolation may be evident in the granular cell layer.3,7 A perivascular lym- Deafness is of the congenital neurosensory type, but is occasionally due to
phocytic infiltrate is present in the superficial dermis.5 recurrent otitis media; conduction defects may also be present.1,7,8 It is often
Ultrastructurally, characteristic loricrin-rich intranuclear granules are seen total and frequently present at birth although not usually recognized until
in the granular cell layer.6 Lamellar granules are increased in number and lipid sometime later in early childhood.8
droplets may be evident in the cornified cells.3 Immunohistochemically, the Ectodermal dysplasia is variably present and features include alope-
cornified cell envelopes show greatly reduced staining for loricrin.6 Swollen cia (either partial or complete, including eyebrows and eyelashes), small
Fig. 3.73
KID syndrome: there is
Fig. 3.72 marked scaling of the
Progressive symmetric scalp with alopecia. Note
erythrokeratodermia: the facial erythema and
Erythematous scaly dark plaques on the
plaques gradually appear cheeks. By courtesy
on the extensor surfaces of R.J.G. Rycroft, MD,
on the extremities and St John's Dermatology
then persist. Centre, London, UK.
malformed teeth with increased caries, scrotal tongue, leukokeratosis, and a

variety of dystrophic nail changes including fragility, hyperkeratosis, dyspla-
sia, leukonychia, and aplasia.1,4,8
Additional features that may be detected include increased susceptibility to
superficial and systemic chronic infections (bacterial and fungal), neuromus-
cular disease, retraction of the Achilles tendon, hypohidrosis, heat intolerance,
and growth deficiency.1,3,8,13–15 The reason for the increased risk of cutaneous
infection is unknown. While an abnormality of immunity has been proposed,
it is felt more likely that colonization of greatly increased and degenerate
keratin is the more important etiological factor.16 No consistent abnormal-
ity of immune function has so far been reported.3,11,14 Mental retardation is a
rare feature, which may be seen in patients with the autosomal recessive vari-
ant.1 Liver disease including cirrhosis has been present in autosomal recessive
patients.1,2 Squamous carcinoma of the tongue and skin (sometimes multiple)
are important complications (Fig. 3.74).3,13,17–19

KID syndrome, at least in some families, has been shown to be associated Fig. 3.75
with mutations in the connexin 26 gene.20,21 KID syndrome: scanning
The histological appearances of the skin lesions are non-specific and view showing basket-
include basket-weave hyperkeratosis with occasional foci of parakerato- weave hyperkeratosis. In
sis, acanthosis, and papillomatosis (Figs 3.75, 3.76).8 Some authors have this example the eccrine
observed prominence and vacuolization of the stratum granulosum.22,23 sweat glands are normal.
Follicular plugging is commonly present and occasionally the orifices of the
eccrine ducts are similarly affected.5,11 A superficial perivascular lymphohistiocytic
infiltrate is sometimes evident.8 Eccrine sweat glands may be diminished in num-
ber and atrophic, with thickened, hyalinized basement membranes and absent or
atrophic hair follicles are seen in the areas of alopecia.3,8,22 Electron microscopic
studies of the epidermis have revealed no significant abnormalities.7,15
A recently reported autopsied case has described both ocular and aural
changes:16
• Ocular changes were limited to the cornea and conjunctiva. Dyskeratosis
and atrophy of the corneal surface epithelium accompanied by
neovascularization and mild chronic inflammation of the substantia
propria were evident. The bulbar conjunctiva showed epithelial
atrophy, dyskeratosis, and mild chronic inflammation. Late changes are
characterized by the development of an inflammatory and vascular pannus.8
• Aural changes related not only to epithelial maturation abnormalities
of the external auditory meatus and tympanic membrane, but also to
cochleal maldevelopment.16 The essential features of the former included
Fig. 3.76
KID syndrome: high-power view emphasizing the basket-weave keratin overlying a
zone of compact keratin. There is focal parakeratosis. There is vacuolization of the
granular cell layer.
parakeratosis of the squamous epithelium overlying the tympanic

membrane. Immaturity and parakeratosis of the ridge pattern of the
epithelium covering the bony aspect of the external auditory meatus may
also be present. Changes of the internal ear included maldevelopment of
the cochlea and absence of the tectorial membrane and organ of Corti,
accompanied by reduction in the number of nerve fibers and spiral
ganglion nerve cells.16 These features are very much in keeping with
sensorineural deafness of cochleal origin.
The liver changes include micronodular cirrhosis, cholestasis, Kupffer cell
hyperplasia, abundant Mallory's hyaline and marked copper storage.1
Hystrix-like ichthyosis with deafness

Fig. 3.74
KID syndrome: squamous Clinical features
carcinoma on the knee.
Tumors may be multiple.
Hystrix-like ichthyosis-deafnesss (HID) syndrome (ichthyosis hystrix type
By courtesy of M. Judge, Rheydt) presents with spiky and cobblestone-like hyperkeratosis.1,2 There
MD, Institute of are many similarities with keratitis-ichthyosis-deafness syndrome. However,
Dermatology, London, HID patients show multiple red patches shortly after birth, which develop
UK. into ichthyotic erythroderma. In contrast to the KID syndrome, patients with
Palmoplantar keratoderma 75
HID show a more widespread involvement of the trunk but less palmoplan-
tar hyperkeratosis. Keratitis of the eyes is less prominent in HID patients, but Palmoplantar keratoderma
they also suffer from neurosensorial deafness, proneness to mycotic/bacterial
skin infections, and skin cancer.2 The palmoplantar keratodermas (PPKs) consist of a large heterogeneous
group of localized cornification disorders characterized by hyperkeratosis
of the palms and soles. Ichthyotic skin disorders and erythrokeratoderma
Pathogenesis and histological features may also show palmoplantar hyperkeratosis but mainly affect other body
Both HID and KID syndromes are associated with an identical connexin areas. PKKs are classified on the basis of mode of inheritance, distribution of
26 missense mutation.3 Therefore they may represent a spectrum of pheno- lesions, additional clinical features, and associated abnormalities.1–5 Many of
typic variability instead of separate entities.3 these genodermatoses have a late onset. At least 30 subtypes are recognized
Histologically, there is orthohyperkeratosis with foci of parakeratosis, and subdivided into two broad subtypes, one in which lesions are restricted
acanthosis, and the nuclei are surrounded by empty spaces reminiscent of to the skin (Table 3.7) and the other in which there is a much broader spec-
a bird's eye. At the ultrastructural level, keratinocytes show reduction of trum of ectodermal defects affecting skin, mucosae, nails, hair, teeth and neu-
tonofibrils and abnormal membrane-bound granules containing mucous sub- rological abnormalities (Table 3.8).4,5 Where more than a single ectodermal
stances that are discharged into the intercellular spaces.4 The absence of these structure is involved Stevens et al. coined the term ‘palmoplantar ectodermal
features in KID syndrome may result from sampling errors, with some skin dysplasia’ to emphasize the generalized nature of the disorder and identified
areas being more severely affected than others.3 a total of 19 subtypes.6
Table 3.7
Isolated palmoplantar keratodermas (PPK)
Palmoplantar keratoderma Inh. Locus Protein Disease
Diffuse AD 17q12-q21 Keratin 9 Epidermolytic palmoplantar keratoderma (Vörner-Unna-Thost)
12q11-13 Keratin 1 Epidermolytic PPK Vörner-Unna-Thost, Epidermolytic hyperkeratosis
with polycyclic psoriasiform plaques
12q11-13 Keratin1 Progressive palmoplantar keratoderma (Greither) and other
nonepidermolytic palmoplantar keratoderma
8p22-23 unknown Keratolytic winter erythema
AR 8qter SLURP1 Mal de Meleda
12q11-13 unknown Gamborg-Nielson palmoplantar keratoderma
Circumscribed AD 18q12.1-12.2 Desmoglein1 Keratosis palmoplantaris areata et striata (type 1–3)
6q24 Desmoplakin
12q Keratin1
unknown unknown Keratosis palmoplantaris nummularis (hereditary painful callosities)
Punctate AD 8q24 unknown Punctate palmoplantar keratoderma (Buschke-Fischer-Brauer)
unknown unknown Marginal papular acrokeratoderma
Table 3.8
Palmoplantar keratodermas (PPK) with associated symptoms
Palmoplantar
keratoderma Disease Inh Locus Protein Symptoms
Diffuse Huriez syndrome AD 4q23 ? Sclerodactyly, nail dystrophy, squamous cell
carcinomas in atrophic areas
Vohwinkel syndrome 13q11-12 Connexin 26 Mutilating keratoderma, sensorineural deafness
Loricrin keratoderma 1q21 Loricrin Associated ichthyosis
Clouston syndrome 13q12 Connexin 30 Diffuse palmoplantar keratoderma, alopecia, nail
dystrophies
Olmsted [1927] syndrome ? ? ? Diffuse mutilating palmoplantar, periorificial
keratoses, ectodermal dysplasia
Papillon-Lefèvre AR 11q14 Cathepsin C Diffuse palmoplantar keratosis with severe
syndrome periodontitis
Naxos syndrome 17q21 Plakoglobin Wooly hair, cardiomegaly, tachycardia
McGrath syndrome 1q32 Plakophilin 1 Painful diffuse palmoplantar keratosis, Skin
fragility, dystrophic nails, sparse hairs
Circumscribed Pachyonychia congenita 1 AD 12q13 Keratin 6A Thickened nails, focal palmoplantar keratoderma,
Jadassohn-Lewandowsky 17q12-q21 Keratin 16 folliculare hyperkeratosis, leukokeratosis
Pachyonychia congenita 2 12q13 Keratin 6B Thickened nails, focal palmoplantar keratoderma,
Jackson-Lawler 17q12-q21 Keratin 17 cysts, natal teeth
Howel-Evans syndrome 17q24 ? Association with carcinoma of esophagus
Tyrosinemia II AR 16q22.1-q22.3 Tyrosine Focal, often painful palmoplantar keratoderma
(Richner-Hanart amino-transferase
syndrome)
Carvajal-Huerta syndrome 6p24 Desmoplakin Epidermolytic PPK, wooly hair, arrhythmogenic
left cardiomyopathy
Punctate Schöpf-Schulz-Passarge ? ? ? PPK with lid cysts, hypodontia and hypotrichosis
syndrome
Table 3.9
Histologic patterns of PPK
Epidermolytic hyperkeratosis Epidermolytic palmoplantar

keratoderma (Vörner-Unna-Thost)
Keratosis palmoplantaris
nummularis
PKK with polycyclic psoriasiform
plaques
Carvajal-Huerta syndrome
Hyperkeratosis overlying depressed Keratosis palmoplantaris punctata
area of the epidermis
Paranuclear eosinophilic globular Pachyonychia congenital
inclusions Tyrosinemia type II
(Richner-Hanhart)
Orthohyperkeratosis and, Other forms of PKK
inconsistently,
focal parakeratosis, epidermal
hyperplasia, discrete perivascular
inflammation Fig. 3.77
Diffuse palmoplantar
keratoderma Vörner-
Unna-Thost: there is
There are three major clinical categories: diffuse, circumscribed, and punctu- hyperkeratosis affecting
ate (Tables 3.7 and 3.8).4,5 Histologically, there are four main histologic patterns the entire sole of the foot.
that are characterized by epidermolytic hyperkeratosis, orthohyperkeratosis By courtesy of W.A.D.
with hypergranulosis and acanthosis, hyperkeratosis overlaying depressed areas Griffiths, MD, Institute of
of the epidermis, and paranuclear eosinophilic inclusions (Table 3.9). In many
subtypes, the underlying molecular defect has been identified and can be related
to structural proteins (keratins), cornified envelope (loricrin, transglutaminase),
cohesion (plakophilin, desmoplakin, desmoglein1), cell-to-cell communication
(connexins), and transmembrane signal transduction (cathepsin C).7
Keratosis palmoplantaris diffusa

Vörner-Unna-Thost
Clinical features
Keratosis palmoplantaris diffusa Vörner-Unna-Thost is an epidermolytic pal-
moplantar keratoderma (PPK) and represents the most common form of pal-
moplantar keratoderma with an incidence of 1:100 000. Reinvestigation of
the original family with Unna-Thost PPK showed that epidermolytic forms
existed within the family as has been described by Vörner. Therfore, it is not
justified to separate Vörner disease from Unna-Thost disease.1
The condition is inherited as an autosomal dominant and usually presents
in the first months or else when the patients start running.1–6 Patients pres-
ent with symmetrical, well-demarcated yellowish, smooth and waxy plaques
covering the palms and soles, and, to some extend, the ventral surface of Fig. 3.78
fingers and toes (Figs 3.77, 3.78). The lesions reach the lateral aspects of Diffuse palmoplantar keratoderma Vörner-Unna-Thost: in this patient the palms
hands and feet but not beyond. The periphery is bordered by an erythematous of the hands were also affected. By courtesy of W.A.D. Griffiths, MD, Institute of
margin (Fig. 3.79).2 Painful blisters are not uncommon. Hyperhidrosis and Dermatology, London, UK.
maceration may be present and facilitate dermatophytosis.3,6 Rarely, associ-
ated knuckle pads or clubbed digits have been documented.7 Identification the rod domain are associated with only mild focal signs of epidermolytic
of the epidermolytic form of PPK has therapeutic consequences since lesions hyperkeratosis in the spinous layer of palmoplantar epidermis.11
become inflammatory and erosive with systemic retinoid therapy. Epidermolytic palmoplantar keratoderma is not associated with malig-
nancy. Patients in one large kindred showed a high incidence of breast and
Pathogenesis and histological features ovarian cancer.10 It is now believed that this represented a coincidental co-
Epidermolytic palmoplantar keratoderma was initially mapped to17q12-q21, the segregation of a keratin 9 mutation with a BRCA1 mutation on 17q21.2
locus of the type I acidic keratin cluster where different point mutations of keratin Histologically, there is a massive orthohyperkeratosis, hypergranulosis,
9 were identified.8 Epidermolytic palmoplantar keratoderma, however, has also papillomatosis, and acanthosis accompanied by features of epidermolytic
been reported to be associated with keratin 1 mutations that map to 12q11–13, hyperkeratosis in the prickle and the granular cell layers with unstained,
the site of the keratin II genes.9,10 Keratin 1 and 9 are the major structural keratins vacuolated cytoplasm, intracytoplasmic eosinophilic granules, and coarse
in the suprabasal keratinocytes of palmoplantar epidermis. Mutations in keratin keratohyalin granules (Figs 3.80, 3.81). A superficial dermal perivascular
9 are associated with more severe manifestations than mutations in keratin 1. lymphohistiocytic infiltrate may sometimes be present. Epidermal spongiosis
Most of the keratin mutations affect the central regions of the protein, and vesiculation may indicate mycotic superinfection.
which are important for filament assembly and stability of the keratin skel- Electron microscopy shows aggregations of keratin filaments and keratin
eton. As a consequence, tonofilament clumping causes cellular degeneration clumps that accounts for the intracytoplasmic eosinophilic granules seen by
and disruption, e.g., epidermolytic palmoplantar keratoderma. Mutations in light microscopy. Large areas of the cytoplasm that are devoid of a keratin
Fig. 3.79 Fig. 3.81

Diffuse palmoplantar keratoderma Vörner-Unna-Thost: the border of the lesion is Diffuse palmoplantar keratoderma Vörner-Unna-Thost: high-power view
marked by a linear zone of erythema. By courtesy of W.A.D. Griffiths, MD, Institute demonstrating the features of epidermolytic hyperkeratosis.
of Dermatology, London.
Histopathologic examination of the psoriasiform plaques demonstrates the
characteristic features of epidermolytic hyperkeratosis. Sequencing of the ker-
atin 1 gene in affected family members reveals a mutation within the highly
conserved helix termination motif of the helix 2B segment.1
Diffuse nonepidermolytic palmoplantar

keratoderma
Clinical features
Diffuse nonepidermolytic palmoplantar keratoderma is a heterogenous, ill-
defined group of conditions. It includes an autosomal recessive disorder with
a high incidence in Sweden and characterized by a thick, horny layer sharply
demarcated from the normal skin and knuckle pads on the dorsal aspect of
the finger joints.1 Symptoms usually present in the first 3 years of life.1 Many
patients suffer from increased sweating and, therefore, maceration is com-
Fig. 3.80 mon. There is a greatly increased risk of dermatophyte infections.1 Patients
Diffuse palmoplantar with this variant may also show axillary and groin involvement, subungual
keratoderma Vörner- hyperkeratosis, onychodystrophy, and central facial lesions.2 Another non-
Unna-Thost: scanning epidermolytic variant of diffuse PPK is Mal de Meleda (see below).
view showing massive Although diffuse palmoplantar keratoderma was originally believed
hyperkeratosis, to be associated with esophageal carcinoma (Howell-Evans syndrome),
papillomatosis, and
re-examination of the affected kindreds disclosed that the keratoderma would
acanthosis.
better be classified as focal (see focal nonepidermolytic palmoplantar kera-
toderma with esophageal squamous carcinoma).3 There are, however, rare
instances of diffuse palmoplantar keratoderma associated with cutaneous
skeleton explain the vacuolar change. Keratohyalin granules cluster in a ran- squamous cell carcinoma, for example Huriez syndrome (palmoplantar kera-
dom fashion around the keratin aggragates. toderma with sclerodactyly) and Schöpf-Schulz-Passarge syndrome (palmo-
plantar keratoderma with squamous carcinoma arising in the areas affected
Epidermolytic hyperkeratosis with polycyclic by keratoderma).4,5
Acquired diffuse palmoplantar keratoderma may also be associated with
psoriasiform plaques malignancy.6
Clinical features Pathogenesis and histological features

Epidermolytic hyperkeratosis with polycyclic psoriasiform plaques is a Diffuse nonepidermolytic palmoplantar keratoderma has been mapped to 12q11–
unique palmoplantar keratoderma with an autosomal dominant inheri- 13, the site of the keratin II genes.7,8 The disease mutation described by Kimonis
tance.1 Clinically, affected individuals manifest transient blistering at birth and coworkers was the first to be identified in a keratin chain variable end region.9
followed by chronic diffuse palmoplantar keratoderma. Intermittent flares The fact that epidermolysis was not present suggests that the amino-terminal
of fixed polycylic erythematous psoriasiform plaques which characteristi- domain of keratins may be involved in supramolecular interactions of keratin fila-
cally deteriorate and then improve are seen although there is marked indi- ments rather than stability.9 There is, however, genetic heterogeneity.10
vidual variation in both the severity and duration of lesions, ranging from This disorder is characterized by marked hyperkeratosis, hypergranulosis,
weeks to months.1 acanthosis, and an exaggerated epidermal ridge pattern (Fig. 3.82). A chronic
Fig. 3.82
Diffuse nonepidermolytic
palmoplantar
keratoderma: there is
massive hyperkeratosis,
hypergranulosis, and
acanthosis.
inflammatory cell infiltrate is sometimes evident in the superficial dermis. The

presence of spongiosis and vesiculation should suggest a concomitant der-
matophyte infection and prompt evaluation of a PAS or silver stained section
(Figs 3.83, 3.84).11 In the diffuse recessive variant, the hyperkeratosis is even
more marked than in the dominant form and the epidermis shows prominent
psoriasiform hyperplasia.1
Progressive palmoplantar keratoderma B
Clinical features Fig. 3.83

Progressive palamoplantar keratoderma, (syn: Greither syndrome, keratosis Diffuse nonepidermolytic palmoplantar keratoderma: (A) in this example, there
palmoplantaris diffusa transgrediens et progrediens) is an autosomal dom- is massive hyperkeratosis with an undulating growth pattern. Intra-epidermal
inantly inherited disease. In childhood, a diffuse symmetric palmoplantar vesiculation is apparent, (B) high-power view.
keratoderma with small pits or fissures and hyperhidrosis develops that pro-
gressively extends to the back of the hands and feet, the region of the Achilles
tendon, ankles, knees or elbows where patchy hyperkeratosis develops. In the
middle of life amelioration occurs (Figs 3.85, 3.86).1

The previously reported cases of Greither's syndrome showed phenotypic
variability suggestive of different underlying gene defects. At least some cases
of Greither's syndrome are caused by keratin mutations.2
Histopathology shows acanthosis with focal orthohyperkeratosis located
on delled areas of the epidermis (Fig. 3.87). There are generally no features
of epidermolytic hyperkeratosis with the exception of a case where a keratin
mutation was detected.3
Keratolytic winter erythema

Clinical features
Keratolytic winter erythema (synonyms: erythrokeratolysis hiemalis,
Oudtshoorn disease) is an autosomal dominant disorder first described in
South Africa.1 Sporadic cases have been reported from other countries.2,3 The
disorder manifests at an early age and is characterized by recurring cycles of
erythema involving the palms and soles, followed by mild hyperkeratosis and
nonpruritic and nonpainful peeling. In severe cases the limbs and trunk are Fig. 3.84
affected with gyrate scaling erythemas. Most remarkably, the onset of symp- Diffuse nonepidermolytic palmoplantar keratoderma: fungal hyphae are apparent in
toms occurs during cold weather.2 the thickened stratum corneum (PAS stain).
Fig. 3.85
Progressive palmoplantar
keratoderma: (A) diffuse
hyperkeratosis with fissures
progressively extends to the
back of the hands and feet
A B and (B) affects the region of
the Achilles tendon.
Fig. 3.86 Fig. 3.87

Progressive palmoplantar Progressive palmoplantar keratoderma: massive hyperkeratosis with a central small
keratoderma: Patchy dell (arrowed).
hyperkeratosis develops
on the knees.
Mal de Meleda
The disorder has been mapped to chromosome 8p22–23 with some genetic Clinical features
heterogeneity, but a causative gene has not yet been identified.4,5 Mal de Meleda is inherited as an autosomal recessive with a high prevalence
The epidermis is acanthotic with a thickened stratum granulosum. in Meleda in the Adriatic Sea. The diffuse keratoderma progresses onto the
At the advancing edge spongiosis and vesicle formation can be observed. dorsal aspects of the fingers and toes (keratosis palmoplantaris transgre-
More centrally, the stratum granulosum becomes pale staining and diens et progrediens Meleda). Further features are inflammatory borders,
pyknotic. Concommitantly, parakeratotic layers form on top. In the severe hyperhidrosis, maceration, and unpleasant smell. In addition, con-
horny layer a cleft appears that contains remnants of parakeratotic cells.1 stricting bands (pseudoainhum), brachydactyly, nail dystrophy, lesions on
A superficial perivascular lymphocytic infiltrate has been reported by knees and elbows, the perioral region and even oral leukokeratosis can be
some authors.3 observed.1,2

Mutations have been identified in the ARS component B gene on chromo-
some 8, encoding a protein named SLURP1.3–6 It is postulated that SLURP1
interacts with neuronal acetylcholine receptors present in keratinocytes and
sweat glands. Since SLURP1 may act as a secreted epidermal neuromodula-
tor essential for both epidermal homeostasis and inhibition of TNF-alpha
release by macrophages during wound healing, this may explain both the
hyperproliferative as well as the inflammatory clinical phenotype of Mal de
Meleda.3–6
Histology shows orthohyperkeratosis with focal parakeratosis, acanthosis
without epidermolytic changes, and a superficial perivascular lymphocytic
infiltrate
Keratosis palmoplantaris areata et striata

Clinical features
Keratosis palmoplantaris areata et striata (striate palmoplantar keratoderma,
Brünauer-Fuchs-Siemens syndrome, acral keratoderma) is an autosomal dom-
Fig. 3.88
inant disorder characterized by linear bands of keratoderma affecting the pal-
Keratosis palmoplantaris areata et striata: linear hyperkeratotic bands are present
mar aspects of the palms and fingers (Fig. 3.88) accompanied by island-like best seen along the ulnar border of the palm. By courtesy of the Institute of
areas of hyperkeratosis on the soles of the feet.1,2 Lesions typically present Dermatology, London, UK.
in adolescence or early adulthood and are exacerbated by manual labor. A
background palmar hyperkeratosis may be present and fissuring can also be
seen.3 Abnormalities of the nails (ridging and cuticle hyperkeratosis), teeth,
described.6 The granular/filamentous material represents condensed kera-
and hair (wooly hair) may also sometimes be encountered.3,4 There are no
tin filaments. Premature expression of involucrin and filaggrin has been
systemic associations.
found.9 In one family, immunohistochemistry demonstrated diminished
lesional desmoplakin staining.6 Electron microscopy displays diminished
numbers of small and/or rudimentary desmosomes accompanied by keratin
Striate palmoplantar keratoderma is a heterogeneous condition. A transi- filament aggregates and enlarged malformed keratohyalin granules.6,8,9
tion mutation in desmoglein 1, mapped to chromosome 18q12.1, has been
identified in one family.5–7 In another, a transition mutation in desmoplakin,
mapped to chromosome 6p21, was identified, and in a third type, mutation
Keratosis palmoplantaris nummularis
of keratin 1 with partial loss of the glycine loops in the V3 domain has been
reported.3,8 Clinical features
Histologically, striate palmoplantar keratoderma is characterized by In keratosis palmoplantaris nummularis (hereditary painful callosities)
massive hyperkeratosis, hypergranulosis, and acanthosis (Fig. 3.89). patients present with nummular keratotic lesions overlaying plantar pres-
Dark-staining granular and filamentous material within the prickle cell sure points. Keratoses develop when children start to walk. Pain is the major
layer accompanied by slight separation of the keratinocytes has also been complaint.1
Fig. 3.89
Keratosis palmoplantaris areata et striata: (A) there
A B is massive hyperkeratosis with hypergranulosis and
acanthosis; (B) high-power view.

The gene defect has not been identified as yet.
Histology shows epidermolytic hyperkeratosis similar to epidermolytic
palmoplantar keratoderma of Vörner-Unna-Thost.1
Punctate palmoplantar keratoderma

Clinical features
Punctate palmoplantar keratoderma (keratosis punctata palmaris et plan-
taris, keratoderma hereditarium dissipatum palmare et plantare, Buschke-
Fischer-Brauer disease, Davis-Colley disease) is characterized by an autosomal
dominant mode of inheritance.1–4 There is an increased incidence in blacks.2
Sometimes, lesions are associated with excessive manual labor.2 In an estab-
lished case, the patient has numerous discrete yellow-brown, small (1–3 mm),
depressed keratotic lesions on the palms and soles and also on the ventral
aspects of the fingers and toes (Figs 3.90, 3.91).5 If the keratin plug is dis-
lodged, a deeply depressed pit remains. Lesions are usually asymptomatic,
but occasionally pain, tenderness or burning are features.2,5
Fig. 3.91
There are occasional reports of punctate palmoplantar keratoderma asso-
Punctate palmoplantar keratoderma: close-up of lesions shown in Figure 3.90.
ciated with internal malignancies including carcinomas of the colon, kidney,
By courtesy of the Institute of Dermatology, London, UK.
breast, and pancreas and Hodgkin's lymphoma.6,7
Punctate keratoderma-like lesions affecting the palms and the soles have
been described as a complication of dioxin exposure.8

The pathogenesis is unknown. A locus has been genetically mapped on chro-
mosome 15q22-q24. The keratin gene clusters have been excluded by linkage
analysis.9
Histologically marked hyperkeratosis is seen overlying areas of epithelial
depression (Fig. 3.92).
Keratosis punctata of the palmar creases

Clinical features
Keratosis punctata of the palmar creases (keratotic pits of the palmar creases)
is a variant of punctate keratoderma in which the lesions are confined to
the palmar and digital creases.1–5 The soles of the feet and heels may also be
Fig. 3.92
Punctate palmoplantar keratoderma: there is massive hyperkeratosis overlying a
dell to the right of center.
involved.3,6 The sexes are equally affected and the disease is predominantly
seen in young to middle-aged adults.7 Although very rare in white patients,
it is common in black adults.3,5,8,9 The development of lesions appears to be
trauma related in many patients since outdoor workers are particularly affected
and the condition improves during a vacation. Although in the majority of
patients the condition appears to be a sporadic occurrence, in some reports an
autosomal dominant mode of inheritance has been documented.2,4
Lesions are small (1–3 mm) depressed yellowish keratotic plugs which are
usually asymptomatic but sometimes may be painful. They are localized to the
flexor creases and when removed leave a cone-shaped depression (Fig. 3.93).
Although usually seen as an incidental finding, on occasions they have been asso-
ciated with ichthyosis vulgaris.4,7 There are also reports of keratosis punctata of
Fig. 3.90 the palmar creases developing in patients with Dupuytren's contracture, derma-
Punctate palmoplantar titis herpetiformis with psoriasis, striate keratoderma, and knuckle pads.7,10
keratoderma:
discrete yellow foci Histological features
of hyperkeratosis are
present over the weight- The lesions are characterized by a hyperkeratotic plug, sometimes with foci of
bearing surfaces. By parakeratosis below which are deep cone-shaped depressions sometimes cen-
courtesy of the Institute tered on the acrosyringium.4 The adjacent epidermis shows acanthosis with
of Dermatology, London, hypergranulosis and in some cases a perivascular lymphohistiocytic infiltrate
UK. is present in the superficial dermis.
Fig. 3.93 Fig. 3.95

Keratosis punctata of the palmar creases: minute punctate lesions are localized Acrokeratoelastoidosis: knuckle pads are conspicuous in this patient. By courtesy of
solely to the palmar creases. There is often a history of manual labor. the Institute of Dermatology, London, UK.
Focal acral hyperkeratosis is clinically identical to acrokeratoelastoidosis,

Marginal papular acrokeratoderma patients presenting with keratotic papules along the sides of the hands, fingers, and
feet.7,8 It has also been designated acrokeratoelastoidosis without elastorrhexis.9
Clinical features Other reported cases have been mistakenly documented as acrokeratoelastoidosis.10
Marginal papular acrokeratoderma refers to a complex, confusing, and Females are affected more often than males. Although originally thought to be a
overlapping group of disorders which includes acrokeratoelastoidosis disorder of black children, more recently it has been described in whites.11
of Costa, focal acral hyperkeratosis, mosaic acral keratosis, degenerate Mosaic acral keratosis is similar if not identical to focal acral hyper
collagenous plaques of the hands, digital papular calcific elastosis, and keratosis, being characterized by keratotic papules distributed in a mosaic
keratoelastoidosis marginalis of the hands.1 All present with frequently or jigsaw-puzzle pattern along dorsal aspects of the feet and adjacent lower
crateriform, keratotic papules along the borders of the hands and feet legs.12 Hyperkeratosis may be seen on the palms and soles.1 Only females,
(Fig. 3.94).1 Although usually discrete, in some patients the papules may predominantly black, are affected.1
coalesce into plaques. Degenerative collagenous plaques of the hands affect the sun-damaged
Acrokeratoelastoidosis presents in childhood and adolescence with yel- skin of the elderly and present as symmetrical yellowish, keratotic or smooth
lowish, warty, and crateriform keratotic or pearly papules predominantly papules and plaques affecting the thumb, first web, and side of the index
affecting the sides of the hands, wrists, fingers, and feet.2–5 There is no racial finger.4,13–18 The ulnar border of the hand and volar aspect of the wrist may
predilection and the sexes are affected equally. Patients may also develop cir- also be involved. Keratoelastoidosis marginalis of the hands is a similar
cumscribed keratodermatous knuckle padlike lesions, palmoplantar hyperk- condition described in Australians in which keratotic papules develop at sites
eratosis, and hyperhidrosis (Fig. 3.95).1,3 Sporadic and autosomal dominant of trauma along the index finger and thumb.19 The skin is typically grossly
variants have been described. The disorder may be linked to chromosome 2.6 sun damaged. Calcified variants of degenerative collagenous plaques are
Repeated trauma is believed to be of etiological importance. known as digital papular calcific elastosis.20,21
Acrokeratoelastoidosis is characterized by massive orthohyperkeratosis over-
lying a crateriform dell lined by acanthotic epidermis. Hypergranulosis may
be present. The dermis shows fragmentation and loss of the elastic tissue
(elastorrhexis) (Fig. 3.96). Collagen may be disorganized or appear homog-
enized and pale staining.2,3
Focal acral hyperkeratosis and mosaic acral keratosis are histologically
identical with the exception that the elastic tissue appears normal.7–12
Degenerative collagenous plaques of the hands are characterized by a
dense zone of thickened and distorted collagen with fragmentation of elastic
fibers and overlying hyperkeratosis and acanthosis.4,13–18 The papillary dermis
is spared. Calcification is sometimes a feature (digital papular calcific elasto-
sis).19–21 Telangiectatic vessels may also be seen and increased dermal mucin
has been described.19
Huriez syndrome
Clinical features
In Huriez syndrome (keratosis palmoplantaris diffuse with sclerodactyly, scle-
Fig. 3.94 rothylosis) patients present with a diffuse mild palmoplantar keratoderma,
Marginal papular acrokeratoderma: there is a linear band of scaling along the border scleroatrophic skin of the limbs, hypohidrosis, hypoplasia, and dystrophy of
of the foot. By courtesy of the Institute of Dermatology, London, UK. the nails (Fig. 3.97).1 Aggressive squamous cell carcinoma may develop in the
Fig 3.96
Acrokeratoelastoidosis:
(A) there is marked
hyperkeratosis; (B) there is
A B diminution of the dermal
elastic tissue.
A B
Fig. 3.97
Huriez syndrome: (A) the leading features are sklerodactyly, hypotrophic and dystrophic nails, (B) there is mid palmar keratosis.
affected skin in approximately 15% of the cases. It has an early onset with a ectodermal dysplasia type VII) is a rare keratoderma which is usually inher-
high risk of metastasis in the third to fourth decades.1 ited as an autosomal dominant although a recessive variant has also been
described.1–3 Onset is in infancy or early childhood.2 Caucasians are pre-
Pathogenesis and histologic features dominantly affected and there is a predilection for females.3 The clini-
The genetic cause of this autosomal dominant condition is still unknown. cal features include palmoplantar keratoderma with a yellowish papular
Histology shows a mild acanthosis, orthohyperkeratosis and well developed and honeycomb-like appearance and hyperhidrosis. Other characteristics
granular layer (Fig. 3.98). Most interestingly, immunohistochemical and ultra- are starfish-like keratoses affecting the dorsal surfaces of the hands, feet,
structural studies revealed an absence of Langerhans cells in involved skin.2 wrists, forearms, elbows. and knees (Figs 3.99 and 3.100).3 Flexion con-
tractures and circumferential hyperkeratotic constriction bands (pseudoain-
hum) affecting the interphalangeal joints associated with autoamputation
Vohwinkel's syndrome are also present.2,3 Additional features include alopecia, nail dystrophy, and
onychogryphosis.2 In the classical variant, sensorineural deafness is an inte-
Clinical features gral feature.1,4,5 The ichthyosis-associated variant of Vohwinkel is a com-
Vohwinkel's syndrome (keratoderma hereditarium mutilans, keratosis pal- pletely different entity (see Loricrin keratoderma or Camisa variant form of
moplantaris mutilans, mutilating palmoplantar keratoderma, palmoplantar Vohwinkel's syndrome).6–9
Fig. 3.100
Vohwinkel’s syndrome: in
Fig. 3.98 this example there is very
Huriez syndrome. There are mild acanthosis, orthohyperkeratosis and well disfiguring keratoderma,
developed granular layer. hence the alternative title,
keratoderma hereditarium
mutilans. By courtesy
of W.A.D. Griffiths, MD,
London, UK.
Pathogenesis and histologic features

Mutations on chromosome 1q21 that result in aberrant, elongated C-terminal
domains of one loricrin allele may lead to an abnormal loricrin expression, and
impairment of cross-linking to itself and other cornified envelope proteins.3–5
Loricrin keratoderma and some cases of progressive symmetrical erythro-
keratoderma may share the mutation and light and ultrastructural features.6
Therefore some authors have proposed that the loricrin keratoderma should
include cases of what has been termed either (Vohwinkel's) keratoderma with
ichthyosis and progressive symmetrical erythrokeratoderma.7
As with progressive symmetrical erythrokeratoderma acanthosis, a promi-
nent stratum granulosum and parakeratosis is present in loricrin keratoderma
(Figs 3.102, 3.103).
Electron microscopy characteristically reveals formation of a well-formed
transitional layer, intranuclear granules in the upper stratum granulosum, and
Fig. 3.99
a thin cornified envelope.4 Immunoreactivity for loricrin can be detected in
Vohwinkel's syndrome: there is marked palmoplantar keratoderma. By courtesy of
W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.
the nuclei of the stratum granulosum and of the parakeratotic cells.4 Mutant
loricrin in the nucleus is thought to impair the function of profilaggrin to
mediate nuclear dissolution in the course of apoptosis which represents an
Pathogenesis and histological features integral part of keratinocyte terminal differentiation.6
Classical, deafness-associated Vohwinkel's syndrome is due to mutations in
the connexin 26 gene.8 Clouston's syndrome
Histologically, the keratoderma is characterized by hyperkeratosis, hyper-
granulosis, and acanthosis.3 Clinical features
Clouston's syndrome (hidrotic ectodermal dysplasia, palmoplantar ectoder-
mal dysplasia type X) is an uncommon disorder with an autosomal dominant
Loricrin keratoderma mode of inheritance. Nail dystrophy is often predominant, but hair defects
and palmoplantar keratoderma are also found (Fig. 3.104).1–7 Rare manifesta-
Clinical features tions include sensorineural deafness, ocular abnormalities, skin hyperpigmen-
Loricrin keratoderma (Camisa variant form of Vohwinkel's syndrome, tation, polydactyly, syndactyly, mental retardation, epilepsy, and dwarfism.5,6
Vohwinkel keratoderma with ichthyosis) is inherited in an autosomal dom- Changes in the nails are variable, but usually they are short and thickened
inant fashion and characterized by a diffuse palmoplantar keratoderma with longitudinal striations, often with discoloration, and may have grooves,
that is very similar to that of Vohwinkels' syndrome including the honey- pits and ridges.5,6 Development of paronychia is a frequent complication.
comb-like appearance (Fig. 3.101).1 In contrast, however, the palmoplantar Scalp alopecia (from hair thinning to complete baldness) is the rule, and facial,
keratoderma is less mutilating, and warty papules and starfish-like keratosis axillary, and pubic hair is usually sparse or totally absent.6 The patients have a
are absent. A concomitant ichthyosis with generalized fine scaling is a con- normal facies and no involvement of the dentition or abnormal sweating.
stant feature and often presents congenitally prior to the development of the Although hidrotic ectodermal dysplasia has been documented predomi-
palmoplantar keratoderma.2 The patients also do not suffer from the deafness nantly in French Canadian families, kindreds have been described in French,
seen in Vohwinkel's keratoderma. Scottish-Irish, and Indians.4,7–10
Fig. 3.101
Loricrin keratoderma:
(A) there is a generalized fine
scaling and (B) palmoplantar
keratoderma with a yellowish
popular and honeycomb-like
appearance less mutilating
A B than in classical Vohwinkel's
syndrome.
Fig. 3.102 Fig. 3.103

Loricrin keratoderma: there is hyperkeratosis and mild acanthosis. Loricrin keratoderma: the stratum granulosum is prominent. Scattered cells (on
the right side of the field) show perinuclear vacuolization and the parakeratotic
keratinocytes in the lower horny layer represent transitional cells.
The gene responsible for this condition has been mapped to 13q11–
12.1.11–14 Hidrotic ectodermal dysplasia results from a connexin 30 one family.6 There is no racial predilection. There is a striking predominance
mutation.15–18 in males (5:1).
The palmoplantar keratoderma is typified by hyperkeratosis, thickening The keratoderma is present at birth or begins in early infancy and when
of the granular cell layer, and acanthosis.5,7 Elsewhere, eccrine sweat glands fully developed presents as bilateral and symmetrical massively thickened,
are normal, but hair and sebaceous glands are greatly reduced in number and yellow, macerated, keratotic plaques covering the whole of the sole and palm
apocrine glands completely absent.8 and often extending to the lateral and even the dorsal surface of the hands
and feet (Fig. 3.105).3,4 The heels and forearms may also be affected. The
border of the plaque is sharply defined and surrounded by a pruritic ery-
Olmsted syndrome thematous border. Lesions are often fissured and extremely painful, mak-
ing walking exceedingly difficult or impossible.3,4 Blistering has occasionally
Clinical features been described.5 Flexion contractures, ainhum-like constriction bands, and
Olmsted syndrome is exceedingly rare and combines the features of mutilat- autoamputation are common complications. Superinfection with bacteria
ing palmoplantar keratoderma with periorificial plaques. Approximately 20 and fungi, particularly Candida albicans, contributes to the problems and as
cases have been documented.1–5 It is usually associated with sporadic occur- a result lesions are frequently very malodorous. Squamous carcinoma is an
rence although X-linked dominant transmission has been suggested at least in occasional complication.7,8
The plaques show increased mitotic activity, increased Ki-67 expres-

sion and increased argyrophilic nucleolar organizer regions (AgNORS).4,9
Keratinization is abnormal with aberrant expression of keratins 5, 10 and
14, filaggrin, and involucrin.4,5 It has, however, been proposed that the kera-
tin abnormalities might be a result of isotretinoin and etretinate therapy.10
Papillon-Lefèvre syndrome
Clinical features
Palmoplantar keratoderma with periodontopathia (palmoplantar kerato-
derma with periodontopathia, palmoplantar ectodermal dysplasia type IV)
is rare and has an autosomal recessive mode of inheritance.1 The incidence
is 1–4 per million of the population.2 There is an equal sex incidence and
onset is usually in the first decade. It is characterized by symmetrical and
marked palmoplantar keratoderma sometimes affecting the dorsal aspects of
the hands and feet (Fig. 3.106).3 Hyperhidrosis may also be present, associ-
ated with gingivitis and marked periodontosis involving both deciduous and
permanent teeth.4,5 Periodontosis is unrelated to oral hygiene and results in
Fig. 3.104 loss of attachment of teeth to the periodontal ligament (Fig. 3.107) and atro-
Clouston's syndrome: there is nail dystrophy accompanied by hyperkeratosis of the phy of the alveolar processes (maxillar and mandibular) with eventual loss
fingertips, thereby accentuating the epidermal surface ridges. of teeth. The periodontal ligament, which is a dense fibrous band, attaches
By courtesy of D. Atherton, MD, the Children's Hospital at Great Ormond Street, the tooth to the alveolar bone and carries the blood vessels, lymphatics, and
London, UK.
nerves.6 Psoriasiform lesions may be evident on the knees and elbows and
Fig. 3.105
Olmsted syndrome: in this variant, the lesions are very disfiguring. Constriction
bands and autoamputation are important complications. By courtesy of W.A.D.
Griffiths, MD, Institute of Dermatology, London, UK.
Affected children also develop erythematous keratotic papules and plaques

around the body orifices including the mouth, nares, ears, and anus.3,4 The eye-
lids, umbilical region, inguinal region, and gluteal cleft can also be involved.
Additional features include scarring alopecia, keratosis pilaris, and nail
dystrophy including ridging, transverse striae, thickening, curvature, subun-
gual keratosis, and infection.3,4 Hyperkeratotic linear streaks may develop in Fig. 3.106
the axillae and cubital fossae. Growth retardation, laxity of the large joints, Papillon-Lefèvre
and corneal involvement are occasional manifestations.3,4 syndrome: (A) there is
marked hyperkeratosis
Histological features affecting the soles of the
The plaques are characterized by massive hyperkeratosis, often with foci of feet; (B) in this patient,
the dorsal aspects of
vertically orientated parakeratosis.2–5 There is hypergranulosis with large
the hands, particularly
coarse granules under the former whereas the granular cell layer is absent the knuckles are also
beneath the areas of parakeratosis. The epidermis is acanthotic and shows affected. By courtesy
psoriasiform hyperplasia or papillomatosis and there is edema and increased of W.A.D. Griffiths, MD,
vascularity of the superficial dermis where a lymphohistiocytic infiltrate is B Institute of Dermatology,
also seen. London, UK.
Fig. 3.107
Papillon-Lefèvre syndrome: gingival inflammation and swelling with the particularly
characteristic irregular positioning of the teeth which, as a result of destruction of Fig. 3.109
supporting tissues, have shifted under the forces of mastication. This patient is Papillon-Lefèvre
a 12-year-old child, but the severity of the periodontal destruction is what might syndrome: there
be expected in a person aged 60 years. By courtesy of R.A. Cawson, MD, Guy's is hyperkeratosis,
Hospital, London, UK. hypergranulosis and
acanthosis.
onychogryphosis has been documented (Fig. 3.108).3 The adnexae are not granule serine proteases with resultant defective bacterial phagocytosis.11,12
usually affected. Presentation is usually in the early years of life (2–4 years The cathepsin C gene is also expressed in squamous epithelium of the palms,
of age). soles, knees, and the oral keratinized gingiva.9 At this site, its function is
There is sometimes associated calcification of the falx cerebri and chor- unknown.
oid plexus.6 Other features, which may sometimes be present, include deaf- The histopathological features of the palmoplantar lesions show marked
ness, deformity of the terminal phalanx, follicular hyperkeratosis, and mental hyperkeratosis with acanthosis and a thickened granular cell layer (Fig.
retardation. Patients show an increased risk of infection, particularly furun- 3.109).3 Parakeratosis and epidermal psoriasiform hyperplasia have also
culosis; this has been associated with defective neutrophil chemotaxis and been described.7 The elbow and knee lesions show epidermal psoriasiform
phagocytosis and impaired B- and T-cell mitogenic responses.7 hyperplasia with parakeratosis, elongation of the dermal papillae, and dilata-
tion of the superficial dermal vasculature.3
Papillon-Lefèvre syndrome has been mapped to 11q14–21.8 The disease
is associated with missense and nonsense mutations, deletions, and inser-
Naxos syndrome
tions in the gene for the lysosomal cysteine protease cathepsin C (dipeptidyl
aminopeptidase I).9–12 In homozygous patients, loss of cathepsin C activ- Clinical features
ity results in impaired activation of bone marrow myeloid and macrophage Naxos syndrome (keratosis palmoplantaris with arrhythmogenic cardiomy-
opathy) is an autosomal recessive inherited disease defined by palmoplan-
tar keratoderma, curly hair, and other ectodermal features associated with
dilatative cardiomyopathy leading to arrhythmogenic episodes.1,2 It was first
reported in families on the Greek island of Naxos.1

A deletion in the plakoglobin gene which results in a frameshift mutation in
plakoglobin, an important component of desmosomes, has been identified in
Naxos syndrome.3 Histology shows compact hyperkeratosis, hypergranulo-
sis, and acanthosis.2
McGrath syndrome
Clinical features
McGrath syndrome (skin fragility and hypohidrotic ectodermal dysplasia) is
inherited in an autosomal recessive mode and is characterized by a diffuse,
sometimes verruciform palmoplantar keratoderma, trauma-induced skin
fragility, and congenital ectodermal dysplasia affecting nails, hair, and sweat
glands.1 In some cases plantar hyperkeratosis is painful and there is disabling
Fig. 3.108 cracking. The nails are thickened and markedly dystrophic. The integument
Papillon-Lefèvre syndrome: a scaly psoriasiform plaque is present over the elbow. shows fragility, with trauma-induced blisters and crusting on pressure points.
By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK. Hairs are noted to be short and sparse. Sweating may be reduced.
Pathogenesis and histologic features described.11 The follicular lesions show plugging of the ostia with surround-
ing hyperkeratosis, parakeratosis, and acanthosis (Fig. 3.114).6 A mononu-
The disease has been shown to be associated with mutations in the
clear perivascular chronic inflammatory cell infiltrate may be present in the
lakophilin-1 gene (PKP1) leading to complete ablation of plakophilin 1
p
superficial dermis. The oral lesions are indistinguishable from those of the
which is responsible for recruitment of desmosomal proteins to the plasma
white sponge nevus, consisting of parakeratosis, acanthosis, and epithelial
membrane and keratin interaction.1,2
vacuolation (Fig. 3.115). No evidence of dysplasia is seen.
Light microscopy of the skin shows thickening of the epidermis and exten-
sive widening of keratinocyte intercellular spaces, extending from the first
suprabasal layer upward. There is complete absence of cutaneous immunos- Pachyonychia congenita type II
taining for plakophilin-1. Electron microscopy reveals loss of keratinocyte–
keratinocyte adhesion. Desmosomes, particularly in the lower suprabasal
layers, are small and reduced in number. The inner and outer desmosomal
Clinical features
plaques are poorly developed.3 Pachyonychia congenita type II (palmoplantar ectodermal dysplasia type
II, Jackson-Lawler syndrome, Jackson-Sertoli syndrome) is inherited as an
autosomal dominant. It is characterized by limited and usually mild focal
Pachyonychia congenita type I
Clinical features
Focal (nonepidermolytic) palmoplantar keratoderma with oral hyperkera-
tosis (Jadassohn-Lewandowsky syndrome, focal palmoplantar keratoderma
with oral hyperkeratosis, palmoplantar ectodermal dysplasia type I) is usu-
ally associated with an autosomal dominant mode of inheritance although an
autosomal recessive variant has been described.1,2 It has a high incidence in
Croatia and Slovenia and also appears to be more commonly seen in Jews.3,4
Clinical features may be present at birth or appear within the first 6 months
of life.1,5 The sex incidence is equal.
The features include massive hyperkeratosis of the distal nail beds of the
fingers and toes, resulting in elevation and apparent thickening of the nail
plate (Fig. 3.110). Also present are palmoplantar keratoderma, hyperhidro-
sis and follicular keratosis, xerosis, and verrucous lesions, which most often
arise on the elbows, knees, and lower legs (Fig. 3.111). Patients also develop
alopecia and nail bed infections.1,5,6 Erythema and blistering of the soles of the
feet, and to a lesser extent on the palms of the hands, are sometimes present;
leukokeratosis oris is almost invariably evident (Fig. 3.112).1,6,7 Laryngeal
involvement has also been documented.8 Fig. 3.111
Pachyonychia congenita
Pathogenesis and histological features type 1: discrete, yellow,
hyperkeratotic plaques on
This variant of focal palmoplantar keratoderma is heterogeneous. Mutations
the soles of the feet are
have been described in keratin K16 and K6a genes.9–14 a common manifestation.
The nail beds show massive hyperkeratosis.1 The palmoplantar lesions By courtesy of R.A.
are characterized by hyperkeratosis, hypergranulosis, and acanthosis (Fig. Marsden, MD, St
3.113).1 Round to oval darkly staining perinuclear inclusions represent- George's Hospital,
ing densely aggregated keratin filaments in the prickle cell layer have been London, UK.
A B
Fig. 3.110
Pachyonychia congenita type 1: (A) there is gross nail deformity with transverse arching of the distal portion. Although the nail plate appears to be thickened, most of the
changes are, in fact, due to massive hyperkeratosis of the nail bed, resulting in elevation and bending of the nail plate; (B) in this view, the subungual hyperkeratosis is more
obvious. (A) By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK, (B) By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.
Fig. 3.112 Fig. 3.114

Pachyonychia congenita type 1: leukoplakia of the buccal mucosa is a frequent Pachyonychia congenita
accompanying feature. By courtesy of R.A. Marsden, MD, St George's Hospital, type 1: follicular lesion
London, UK. showing keratin plugging
of the ostium with
adjacent hyperkeratosis
and associated
acanthosis.
Tyrosinemia type II
Clinical features
Tyrosinemia type II (Richner-Hanhart syndrome, tyrosine aminotransferase
deficiency, keratosis palmoplantaris with corneal dystrophy) is an oculocu-
taneous syndrome characterized by herpetiform corneal ulcers that develop
during the first months of life. Later painful punctuate, sometimes striated
and circumscribed hyperkeratoses of digits, palms, and soles evolve, often
accompanied by hyperhidrosis. Aberrant keratotic plaques have been sporad-
ically observed on the elbows, knees, and even the tongue. Other symptoms
include severe mental and somatic retardation.1

Tyrosinemia type II is caused by autosomal recessively inherited deficiency
of hepatic tyrosine aminotransferase. Point mutations in the tyrosine amin-
otransferase gene have been identified which map to the long arm of chro-
Fig. 3.113 mosome 16. 2,3 Diagnosis can be confirmed by identifying tyrosinemia and
Pachyonychia congenita phenylacetic acidemia with excessive levels of P-hydroxyphenylactic acid in
type 1: volar skin showing
the urine. Clinical and biochemical improvement may be achieved by a low
massive hyperkeratosis,
phenylalanine-low tyrosine diet.1
acanthosis. Histologically the epidermis is acanthotic, the granular layer is thickened,
and the keratinocytes contain eosinophilic globular inclusions. 4
Electron microscopy demonstrates an increased synthesis of tonofibrils
and keratohyalin, large numbers of microtubules, and unusually tight pack-
palmoplantar keratoderma over pressure areas, subungual hyperkeratosis, ing of tonofibrillar masses, which contain tubular channels or inclusions
epidermal cysts, steatocystoma multiplex, abnormal eyebrows and body of microtubules.4 Presumably, excessive amounts of intracellular tyrosine
hair (pili torti), natal teeth, angular cheilosis, and hoarseness.1,2 Plantar enhance cross-links between aggregated tonofilaments leading to a globular
lesions may be delayed until late childhood. In contrast to pachyonychia appearance.4
congenita type I, patients do not develop leukokeratosis oris. This palmo-
plantar ectodermal dysplasia has no known association with malignancy.
Carvajal-Huerta syndrome
Pachyonychia congenita type II results from mutations in keratin 17 and ker- Clinical features
atin 6b genes.3–7 Interestingly, mutations in keratin 17 may also result in ste- The Carvajal-Huerta syndrome is an autosomal recessively inherited dis-
atocystoma multiplex in isolation.3 ease with palmoplantar keratoderma, woolly hair, and dilated cardiomy-
Histologically, the subungual changes and keratoderma are similar to opathy.1,2 The patients are born with woolly hair. Around the first year,
those described in the type I variant, although milder. The epidermoid cysts palmoplantar keratoderma and other keratotic signs appear. The clinical
and steatocystomata show typical features. symptoms of Carvajal-Huerta syndrome resemble those of Naxos disease
At the ultrastructural level, loosening of intercellular connections, disrup-

tion of desmosome–keratin intermediate filament interactions, and rudimen-
tary desmosomal structures can be demonstrated.2
Howell-Evans syndrome
Clinical features
The combination of autosomal dominant focal nonepidermolytic palmoplan-
tar keratoderma with esophageal squamous carcinoma was first recognized
in 1958 and subsequently termed the Howell-Evans syndrome.1–5 Although
initially regarded as a diffuse keratoderma, a subsequent clinical re-evalu-
ation determined that the lesions were focal, sparing nontraumatized areas
(Fig. 3.116).4 The condition typically presents between 6 and 15 years of
age. The patients develop painful hyperkeratoses on the pressure areas,
which disappear with prolonged bed rest.5 Palmar involvement may be seen
A
B
Fig. 3.115
Pachyonychia congenita type 1: (A) scanning view of oral mucosa showing
massive acanthosis with large blunt rete ridges; (B) high-power view showing focal
parakeratosis and vacuolization of superficial keratinocytes. A single dyskeratotic
cell is evident (arrowed).
but the PPK in the former is of a striated and not diffuse type. The first car-
diac abnormalities are exclusively electrocardiographic and occur in asymp-
tomatic patients. In these patients, dilatation of the left ventricle, together
with alterations in muscle contractility, may lead to congestive heart failure
and death.

Mutations in the gene on chromosome 6p24 encoding desmoplakin have
been found.3 Desmoplakin is a major constituent of desmosomes and as such B
is crucial for the rigidity and strength of the epidermis and cardiac tissue.
Biopsies of skin lesions show features of epidermolytic hyperkeratosis.1 Fig. 3.116
Immunohistochemistry confirms perinuclear localization of keratin in the Howell-Evans syndrome: (A) focal autosomal dominant palmoplantar keratoderma
suprabasal keratinocytes. This suggests collapse of the intermediate filament is associated with an increased risk of esophageal squamous carcinoma; (B) in
network as a response to the failure of desmoplakin to attach the intermediate this patient, the palms were also severely affected. By courtesy of the Institute of
filaments to the desmosomes. Dermatology, London, UK.
Acquired palmoplantar keratoderma and internal malignancy 91
in manual workers. This syndrome, also termed palmoplantar ectodermal Keratoderma climactericum
dysplasia type III, includes keratosis pilaris particularly affecting the upper
arms and thighs, multiple epithelial cysts, and gray-white buccal mucosal
hyperkeratosis (This last feature typically predates the onset of keratoderma
Clinical features
and may therefore represent a clinical diagnostic clue of early involvement in Keratoderma climactericum (Haxthausen's disease, climacteric kerato-
family members of a pedigree.).5–9 Nails are unaffected.6 In the largest kin- derma) is an acquired disorder which is restricted to menopausal women.1,2
dred reported to date, 28% developed esophageal squamous carcinoma (89 Lesions present on the weight-bearing surfaces of the sole of the foot as ery-
affected members) of whom 84% died of their tumor.4 thematous hyperkeratotic and fissured plaques and then spread to involve
the rest of the plantar skin (Fig. 3.118). Patients are often overweight.
Pathogenesis and histological features Palmar involvement is sometimes seen with lesions affecting the area
between the thenar and hypothenar eminences.2 Similar lesions have been
The condition has been mapped to 17q23-qter region (TEC locus) distal to
documented in younger women who have undergone bilateral oophorec-
the keratin gene cluster, thereby excluding a keratin gene mutation.10–12
tomy.3 The condition is distinguished from congenital palmoplantar kerato-
The cutaneous lesions are characterized by hyperkeratosis, hypergranulo-
derma by its late onset.
sis, and acanthosis. Features of epidermolytic hyperkeratosis are absent.
The buccal mucosal lesions are characterized by parakeratosis, acantho-
sis, and spongiosis accompanied by cytoplasmic vacuolation of the prickle
cell layer.4 The plantar skin shows massive hyperkeratosis, hypergranulosis, acanthosis,
and spongiosis with lymphocytic exocytosis.2 A superficial perivascular der-
mal lymphohistiocytic infiltrate is present and vertically orientated dermal
Schöpf-Schulz-Passarge syndrome collagen associated with atypical myofibroblasts is often seen.2
Clinical features
Clavus
The Schöpf-Schulz-Passarge syndrome (palmoplantar keratoderma with eye-
lid cysts, hypodontia, and hypotrichosis) is probably inherited in an auto- Clavi (corns) are extremely common painful keratotic lesions that develop
somal recessive pattern.1 Patients have a relatively mild, diffuse erythematous on the dorsal or lateral aspect of the toes, often as a consequence of ill-fitting
keratoderma association with hypodontia, hypotrichosis, nail dystrophies, shoes. Histologically, they are characterized by a deep keratin-filled depres-
and late-onset eyelid cysts. sion often associated with atrophy of the underlying epidermis (Fig. 3.119).
They are distinguished from plantar warts by the absence of koilocytes and
Histological features irregular keratohyalin granules.
The eyelid lesions represent apocrine hidrocystomas. Multiple eccrine syrin-
gofibroadenomas and squamous cell carcinomas may arise on the acral sur- Callus
faces in older patients.1,2 The underlying defect remains unknown.3 In contrast to a clavus, a callus is a nonpainful localized focus of hyperkerato-
sis usually arising on the ball of the foot or heel from pressure or foot defor-
Acquired palmoplantar keratoderma and mity. Palmar lesions arise as a consequence of chronic rubbing. Histologically,
they are similar to a clavus, consisting of a keratin-filled epidermal dell with
internal malignancy hypergranulosis. Parakeratosis is often present.
Acquired diffuse palmoplantar keratoderma may represent a paraneoplas-
tic phenomenon associated with a number of internal malignancies includ- Acrokeratosis verruciformis of Hopf
ing carcinoma of the bronchus, esophagus, stomach, urinary bladder, and
myeloma (Fig. 3.117).1–6 There are also reports of acquired filiform (filiform Clinical features
palmoplantar keratoderma) and punctate (punctate porokeratotic kerato- This is an exceedingly rare dermatosis with an autosomal dominant mode of
derma) variants associated with a range of visceral cancers including breast, inheritance.1–3 The disease presents in infancy or early childhood as dry, rough,
kidney, colon, and lung.7,8 brownish or skin-colored verrucoid, keratotic papules, located particularly on
Fig. 3.117
Acquired palmoplantar
keratoderma: acquired
disease may be a
manifestation of
underlying malignancy. By
courtesy of the Institute Fig. 3.118
of Dermatology, London, Keratoderma climactericum: there is massive hyperkeratosis with fissuring over the
UK. heels. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.120
Acrokeratosis
verruciformis: numerous
brown flat-topped
papules are symmetrically
distributed over the dorsal
aspects of the hands.
Fig. 3.119 By courtesy of
Clavus: massive R.A. Marsden, MD,
hyperkeratosis overlies an St George's Hospital,
epidermal depression. London, UK.
the backs of the hands (Fig. 3.120) and feet, and on the knees and elbows.4
Keratotic punctate pits are found on the palms and soles. Lesions, which are
clinically and histologically indistinguishable, may occasionally be seen in
Darier's disease.5–7 Exceptionally, a similar association with Hailey-Hailey dis-
ease has been documented and there is a report of acrokeratosis verruciformis
presenting in a patient with nevoid basal cell carcinoma syndrome.8,9 Nail
involvement, including longitudinal splitting, striations and subungual hyper-
keratosis may also be seen.10

Loss of function of the sarco- (endo-) plasmic reticulum Ca2+ ATPase2
mutant in acrokeratosis verruciformis provides evidence that acrokeratosis
verruciformis and Darier's disease are allelic disorders.11 However, identifica-
tion of mutations in genes other than ATP2A2 suggests genetic heterogeneity
of acrokeratosis verruciformis.12
The lesions are acanthotic with a prominent granular cell layer, typically
showing a ‘church spire’ appearance (Fig. 3.121). There is usually moderate
to marked hyperkeratosis. Parakeratosis is not a feature. Step sections some-
times reveal acantholytic dyskeratosis in those cases associated with Darier's Fig. 3.121
disease. Acrokeratosis verruciformis: there is hyperkeratosis and church-spire papillomatosis.
Acrokeratosis verruciformis-like features may occasionally be seen in lin- presents in adulthood as persistent lesions that are highly resistant to
ear epidermal nevi.13 There is also considerable histological overlap with therapy.
stuccokeratosis. • Localized porokeratosis usually consists of a single large lesion.
• Disseminated superficial actinic porokeratosis, the most common variant,
is characterized by numerous small, dry, shallow lesions arising on
Porokeratosis the sun-damaged skin of adults (Figs 3.123 and 3.124).2 It may also
complicate PUVA therapy and develop in the immunosuppressed.3–5 It
Clinical features presents in the third and fourth decades and, despite its relationship
Porokeratosis is a not uncommon pathological process. It consists of a pig- to sunlight, rarely affects the face. The legs, forearms, back, upper
mented or reddish atrophic center bordered by a peripheral grooved keratotic arms, and thighs are most commonly affected, in decreasing order of
ridge, from the center of which a keratotic core (cornoid lamella) projects frequency.6
at an obtuse angle.1 There are six major categories: classical, localized, lin- • Disseminated superficial (nonactinic) porokeratosis (porokeratosis
ear, punctate, disseminated superficial porokeratosis (DSP), and disseminated palmoplantaris et disseminata) is characterized by asymptomatic lesions
superficial actinic porokeratosis (DSAP), all of which may be inherited as an with a tendency to involve the trunk, genitalia, palms, and soles. An
autosomal dominant, but sporadic cases also occur. intensely itchy eruptive variant of this has recently been described.7
• In the classical variant described by Mibelli, patients develop one or • In linear porokeratosis, the lesion is clinically reminiscent of an epidermal
several plaquelike lesions on the extremities (Fig. 3.122). It usually nevus affecting the extremities and usually presents in infancy or early
Fig. 3.122
Porokeratosis of Mibelli: (A) these lesions have an
extensive and linear distribution; (B) the lesions are
erythematous, atrophic and scaly, with sharply defined and
A B slightly raised margins By courtesy of M.M. Black, MD,
Institute of Dermatology, London, UK.
Fig. 3.124
Fig. 3.123 Disseminated superficial actinic porokeratosis: in this variant, the lesions are small
Disseminated superficial and discrete. Note the characteristic raised edge. By courtesy of the Institute of
actinic porokeratosis: Dermatology, London, UK.
there are numerous small,
reddish or brownish carcinoma.1,8,10–15 The reported incidence has varied from 6.8% to 11.6%.10,13,14
keratotic macules on sun In some instances there is a probable causal relationship with previous treat-
damaged skin. ment with radiotherapy.10 Tumors usually develop many years after the onset
of the disease, are frequently multiple, and arise most often on large or coalesc-
childhood (Fig. 3.125).8 A zosteriform variant has also been described ing lesions.8,10,16 They are most often found on the trunk and extremities.8
which generally affects children and shows a predilection for the lower
limbs, upper limbs, and trunk.9 Pathogenesis and histological features
• In punctate porokeratosis (porokeratosis palmoplantaris punctata, spiny The pathogenesis of porokeratosis is unknown. The presence of localized
keratoderma) tiny spines develop on palms and soles in the second or dysplastic features was suggested by Reed and Leone to indicate that the
third decade. Some argue that the typical ultrastructural changes of disease represented a focal, expanding clone of abnormal keratinocytes asso-
porokeratosis of Mibelli are not present. It must be distinguished from ciated with the development of a cornoid lamella.17 The more recent literature
other forms of punctate keratoderma.6 appears to support this claim.
Porokeratosis may involve the mucous membranes, cause nail dystrophy, Porokeratotic lesions have been shown to be associated with abnormal
and result in patchy alopecia. It is associated with a slightly increased risk of epidermal DNA ploides in association with increased DNA indices, midway
cutaneous neoplasia. Lesions of porokeratosis may therefore be complicated between normal skin and Bowen's disease.18,19 Uninvolved skin, however, is
by the development of Bowen's disease, and basal cell and squamous cell usually diploid.8 Chromosomal abnormalities have been identified within
cultured keratinocytes and fibroblasts derived from patients suffering from causally related to hepatitis C infection, Crohn's disease, renal failure, and
both the localized and Mibelli variants.8,10,20,21 These findings have since been hemodialysis.25–29
confirmed in both cultured fibroblasts from normal untreated skin and lym- p53 and pRb proteins are overexpressed within keratinocytes immedi-
phocytes, and it has been shown that chromosome 3 is preferentially affected.22 ately beneath and adjacent to the cornoid lamellae; mdm-2 and p21waf-1 are
Mutations in the proximal segment of the short arm of chromosome 3 have reduced.30–33 This imbalance in cell cycle control mechanisms offers a poten-
been associated with a wide variety of malignancies.22 Ionizing radiation, ultra- tial explanation for the development of malignancy in porokeratosis although
violet light including sun tanning beds, and PUVA may be associated with the to date p53 mutation has not been identified.32,34
development of new skin lesions in porokeratosis.23 The first may be of par- Recently, a gene for disseminated superficial actinic porokeratosis has been
ticular relevance to the development of malignancy in these lesions.14,24 mapped to chromosome 12q23.2–24.1 in a large Chinese family.35
Cultured fibroblasts from porokeratosis patients have been shown to be The biopsy must be taken through the peripheral grooved ridge. If the long
hypersensitive to the lethal effects of X-radiation, but not ultraviolet radia- axis of the specimen does not transact the border, the diagnostic features will be
tion.21,22 This has been shown to be associated with chromosomal instability missed. These consist of a keratin-filled epidermal invagination with an angu-
in approximately 50% of patients.20 While it has been proposed that this may lated parakeratotic tier, the cornoid lamella (Fig. 3.126). Despite its name,
result from abnormal DNA repair mechanisms (see xeroderma pigmentosa) the lesions of porokeratosis are rarely related to the ‘pore’ of the eccrine duct.
the evidence necessary to support such a hypothesis is not yet available.21 While they may involve the follicle, their most common origin is from nonad-
Porokeratosis of Mibelli, disseminated superficial porokeratosis, and nexal epithelium. The corneocytes of the cornoid lamella contain characteristic
disseminated superficial actinic porokeratosis may also develop against a PAS-positive granules. The epithelium deep to the tier is vacuolated and devoid
background of solid organ transplantation or blood transfusion, possibly of a granular cell layer (Fig. 3.127). Dyskeratotic cells may be present and
Fig. 3.127
Fig. 3.125 Porokeratosis of Mibelli:
Linear porokeratosis: in the epidermis at the base
this variant, the lesion of the cornoid lamella
has a linear, nevoid is vacuolated and the
distribution. granular cell layer absent.
A B
Fig. 3.126
Porokeratosis of Mibelli: (A) there is hyperkeratosis with two well-developed cornoid lamellae. Note the epidermal depression at their bases. (B) The cornoid lamella can be
seen to be composed of an angulated tier of parakeratosis.
Fig. 3.128
Disseminated superficial actinic porokeratosis: in this example, the cornoid lamella
has arisen overlying an acrosyringium. The epidermis towards the center on the
lesion appears atrophic and the papillary dermis contains ectatic blood vessels.
epithelial dysplasia, ranging from mild changes through to carcinoma in situ, A

is occasionally a feature. Liquefactive degeneration of the basal cell layer of the
epithelium is sometimes present and occasionally there are conspicuous cytoid
bodies. The adjacent epithelium towards the center is often atrophic, but may
be of normal thickness or even acanthotic. In the dermis, a non-specific chronic
inflammatory cell infiltrate and telangiectatic vessels are sometimes seen. The
typical features are best seen in the Mibelli variant. The changes tend to be less
pronounced in the other subtypes (Fig. 3.128). In the actinic variant there is
often solar elastosis and atrophy of the adjacent epidermis.6
With the appropriate clinical information, the histopathological changes
of porokeratosis are diagnostic. Cornoid lamella formation, however, does
occur as a non-specific finding in a variety of conditions including psoriasis
vulgaris, seborrheic, solar keratosis, verruca vulgaris, and squamous cell and
basal cell carcinomas.36 Cornoid lamellae are also features of verrucous epi-
dermal nevus and porokeratotic eccrine nevus.37,38 They are also not uncom-
mon in normal, and particularly actinically damaged, skin. PAS-positive
B
structures in the cornoid lamella may be a useful marker for porokeratosis
although this has not been authors experience.39 Fig. 3.129
Flegel's disease: (A) there are characteristic disseminated erythematous scaly
lesions; (B) the lower legs are commonly affected. Lesions are small, multiple
Hyperkeratosis lenticularis perstans and covered by a well-developed scale. By courtesy of M. Price, MD, Institute of
Clinical features
Hyperkeratosis lenticularis perstans (Flegel's disease) is a not uncommon der-
matosis that is sometimes mistaken for Kyrle's disease.1–5 It has an equal sex
incidence and patients present most often in their fourth or fifth decade. It is Pathogenesis and histological features
characterized by a very protracted course, many patients having lesions for Flegel's disease is of unknown etiology and pathogenesis and is characterized
decades. Patients present with large numbers of 1–5-mm discrete, gray, gray- by focal areas of abnormal hyperkeratinization.7–10 Early lesions are not diag-
brown or red-brown, circular scaly papules (Fig. 3.129). Initial lesions often nostic, showing merely lamellar hyperkeratosis, focal parakeratosis, and an
arise on the dorsum of the foot. Other sites of predilection include the lower essentially normal epidermis. In an established lesion, in addition to hyper-
legs, upper arms, and pinnae. The buttocks, trunk, and dorsal aspects of the keratosis and occasional parakeratosis, there is epidermal atrophy with an
hands may also be affected, and punctate keratoses have been described on inconspicuous or absent granular cell layer (Figs 3.130, 3.131). The lower
the palms and soles. The lesions are either asymptomatic or mildly pruritic. layers of the epithelium may show intercellular edema and occasional foci of
Characteristically, removal of the scale is associated with pinpoint bleeding, basal cell degeneration. Cytoid bodies are sometimes evident. Typically, the
a feature that distinguishes this disorder from stucco keratoses. Other than papillary dermis is edematous and a chronic inflammatory cell infiltrate is
an isolated report of an increased incidence of both basal cell and squamous often present, adopting a perivascular or lichenoid distribution. Pigmentary
carcinomas, there is no particular associated disease process (compare incontinence is not usually a feature.
with Kyrle's disease).6 Although most cases appear to be sporadic, there is The lymphocytes are an admixture of CD4+ T-helper cells and, less fre-
some evidence to support an autosomal dominant mode of inheritance in a quently CD8+ T-suppressor cells.8,9 Sézary-like forms have been described.
proportion of cases. Langerhans cells are highly reduced.9 In the atrophic areas, differentiation
Fig. 3.131
Flegel's disease: high-power view showing spongiosis with microvesiculation,
cytoid bodies, and a predominantly lymphocytic infiltrate.
less commonly, in nonintertriginous skin including the lower back, buttocks,

and flanks.5–8 Women are affected more commonly than males. The disease
mainly affects the middle aged to elderly; children are rarely involved.8–10
It presents as pruritic or burning erythematous, hyperpigmented, and
hyperkeratotic patches, papules, or plaques (Fig. 3.132). Fissures and a
‘cobblestone’ appearance may be seen. The condition has been documented
to respond to retinoids and to calcipotriene and ammonium lactate.11,12

B The etiology is unknown. It has been suggested that the condition develops
as a result of a contact reaction to an antiperspirant or as a result of exces-
Fig. 3.130 sive use of other topical products including creams, shampoos, and soaps.1–6,8
Flegel's disease: (A) scanning view of an established lesion showing focal However, this does not explain the involvement of areas distant from the
hyperkeratosis, parakeratosis, and a superficial bandlike chronic inflammatory axilla. The molecular mechanism proposed to explain the disease consists of
cell infiltrate; (B) there is hyperkeratosis, focal epidermal atrophy and basal cell a failure to transform profilaggrin to filaggrin with the resultant failure in
liquefactive degeneration. Note the cytoid bodies
degradation of keratohyalin granules.1,7
The histological appearances typically consist of a massive hyperkerato-
sis with parakeratosis and retention of keratohyalin granules in the stratum
markers such as cytokeratin 1 and 10, filaggrin, and loricrin are absent. corneum (Fig. 3.133). The underlying epidermis may show mild acanthosis
Ultrastructurally, the most commonly documented changes have been or even some degree of thinning. Hair infundibula are occasionally affected.
rudimentary keratohyalin granules, absence, vacuolation or abnormally Necrotic areas with invasion of neutrophils or perforation of the epidermis
lamellated membrane coating (Odland) bodies, failure to form a compact are rarely found. The superficial dermis contains a sparse perivascular lym-
keratin, and cornified envelope in the corneocytes.8,9 phocytic infiltrate.1–7
Clinically, Flegel's disease differs from Kyrle's disease by the absence of Differential diagnosis
keratin-filled penetrating plugs and the frequent presence of palmar and plan- Apart from representing a dermatosis, granular parakeratosis is a diagnos-
tar lesions, which are not seen in Kyrle's disease. Flegel's disease is sometimes tic feature in solitary keratosis, i.e., granular parakeratotic acanthoma.13
confused with stuccokeratoses, but these do not affect the trunk, palms, and Granular parakeratosis can be also found as an incidental finding in many
soles and the lesions may be readily removed without bleeding. Histologically, diseases, e.g., dermatophytosis, molluscum contagiosum, dermatomyositis,
stucco keratoses are characterized by orthohyperkeratosis and ‘church spire’ solar keratosis, squamous cell carcinoma, keratoacanthoma, lymphomatoid
papillomatosis. Although there may be histological overlap with other condi- papulosis, and basal cell carcinoma (Fig. 3.134).14 As such, granular parak-
tions showing lichenoid features, the striking keratotic tier with parakeratosis eratosis can best be considered as a histologic pattern similar to focal acan-
and absent granular cell layer are useful diagnostic pointers. tholytic dyskeratosis or epidermolytic hyperkeratosis.14
Granular parakeratosis Circumscribed palmar or plantar

Clinical features hypokeratosis
Granular parakeratosis is a distinctive acquired disorder of keratinization
originally reported in 1991.1–4 The condition most often affects the axillae Clinical features
but it has also been described involving other intertriginous areas including Circumscribed palmar or plantar hypokeratosis is a recently described
submammary and intermammary skin, groins, vulva, perianal region and, entity that is characterized by the development of well-circumscribed,
Fig. 3.132
Granular parakeratosis: (A)
in the axilla of a middle-
aged woman erythematous,
hyperpigmented and
hyperkeratotic papules
develop in a reticulated
A B fashion, (B) a few of them
are erosive.
A B
Fig. 3.133
Granular parakeratosis: (A) there is marked thickening of the horny layer with parakeratosis, (B) high-power view showing retention of the keratohyalin granules.
depressed, erythematous lesions on the thenar and hypothenar regions of of the continuous growth of some lesions, and suggest a trauma or a human
the palms or the medial side of the soles (Fig. 3.135).1 The lesions some- papillomavirus type 4 as a causative.1–5
times have an arcuate or polycyclic outline, a slightly scaling border, range Histologically, the lesional depression relates to a sharply circumscribed
in diameter from a few millimeters up to 3 centimeters, and are symp- loss of the cornified layer above an otherwise normal epidermis (Fig. 3.136).1–7
tomless. All patients were middle aged or elderly with a predominance of Other authors observed a thin layer of parakeratosis in the hypokeratotic
women.2 zone and some psoriasiform hyperplasia of the epidermis with expression of
the hyperprolifertaive keratin 16.6,7
Pathogenesis and histological features Additional features are hyperplasia of sweat ducts, and tortuous and elongated
The pathogenesis of circumscribed palmar or plantar hypokeratosis is a mat- capillaries in the papillary dermis; still, an inflammatory cell infiltrate is lacking.5
ter of debate. While some authors favor the interpretation of an epidermal Ultrastructurally, breakage of the corneocytes within their cytoplasm
malformation in view of persistence over years, others dispute this because suggests enhanced corneocyte fragility.7
Fig. 3.134
Granular parakeratosis:
(A) this example arose
against a background of
A B lymphomatoid papulosis;
(B) high-power view.
Fig. 3.136
Circumscribed palmar or plantar hypokeratosis: (A) scanning view from the edge of
a lesion, (B) note the focal thinning of the stratum corneum.
Fig. 3.135
Circumscribed palmar or plantar hypokeratosis: (A) on the thenar a well-
circumscribed, depressed, erythematous lesion is present, (B) a closer view reveals
a scaly border.
Inherited and autoimmune Chapter
See
for references and
additional material
subepidermal blistering diseases
4
Split skin immunofluorescence 100 Lichen planus pemphigoides 131 Dermatitis herpetiformis 144
Immunoperoxidase antigen mapping 101 Mucous membrane pemphigoid (cicatricial Linear IgA disease 147
pemphigoid) 133
Epidermolysis bullosa 101
Epidermolysis bullosa acquisita (dermolytic
Bullous pemphigoid 117
pemphigoid) 137
Pemphigoid gestationis 127
Bullous systemic lupus erythematosus 142
Blisters, which are clinically subdivided into vesicles (L. vesicula, dim. of substrate as a mechanism of localizing the site of epidermodermal separation.1
vesica, bladder) and bullae (L. bubble), are defined as accumulations of fluid If a sample has not been taken for indirect immunofluorescence, immunoper-
either within or below the epidermis and mucous membranes. Although oxidase antigen mapping on paraffin-embedded material may on occasions
somewhat arbitrary, the term ‘vesicle’ is applied to lesions less than 0.5 cm in be of value at least as a screening procedure. Although the results of electron
diameter and ‘bulla’ to those greater than 0.5 cm. Subepidermal blisters, i.e., microscopic investigations and, in particular, molecular studies have formed
those that develop at the epidermal or mucosal basement membrane region, the basis of the current classification of subepidermal bullous dermatoses,
include inherited variants and acquired (often autoimmune mediated) such techniques are usually not essential to the everyday investigation of a
conditions. The former are usually classified as noninflammatory (cell-poor) patient with an acquired blistering disorder.
blisters whereas the latter are commonly inflammatory (cell-rich) in nature The mechanisms involved in the development of a subepidermal blister are
(Fig. 4.1). variable. They include inherited mutational defects of basement membrane
Subepidermal blisters may develop within the lower epidermis, the lamina proteins, i.e., epidermolysis bullosa, acquired autoimmune bullous diseases
lucida (e.g., bullous pemphigoid) or deep to the lamina densa (e.g., such as bullous pemphigoid, cellular immunity-mediated disorders (e.g.,
epidermolysis bullosa acquisita) (Fig. 4.2). In addition to clinical observa- erythema multiforme and toxic epidermal necrolysis), metabolic diseases
tions, the precise diagnosis of a blistering disorder requires careful histologi- including porphyria cutanea tarda, and profound subepidermal edema such
cal and immunofluorescence correlation. When possible, the last should as may be seen in bullous arthropod bite reactions and dermal acute
include indirect studies and, in particular, NaCl-split skin should be used as inflammatory processes (e.g., Sweet's disease).
Fig. 4.1
Classification of subepidermal
blisters: lesions may be
A B subdivided into (A) cell-poor
and (B) cell-rich variants.
100 Inherited and autoimmune subepidermal blistering diseases
Intact skin
K5, K14 (IF)
Epidermis
300K>IFAR LL
LD
Plectin BP230
a6
HD
CM Dermis
BP180 b4
LL
NaCL split skin
Laminin-5
LD Epidermis
AF
AP Artificial
blister cavity
Fig. 4.2
Basement membrane constituents: blisters can be classified into those that develop LD
within the lamina lucida (LL) and those that arise below the lamina densa (LD). (AF,
anchoring fibrils; AP, anchoring plaque; CM, cell membrane.) Dermis Fig. 4.3
Split skin immunofluorescence.
In this chapter, only those conditions in which subepidermal blister forma-

electron microscopy or immunofluorescence) (Figs 4.4, 4.5), the technique
tion represents an inherited or autoimmune primary event are considered.
enables precise localization of a circulating basement membrane zone anti-
Other conditions, which may be associated with subepidermal blistering, are
body to either the floor or the roof of the artificial blister cavity. In bullous
dealt with in more appropriate chapters.
pemphigoid, pemphigoid gestationis, and the majority of cases of mucous
membrane pemphigoid, linear immunofluorescence is found along the roof of
Split skin immunofluorescence the artificial blister whereas in diseases characterized by a sublamina densa
split (e.g., epidermolysis bullosa acquisita, antilaminin mucous membrane
This technique represents a modification of indirect immunofluorescence pemphigoid, anti-p105 pemphigoid, anti-p200 pemphigoid, and bullous der-
(IMF) where normal skin is split through the lamina lucida of the basement matosis of bullous lupus erythematosus), the immunofluorescent signal is
membrane region to produce an artificial blister cavity (with the lamina densa found along the floor of the blister (see references 3 and 4 for a review)
lining the floor) for use as substrate. Artificial separation can be achieved by (Fig. 4.6). In some diseases, positive immunofluorescence may be found on
the suction technique (in vivo) or by immersion of normal skin in 1 M NaCl either the roof or the floor or even at both sites simultaneously (e.g., linear IgA
for 48 hours at 4°C (Fig. 4.3). In general, the latter technique is preferred.2 As disease and some variants of mucous membrane pemphigoid). Such variable
such a split is invariably through the lamina lucida region (confirmed by labeling reflects the antigen heterogeneity in a number of bullous dermatoses.
A B
Fig. 4.4
(A, B) Split skin immunofluorescence: the split is through the lamina lucida, the lamina densa lining the floor of the artificial blister cavity.
Fig. 4.5 Fig. 4.7

Split skin immunofluorescence: type IV collagen lines the floor of the split skin Paraffin-embedded immunoperoxidase antigen mapping: in bullous pemphigoid,
artificial blister which therefore forms within the lamina lucida. By courtesy of B. type IV collagen is present along the floor of the blister.
Bhogal, FIMLS, Institute of Dermatology, London, UK.
Fig. 4.6
Split skin immunofluorescence: (left) linear IgG at the basement membrane;
(middle) in epidermolysis bullosa acquisita (EBA), the antibody binds to the floor of
the blister cavity; (right) in bullous pemphigoid (BP), the antibody binds to the roof
of the blister. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, Fig. 4.8
UK. Paraffin-embedded immunoperoxidase antigen mapping: in epidermolysis bullosa
acquisita, type IV collagen is present along the roof of the blister cavity.
Immunoperoxidase antigen mapping Epidermolysis bullosa

As an alternative to split skin immunofluorescence, paraffin-embedded Epidermolysis bullosa (EB) refers to a heterogeneous group of diseases in
sections of lesional skin have been proposed in a direct immunoperoxidase which the skin and sometimes the mucous membranes blister easily in
antigen mapping technique to identify the level of the epidermodermal response to mild trauma, hence the alternative title ‘mechanobullous derma-
separation.5–8This procedure localizes known basement membrane region tosis’, which has sometimes been applied.1 All are rare conditions; the estimated
constituents such as keratins 5/14, laminin, and type IV collagen to the roof incidence for the group as a whole is in the order of 1:20 000. Apart from the
or floor of the blister cavity. The site of blister formation can therefore be acquired autoimmune variant (epidermolysis bullosa acquisita), they are all
characterized as intrabasal, within the lamina lucida or deep to the lamina autosomal inherited disorders.
densa. For example, in epidermolysis bullosa simplex variants, all of these EB was initially described as a defined entity in 1886.2 This group of con-
immunoreactants are present along the floor of the blister cavity. In bullous ditions has been classified in several ways over the years. The three major
pemphigoid, keratin is present along the roof of the blister while laminin and types were defined in a groundbreaking electron microscopy study in 1962.3
type IV collagen are found along the floor (Fig. 4.7). In dystrophic epidermolysis In 1988, the contemporary classification and subtyping of the major variants
bullosa, epidermolysis bullosa acquisita, and bullous systemic lupus commenced with the first consensus meeting of the Steering Committee of
erythematosus, all three immunoreactants are present in the roof of the blister the National EB Registry (established in 1986) held in conjunction with the
(Fig. 4.8). However, in many hereditary and acquired blistering diseases American Academy of Dermatology.4,5 At that time, 23 seemingly clinically
the relevant antibodies against the target antigens do not work well in distinct variants were recognized (Table 4.1).5 In the following decade, a
paraffin-embedded material and false-positive and false-negative results are second consensus conference was held.6 As a result of the considerably
common, making this method unreliable for use in routine diagnosis. For increased number of cases available for study, a much greater degree of clinical
example, antigen mapping of the group of hereditary subepidermal blistering overlap between the various subtypes was recognized. For this reason and
diseases is done exclusively on frozen sections with excellent results. because of a much better understanding of the molecular basis for many of
Table 4.1 Table 4.2

First consensus conference (1988): classification of subepidermal blisters Second consensus conference (1999): classification of epidermolysis bullosa
EB simplex
Major EB Protein/gene
Localized Major EB type subtype systems involved
EB simplex of hands and feet (Weber-Cockayne variant)
EBS (‘epidermolytic EBS-WC K5, K14
EB simplex with anodontia/hypodontia (Kallin syndrome)
EB’) EBS-K K5, K14
Generalized EBS-DM K5, K14
EB simplex, Koebner variant EBS-MD Plectin
EB simplex herpetiformis (Dowling-Meara variant)
Junctional EB JEB-H Laminin-5*
EB simplex with mottled or reticulate hyperpigmentation with or without
HEB-nH Laminin-5; type XVII collagen
punctate keratoderma
EB simplex superficialis JEB-PA† α6β4 integrin‡
EB simplex, Ogna variant DEB (‘dermolytic EB’) DDEB Type VII collagen
Autosomal recessive EB simplex (letalis) with or without neuromuscular RDEB-HS Type VII collagen
disease RDEB-nHS Type VII collagen
EB simplex, Mendes da Costa variant
Reproduced with permission from Fine, J.D. et al (1991) Pediatrician, 18, Reproduced from Fine et al (2000) J Am Acad Dermatol, 42, 1051–1066 from American
175–187. Academy of Dermatology.
DDEB, dominant dystrophic EB; DEB, dystrophic EB; RDEB, recessive DDEB, dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner;
EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber-Cockayne; JEB-H,
dystrophic EB.
junctional EB, Herlitz; JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with
Junctional EB pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS,
Localized recessive dystrophic EB, non-Hallopeau-Siemens.
*Laminim-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains;
Junctional EB, inversa
mutations in any of the encoding genes result in a junctional EB phenotype.
Junctional EB, acral/minimus †Some cases of EB associated with pyloric atresia may have intraepidermal cleavage
Junctional EB, progressiva variant or both intralamina lucida and intraepidermal clefts.
Generalized ‡α β integrin is a heterodimeric protein; mutations in either gene have been
6 4
Junctional EB, gravis variant (Herlitz variant) associated with the JEB-PA syndrome.
Junctional EB, mitis variant (non-Herlitz variant; EB atrophicans
generalisata mitis; generalized atrophic benign EB)
Cicatricial junctional EB
Dystrophic EB
In 1999, a fourth category – hemidesmosomal EB (where the level of split
Localized is within the hemidesmosome) – was added.10 This provisional category has
RDEB, inversa now been removed and Kindler syndrome now constitutes a fourth major cat-
DDEB, minimus egory. The most recent classification, which takes into account the current
DDEB, pretibial
precise molecular data which is now known for virtually all of the subtypes
RDEB, centripetalis
of this disease, is particularly valuable when considering the pathological
Generalized
basis of EB and forms the basis for this account. There have been some
Autosomal dominant forms of DEB changes in nomenclature based on an attempt to produce names that are
DDEB, Pasini variant
more accurately descriptive of the diseases and concordant with current
DDEB, Cockayne-Touraine variant transient bullous dermolysis
of the newborn
molecular classification of this disease.
Autosomal recessive forms of DEB Mutations of sundry types in a variety of genes encoding plakophilin-1
RDEB, gravis (Hallopeau-Siemens variant) (PKP1), desmoplakin (DSP), keratins 5 and 14 (KRT5, KRT14), plectin
RDEB, mitis (PLEC1), BP180, α6 and β4 integrin subunits (ITGA6, ITGB4), laminin-5
(now termed laminin-332 and encoded by LAMA3, LAMB3, LAMC2), types
XVII and VII collagen (COL17A1, COL7A1) and kindling-1 (KIND1) cur-
rently account for the different subtypes of EB (a more detailed account of
the variants of EB, a considerably simplified classification system was rec- these basement membrane proteins is given in Chapter 1).10–12
ommended at that time (Table 4.2).7,8 Most recently, at the Third International Molecular studies including Western blot and immunoprecipitation,
Consensus Meeting on Diagnosis and Classification of EB, the classification however, are not always available for every case of EB, particularly at
scheme was further revised and this current proposed scheme forms the presentation, and therefore initially at least the patient may well be
framework for the discussion in this chapter (Tables 4.3, 4.4).9 Research provisionally subclassified on the basis of:
over the past two decades has generated a wealth of literature specifically • clinical variation,
addressing the molecular basis of the various subtypes of EB. As a result, it • presence or absence of extracutaneous manifestations,
is now possible to subgroup EB on the basis of the level of separation within • mode of inheritance,
the basement membrane region as well as on specific molecular findings. • immunoepitope mapping and/or electron microscopy.
Though molecular classification now drives our understanding of this dis- Clinical evaluation of a patient with suspected EB should include the age
ease group, knowledge of the traditional clinical subtypes can be helpful in of onset and nature and distribution of the cutaneous lesions and whether or
explaining the disease course to patients, despite the often overlapping not scarring and contractures are present. In addition, the family pedigree
spectrum of manifestations. should be studied and the patient investigated for the presence or absence of
Traditionally, EB has been classified into three major groups based on extracutaneous involvement (eyes, oropharynx, larynx, gastrointestinal and
clinical differences, antigen mapping, and electron microscopic observations: genitourinary tracts, and musculoskeletal system) and other specific lesions
• simplex (epidermolytic; in which the level of split is within the basal (including enamel hypoplasia, anodontia or hypodontia, pyloric atresia, and
keratinocyte), muscular dystrophy) that might point towards a particular variant.4,5
• junctional (lucidolytic; where the level of split is within the lamina Four major subtypes of EB are now recognized: simplex, junctional,
lucida), dystrophic and Kindler Syndrome: 4–7,9
• dystrophic (dermolytic; where the level of split is deep to the lamina • EB simplex (historically also known as the epidermolytic variant) is
densa). characterized by the level of separation within the epidermis, usually as a
Table 4.3
Third consensus conference (2007): classification of epidermolysis bullosa
Major EB type Major EB subtype Protein involved

EBS Suprabasal
Lethal acantholytic EB Desmoplakin
Plakophilin deficiency Plakophilin-1
EBS superficialis (EBSS) ?
Basal
EBS, localized (EBS-loc)+ K5, K14
EBS, Dowling-Meara (EBS-DM) K5, K14
EBS, other generalized (EBS, gen-nonDM; EBS, gen-nDM)^ K5, K14
EBS with mottled pigmentation (EBS-MP) K5
EBS with muscular dystrophy (EBS-MD) Plectin
EBS with pyloric atresia (EBS-PA) Plectin, α6β4 integrin‡
EBS, autosomal recessive (EBS-AR) K14
EBS, Ogna (EBS-Og) Plectin
EBS, migratory circinate (EBS-migr) K5
Junctional EB JEB, Herlitz (JEB-H) Laminin-332 (laminin-5)*
JEB, other (JEB-O)
JEB, non-Herlitz, generalized (JEB-nH gen)$ Laminin-332; type XVII collagen (BP180)
JEB, non-Herlitz, localized (JEB-nH loc) Type XVII collagen
JEB with pyloric atresia (JEB-PA)† α6β4 integrin‡
JEB, inversa (JEB-I) Laminin-332
JEB, late onset (JEB-lo)# ?
LOC syndrome (laryngo-onycho-cutaneous syndrome) Laminin-332 α3 chain
DEB (‘dermolytic EB’) Dominant dystrophic EB (DDEB)
DDEB, generalized (DDEB-gen) Type VII collagen
DDEB, acral (DDEB-ac) Type VII collagen
DDEB, pretibial (DDEB-Pt) Type VII collagen
DDEB, pruriginosa (DDEB-Pr) Type VII collagen
DDEB, bullous dermolysis of the newborn (DDEB-BDN) Type VII collagen
Recessive dystrophic EB (RDEB)
RDEB, severe generalized (RDEB-sev gen)@ Type VII collagen
RDEB, generalized other (RDEB-O) Type VII collagen
RDEB, inversa (RDEB-I) Type VII collagen
RDEB, pretibial (RDEB-Pt) Type VII collagen
RDEB, pruriginosa (RDEB-Pr) Type VII collagen
RDEB, centripetalis (RDEB-Ce) Type VII collagen
RDEB, bullous dermolysis of the newborn (RDEB-BDN) Type VII collagen
Kindler syndrome Kindlin-1
Adapted from Fine et al (2008) J Am Acad Dermatol, 58, 931–50 from American Academy of Dermatology.
Rare variants are italicized.
+Previously termed EBS, Weber-Cockayne
^Includes cases previously termed EBS-Koebner
‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with both EBS-PA and JEBS-PA. Some cases of EB associated with pyloric atresia may have
6 4
intraepidermal cleavage or both intralamina lucida and intraepidermal clefts.
*Laminin-332 (laminin-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains; mutations in any of the encoding genes result in a junctional EB phenotype.
$Previously termed generalized atrophic benign EB (GABEB).
#Previously termed EB progressiva.
@Previously termed RDEB, Hallopeau-Siemens.
Dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner; EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber–Cockayne; JEB-H, junctional EB, Herlitz;
JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS, recessive dystrophic EB,
non-Hallopeau-Siemens.
†Some cases of EB associated with pyloric atresia may have intraepidermal cleavage or both intralamina lucida and intraepidermal clefts.
‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with the JEB-PA syndrome.
6 4
consequence of cytolysis. Traditionally, all variants have been associated distinguished by the split through the hemidesmosome. The group
with mutations in the genes encoding keratin 5 or 14.8,9 However, the included EB with late-onset muscular dystrophy (previously included in
most current classification scheme divides this group into suprabasal and the simplex group), some examples of generalized atrophic benign EB
basal forms, and now certain rare variants are known to be associated (others associated with laminin-332 mutations are included within the
with mutations in the genes encoding desmoplakin, plakophilin-1, junctional group) and EB with pyloric atresia (previously included in the
plectin, and α6 and β4 integrin subunits.9 junctional group).10,14–16 These three variants of EB develop as a
• Epidermolysis bullosa with late-onset muscular dystrophy, which had consequence of mutations of genes encoding the hemidesmosomal
traditionally been included in the simplex category, is now known to proteins plectin, BP180, and the α6 and β4 integrin subunits
result from a mutation in the plectin gene and was included in the respectively.10 In the newest classification scheme, these are now
provisional hemidesmosomal group of EB as delineated by Pulkkinen and included in the suprabasal and basal types of EB simplex (Table 4.4).
Uitto in the 1999 classification scheme.10,13 Hemidesmosomal EB was The hemidesmosomal group designation is no longer used as the
Table 4.4 a recently described inherited disease known as ectodermal dysplasia-skin

Simplified classification of epidermolysis bullosa fragility syndrome. Plakophilin-1 (PKP1) deficiency is an autosomal recessive
disease that is associated with skin fragility and an inflammatory response
Subtype Mutation
resulting in erosions, scale-crust, and progressive palmoplantar keratoderma.
Simplex Suprabasal Plakophilin-1; desmoplakin Ectodermal effects such as sparse hair and anhidrosis and astigmatism are
Basal Keratin 5 or 14; plectin; α6β4 integrin also noted.20 While initially described in a single child, approximately ten
Junctional Herlitz Laminin-332 (laminin-5) cases with mutations in this gene have now been described.20,21
Non-Herlitz Laminin-332; type XVII collagen;
α6β4 integrin Epidermolysis bullosa simplex superficialis
This rare form of EB transmitted in an autosomal dominant fashion was first
Dystrophic Dominant Type VII collagen
described in 1989. It specifically differs from the other simplex variants by
Recessive Type VII collagen
the site of epidermal cleavage: variable subcorneal split between the stratum
Kindler syndrome Kindlin-1 corneum and granular cell layer or sometimes within the stratum spinosum
rather than intrabasal.22 Patients present at birth or within the first 2 years of
life with erosions and crusts sparing the palms and soles. Atrophic scarring,
nail dystrophy, and milia are additional common features; oral and ocular
consensus conference considered its application to be less useful than the epithelia can be affected.23 As well as the cutaneous manifestations, anemia
current scheme. The main reason for this decision is that it is a somewhat and gastrointestinal lesions affect a minority of patients. Some cases are asso-
artificial category. It separated non-Herlitz junctional EB into two ciated with mutations causing structural dysfunction of type VII collagen.23
categories namely, junctional EB and hemidesmosomal EB, based only on The condition may be clinically confused with peeling skin syndrome but in
the presence of mutations in the genes encoding either laminin-332 or the latter there are no blisters and peeling is continous and spontaneous.
type XVII collagen, respectively. Both conditions have very similar
clinical features and cannot be separated on clinical grounds, making this
Basal EBS
distinction confusing for clinicians, patients, and their parents. Thus all
the diseases in the hemidesmosomal category are now reclassified into Nine subtypes of basal EBS are currently recognized, five of which are very
either the junctional or simplex types of EB. rare.
• Junctional EB is characterized by the development of cleavage within the EB simplex, localized (Weber-Cockayne; EB simplex of the
lamina lucida. It results from mutations in one of the three genes hands and feet)
encoding the hetrotrimeric subunits of laminin-332 (laminin-5), α6 and β4 This is the most common form of epidermolysis bullosa and has an autosomal
integrin subunits, and type XVII collagen.17 As mentioned above, some of dominant mode of inheritance.4 5 Lesions are limited to the palms and soles
these cases were deamed in the provisional hemidesmosomal category in and are usually detected in infancy or the first few years of life (Fig. 4.9).
the previous classification scheme (e.g., α6 or β4 integrin subunits with EB Occasionally, in patients with mild involvement, blisters and erosions may
with pyloric atresia). not develop until childhood or even early adulthood in association with
• Dystrophic EB (also known as the dermolytic variant) is defined by a strenuous activity. The lesions, which sometimes heal with atrophic scarring,
split developing immediately below the lamina densa in the region of the show seasonal variation, often occurring only in the summer months.
anchoring fibrils. This type is composed of genetically dominant and Hyperhidrosis may sometimes be present. Milia, atrophic scarring, and nail
recessive subtypes invariably due to type VII collagen gene mutations.18,19 dystrophy are uncommon features.5,7 The teeth are uninvolved and there is no
evidence of any systemic involvement, except perhaps for oral erosions, which
Clinical features may affect an appreciable number of patients in infancy.7 Ocular lesions are
not a feature. Repeated episodes of secondary infection may occur in some
EB simplex (EBS)
patients. Postinflammatory hyper- and hypopigmentation may sometimes
Two major types of EB simplex (with 12 subtypes) are now recognized: be a cosmetic problem.8
• suprabasal,
• basal. EBS, Dowling-Meara (EBS herpetiformis)
This variant, which is the second commonest form of EB simplex, shows clin-
Suprabasal EBS ical features resembling dermatitis herpetiformis and has an autosomal domi-
Three suprabasal subtypes are recognized; all of them are rare variants. nant mode of inheritance (Fig. 4.10).7,24–27 Herpetiform grouping of blisters is
characteristic. Lesions are usually present at birth and have a distribution
Lethal acantholytic EB sometimes mimicking severe dystrophic or junctional disease.7 Some patients
Lethal acantholytic EB has been described in two cases with severely defective die in early infancy due to infection, fluid loss or electrolyte imbalance.1 Milia
skin and mucosal epithelia.19 The disease was lethal in the neonatal period formation is common, but atrophy and scarring are rare.7 Distal flexural
due to epidermolysis that was first noted during parturition leading to uncon- contractures are occasionally present.25 Nail dystrophy is often found and
trollable loss of fluid from the skin. Additional defects included universal palmoplantar keratoderma is characteristic. Anodontia and hypodontia have
alopecia and complete shedding of nails and the presence of neonatal teeth. also been described. Normalization during episodes of high fever is a typical
Histology revealed clefting of the suprabasal layer producing a tombstone-type finding but seasonal variation is not a feature.26 Blistering significantly
appearance reminiscent of pemphigus vulgaris. Molecular investigation improves with advancing years.27 Mutations in keratins 5 and 14 underlie this
revealed that the patient had inherited two different nonfunctional copies of disease.28–31 Death as a result of complications of the disease is rare and gener-
the gene encoding desmoplakin (DSP, a desmosomal protein that links the ally occurs by age 1 as a result of sepsis or respiratory failure.32
transmembrane cadherins to the various proteins of the cytoplasmic interme-
diate filaments), one from each parent, indicating that the disease is autosomal EBS, other generalized (includes Koebner variant)
recessive. The mutations both lead to truncation of the desmoplakin protein This group has an autosomal dominant mode of inheritance and includes pri-
and an inability to act as a linker. Additional cases will be necessary to further marily those cases previously termed Koebner-type and all other generalized
define this syndrome. subtypes of EBS.5 In the Koebner variant, blisters are present at birth or
shortly thereafter and, although the entire body may be affected, lesions are
Plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome, particularly severe on the extremities, where the dorsal surfaces tend to be
McGrath syndrome) involved (Fig. 4.11).5 The blisters usually heal without scarring or atrophy
Plakophilin is a required component of desmosomes and an important pro- and milia are very uncommon.5 The eruption often worsens in the summer
tein in ectodermal development. The rare deficiencies in this protein result in months. The nails are rarely dystrophic and teeth abnormalities are typically
A B
Fig. 4.9
EB simplex (Weber-Cockayne): typical lesions affecting (A) the fingers and (B) the toes. The pale color of the latter is due to the marked thickness of the roof of the blister.
Fig. 4.11
EB simplex (Koebner):
intact blisters are present
in the axilla and on the
chest. By courtesy of
M.J. Tidman, MD, Guy's
Hospital, London, UK.
Fig. 4.10
EB bullosa simplex:
Dowling-Meara variant involvement.36–38 Blisters and erosions present at birth or soon thereafter and
showing characteristic are usually generalized. Patients may also suffer from atrophic scarring, milia,
grouping of blisters and
nail dystrophy or anonychia, alopecia, and oral lesions36,37 Severe mucose
erosions. By courtesy
of R.A.J. Eady, MD,
membrane involvement is rare.39 The mortality of this variant is high.6
Institute of Dermatology, Mutations in plectin are associated with these forms of the disease.40–42 Plectin
London, UK. is a large (greater than 500 kD) intermediate filament binding protein that pro-
vides mechanical rigidity to cells by acting as crosslinking adaptor to the
cytoskeleton.43 The PLEC1 gene bears a domain structure similar to BPAG1,
indicating they belong to a common family and may have similar functions.
absent. Although oral lesions may be present in infancy, systemic involvement
A lethal variant of EBS with mutations in plectin at the level of the plakin
is not a feature of this variant.
domain may occur exceptionally and it is associated with aplasia cutis of the
EBS with mottled pigmentation limbs and developmental impairment.42
This autosomal dominant variant was originally described in six members of
EBS with pyloric atresia
a single kindred.33 The cutaneous lesions are similar to the Dowling-Meara
This category was placed in the provisional hemidesmosomal category in the
variant with the addition of mottled or reticulate pigmentation, particularly
prior edition of this book. Cases with pyloric atresia are currently considered
affecting the neck and trunk. Atrophic scarring, milia, and nail dystrophy are
in two groups: EBS discussed here, and another category in junctional EB dis-
uncommon. Punctate keratoderma affecting the palms and warty hyperkera-
cussed below. This is a rare variant of epidermolysis bullosa in which affected
totic lesions involving the hands, elbows, and knees may be additional fea-
infants are at risk of ureterovesical junction obstruction with fibrosis involv-
tures.33–35 Dental caries is also sometimes present and intraoral lesions are
ing the entire urinary tract and aplasia cutis congenita in addition to pyloric
occasionally seen.
atresia (Figs 4.12, 4.13).44–47 Polyhydramnios is also seen. The pyloric atresia
EBS with muscular dystrophy (pseudojunctional EB) may be due to a diaphragm or stenosis (Fig. 4.14). The mortality rate of this
This is an autosomal recessive variant in which patients concomitantly develop variant is very high, up to 78% of affected infants succumbing.46 It appears to
muscular dystrophy or exceptionally myasthenia gravis and even cardiac be the most lethal form in the EBS category. Mutations in both plectin and
Fig. 4.12
EB with pyloric atresia:
stillborn infant with
widespread blistering.
By courtesy of M.J.
Tidman, MD, Institute of
Fig. 4.14
(A, B) EB with pyloric atresia: pyloric canal is obliterated by fibrous connective tissue.
EBS, Ogna
This form is autosomal dominant and presents at birth. It primarily involves
acral sites, but can become widespread. Blistering is prominent and ony-
chogryphosis is common. A tendency to bruise has been described.9,52 Lack of
muscular involvement distinguishes this form of disease from EBS with mus-
cular dystrophy described above; the mutation genotype may be predictive of
disease expression.42,53
Fig. 4.13 Mutations in plectin underlie this syndrome.39,52
EB with pyloric atresia: in addition to blistering there is also deep ulceration.
By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK. EBS, migratory circinate
This generalized form of EBS presents at birth with an autosomal dominant
inheritance pattern. Blistering is very prominent and associated with a migra-
tory circinate erythema and postinflammatory hyperpigmentation.9 Mutations
α6β4 integrin subunits (junctional EB) have been described.48 Since both α6β4 in keratin 5 have been described, but none is currently reported in keratin
integrin and plectin are expressed in villous trophoblast from the first trimes- 14.39,54,55
ter of pregnancy this feature has been used successfully for the prenatal diag-
nosis of this group of conditions.49 Hemidesmosomal EB
This group previously included three variants:
EBS, autosomal recessive • patients with generalized atrophic benign EB (GABEB) (others were
Autosomal recessive EBS is generalized with onset at birth. Blistering is prom- included in the junctional group; see below),
inent with mild atrophic scarring. Ichthyotic plaques and focal palmoplantar • EB with late-onset muscular dystrophy (formerly included in the simplex
keratoderma are sometimes encountered. Nails may be dystrophic or absent. group),
Anemia, growth retardation, dental caries, and constipation can be complica- • EB with pyloric atresia (formerly included in the junctional category).
tions.9 Mutations in keratin 14 underlie this disease; keratin 5 mutations have This subtype is of historical interest only as it no longer exists in the most
not been described.50,51 current classification scheme.
Junctional epidermolysis bullosa

Two major subtypes of this variant are recognized: junctional EB-Herlitz and
junctional EB-non-Herlitz (Other). This later group encompasses both local-
ized and generalized forms, cases with pyloric atresia, and three additional very
rare variants under the newly revised classification scheme.9 Junctional EB with
pyloric atresia was classified in the hemidesmosomal group in the prior classi-
fication scheme. All have an autosomal recessive mode of inheritance.
Junctional EB, Herlitz (Herlitz, gravis variant of junctional

EB, EB hereditaria letalis, EB atrophicans generalisata
gravis)
Within this generalized variant, no additional subtypes are recognized. Blisters
and erosions are present at birth accompanied by scarring and atrophy
(Fig. 4.15).56–58 Milia may be a feature.7 Healing with the formation of
exuberant, vegetative or tumorous granulation tissue is a pathognomonic
feature (Fig. 4.16).5 This is found particularly around the mouth, sides of the
neck, trunk, and about the nails.4 The nails may be dystrophic or absent and
scarring alopecia is sometimes evident.5 Severe oral involvement (including
scarring and microstomia) is usually present and pitted dystrophic enamel is Fig. 4.16
characteristic (Fig. 4.17). Dental caries are frequently severe. Other features Junctional EB (Herlitz): infant showing granulation tissue at the edge of a healing
may include musculoskeletal deformities, gastrointestinal lesions, laryngotra- blister. By courtesy of the Institute of Dermatology, London, UK.
cheal stenosis, and genitourinary and ocular involvement. Esophageal involve-
ment may result in stenosis. Perforation with resultant infection is an
important cause of death. Severe growth retardation and anemia are usually yperpigmentation and hypopigmentation are characteristic.63 Skin lesions
h
evident. Infantile mortality is high (42.2%).7 Mutations in one of the three may be exacerbated during summer. Milia are variably present. Exuberant
subunits of laminin-332 underlie this syndrome.59–61 granulation tissue is less common than in the Herlitz variant. Other features
include dystrophic or absent nails (Fig. 4.18), oral erosions with mild scar-
Junctional EB, Other ring, pitted dystrophic enamel, and severe dental caries. Ocular lesions include
The category contains six subtypes, two common and four rare. recurrent corneal erosion, blistering, and corneal scarring.64 Follicular atro-
phy with resultant alopecia involving the scalp, axillary, and pubic hair in
JEB, non-Herlitz, generalized (generalized non-Herlitz junctional EB, addition to sparse eyelashes and eyebrows is common (Fig. 4.19).63 Large or
EB atrophicans generalisata mitis, generalized atrophic benign EB multiple melanocytic nevi have also been described as part of the phenotype58
(GABEB), hemidesmosomal EB, junctional EB mitis) but this is not currently believed to be a specific feature.5 Contractures do not
This somewhat milder form, in which the cutaneous features are similar to develop. Systemic involvement is usually limited to mild laryngeal and/or
the gravis form, includes some patients with laminin-332 gene mutations and esophageal lesions.4 Growth may be retarded and anemia is present in some
others with mutations in type XVII collagen previously classified in the hemi- patients. Infantile mortality is high (up to 44.7%).7,32
desmosomal group.9,62 Systemic involvement is typically mild or absent.63–66
Patients present at birth with extensive blistering and erosions accompanied JEB, non-Herlitz, localized
by mild scarring and widespread cigarette paper-like atrophy. Variable This milder and localized form of JEB is associated with mutations in type
XVII collagen rather than laminin-332.67,68 Genotypic correlations and immu-
nofluorescence antigen mapping may allow distinction of this form from the
more several generalized form.68
JEB with pyloric atresia
All EB with pyloric atresia was previously placed in the now defunct hemides-
mosomal category. These cases are now divided into two categories within
EBS and JEB. While both plectin and α6β4 integrin subunit mutations have
been noted in EBS with pyloric atresia, only the latter is believed associated
with JEB with pyloric stenosis.69–71 The clinical features are similar, with gen-
eralized blisters present from birth associated with atrophic scarring, dystro-
phic or absent nails, and milia on occasion. Large areas of aplasia cutis have
been described.67 This disease is usually fatal at an early age.
JEB inversa
Lesions, which are present at birth or develop in early infancy, are initially gen-
eralized, but later are predominantly localized to inverse (flexural) sites includ-
ing the axillae and groin.5 Blisters and erosions are accompanied by atrophic
scarring and nails may be dystrophic or absent. Other features that are some-
times evident include mouth erosions, maldeveloped teeth with enamel hyp-
oplasia, and occasional gastrointestinal lesions, particularly affecting the
esophagus and anus. Mutations in the subunits of laminin-332 are noted.9,58
Fig. 4.15
Junctional EB (Herlitz):
JEB-late onset (progressiva)
newly born infant with
blistering and nail
In this variant, lesions do not present until late childhood, and consist of
involvement. By courtesy blisters and erosions affecting the hands, elbows, knees, and feet.5 Nails
of J. McGrath, MD, may be dystrophic or absent and enamel hypoplasia is characteristic. Mouth
Institute of Dermatology, erosions may be evident. Mild finger contractures are sometimes a compli-
London, UK. cation.3,5 The mutation underlying this form of the disease is unclear.9
Fig. 4.17 Fig. 4.19

Junctional EB (Herlitz): note the scarring with microstomia and severe dental involvement. Generalized atrophic benign EB: note the sparsely distributed eyebrows and eye
By courtesy of J. McGrath, MD, St John's Dermatology Centre, London, UK. lashes. By courtesy of the Institute of Dermatology, London, UK.
Dominant dystrophic EB
Five subtypes are recognized; four of these are rare.
Dominant dystrophic EB, generalized
Autosomal dominant EB, generalized includes both the Cockayne-Touraine
and Pasini variants. This is because the two conditions are characterized by
identical type VII gene mutations and the albopapuloid lesions (white perifol-
licular papules and plaques) have been found to be an inconsistent finding
(Fig. 4.20).6,7 Generalized blisters are seen at birth (Fig. 4.21a).4,8 Alopecia
may be present and milia, atrophic scarring, and dystrophic or absent nails
are typical features (Fig. 4.21b). Oral involvement may be mild or absent.
Enamel hypoplasia is sometimes evident. Gastrointestinal and genitourinary
tract involvement is seen in a minority of patients. There is a slightly increased
risk of basal cell carcinoma and melanoma.75
Dominant dystrophic EB, acral

In this mild autosomal dominant localized variant, lesions present at birth or
in early childhood, particularly in an acral distribution. Blisters and erosions
in the absence of other significant lesions except for atrophic scarring, milia,
Fig. 4.18
Generalized atrophic benign EB: there is scarring and complete absence of nails.
Laryngo-onycho-cutaneous (LOC) syndrome

A mutation in the gene encoding the laminin-332 α3 chain resulting in an
unusual N-terminal deletion underlies this syndrome.72 It was first described
by Shabbir and colleagues in 22 patients of Punjabi extraction and about 10
additional cases have been described.73,74 So far, this autosomal recessive con-
dition has not been described outside of this population. It can occur in a
nonconsanguineous context. It consists of epithelial defects resulting in cuta-
neous erosions, nail dystrophy, and chronic conjunctival and laryngeal granu-
lation tissue. Symblepharon and blindness are serious complications. Airway
obstruction and infection can also be problematic. The degree of skin fragility
is less than that seen in other variants of JEB. Under the new classification
system, based on molecular and clinical similarities to JEB, this syndrome has
been added as a rare variant.9,59
Dystrophic EB
Two major subtypes – dominant dystrophic EB and recessive dystrophic EB Fig. 4.20
(Hallopeau-Siemens) – are recognized and these are categorized into three Dystrophic EB: albopapuloid lesions on the lumbosacral area. These are an
major subtypes (one dominant and two recessive) and nine rare dominant or inconstant finding in dystrophic EB. The lesions are not preceded by blistering and
recessive groups. All subtypes are associated with mutations in the gene probably represent connective tissue nevi. By courtesy of M.J. Tidman, MD, Guy's
encoding type VII collagen. 9 Hospital, London, UK.
Fig. 4.21
Dominant dystrophic EB
(Cockayne-Touraine): (A)
truncal involvement is present
in addition to the more typical
limb lesions; (B) hemorrhagic
blisters, scarring, milia and
nail dystrophy. By courtesy of
A B the Institute of Dermatology,
London, UK.
and nail dystrophy may cease altogether after childhood.1 Extracutaneous

manifestations have not been recorded.
Dominant dystrophic EB, pretibial
This is a mild, localized, and typically symmetrical autosomal dominant form.
An autosomal recessive variant has recently been described (see below).76 The
onset is often delayed, patients usually presenting in early childhood.77 Blisters
and erosions accompanied by atrophic scarring and milia are particularly
seen on the pretibial region and dorsal aspects of the feet (Figs 4.22, 4.23).
The scarring may have a violaceous appearance reminiscent of hypertrophic
lichen planus.76 Lesions are also sometimes seen on the forearms and trunk.76
Pruritus and nail dystrophy are common. There are no teeth or hair
changes.77
Dominant dystrophic EB, pruriginosa
This variant, which presents in childhood, includes dominant and recessive
variants (see below).78 Patients present with highly pruritic, violaceous
Fig. 4.23
Dystrophic EB–pretibial: close-up view. By courtesy of the Institute of Dermatology,
London, UK.
odular prurigo-like nodules developing against a background of blisters,

n
milia, nail dystrophy, and albopapuloid lesions.
Dominant dystrophic EB, bullous epidermolysis of the newborn
This exceptionally rare, self-limiting condition presents in the newborn with
blisters that usually resolve within the first 2 years and heal with mild atro-
phy, milia, and scarring.79,80 Most cases have been inherited as an autosomal
dominant, although recessive variants have also been documented.6
Recessive Dystrophic EB
This category is composed of seven subtypes, of which five are rare.
Recessive dystrophic EB, severe generalized (Hallopeau-Siemens;

polydysplastic EB; EB gravis)
This autosomal recessive variant is a much more serious form than its auto-
somal dominant counterpart.4,8 Blisters and erosions are present at birth and,
atrophy, scarring, anemia, and growth retardation are consistently present
(Figs 4.24, 4.25). Nikolsky's sign is positive. Destructive involvement of the
distal peripheries results in contractures and severe deformities including the
characteristic ‘mitten lesions’ (pseudosyndactyly) of the hands and feet (Figs
4.26–4.28).81 If the latter is left untreated, there may eventually be resorption
Fig. 4.22 of the underlying bones (autoamputation). Nail dystrophy and milia are
Dystrophic EB–pretibial: extensive erosions with scarring are localized to the front marked, and scarring alopecia is common (Fig 4.29). Oral involvement is
of both shins. By courtesy of the Institute of Dermatology, London, UK. severe, with blisters, erosions, and scarring. Excessive caries are usual.
Fig. 4.24
Recessive dystrophic EB (Hallopeau-Siemens): extensive blistering present at birth.
The disease process has involved the nails and those of the first two toes are
absent. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 4.27
(A, B) Recessive dystrophic EB (Hallopeau-Siemens): in addition to the gross mitten
deformity, there is very severe scarring and scaling. (A) By courtesy of R.A.J.
Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London; (B) by courtesy of the
Fig. 4.25
Recessive dystrophic EB (Hallopeau-Siemens): note the scarring and extensive
erosions. By courtesy of the Institute of Dermatology, London, UK.
Fig. 4.26
Recessive dystrophic EB (Hallopeau-Siemens): weblike folds enveloping the toes Fig. 4.28
have resulted in a clublike appearance. By courtesy of R.A. Marsden, MD, St George's Recessive dystrophic EB (Hallopeau-Siemens): there is gross deformity of the knees.
Hospital, London, UK. By courtesy of J. McGrath, MD, Institute of Dermatology, London, UK.
Fig. 4.30
Recessive dystrophic EB:
extensive esophageal
involvement with
complete separation of
Fig. 4.29 the mucosa has resulted
Recessive dystrophic EB in this dramatic, but
(Hallopeau-Siemens): note fortunately very rare,
the conspicuous milia. manifestation. By courtesy
By courtesy of the of R.A. Marsden, MD,
Institute of Dermatology, St George's Hospital,
London, UK. London, UK.
Gastrointestinal and renal complications are common.82,83 There is often con-

junctival involvement with keratitis and scarring, and lesions of the mucous
membranes result in difficulty in opening the mouth, dysphagia, and esopha-
geal stricture formation, with some infants eventually succumbing to terminal
respiratory infections (Fig. 4.30).84 Anal and genitourinary involvement may
also be present. Squamous cell carcinoma is a common complication of the
cutaneous scarring (occurring in 39.6% of cases) and is a significant cause of
mortality (Figs 4.31–4.33).85,86 Tumors are frequently multiple, have an aggres-
sive behavior, and may be associated with extensive metastatic spread.
Melanoma much less commonly develops. This variant of EB has a high mor-
tality: 38.7%.7
Recessive dystrophic EB, generalized other

This type is often referred to as non-Hallopeau-Siemens type. In contrast to
the severe generalized form, anemia and mental retardation are less common
and dental caries are not increased. In this variant the features are similar to
the Hallopeau-Siemens variant except that the extracutaneous lesions and
complications (e.g., anemia, mental retardation, and dental caries) are less
severe and the risk of developing cutaneous squamous cell carcinoma is
diminished (14.3%).4,8 The mortality for this variant of EB is 10.0%.87
Genotypic differences in mutational types and sites in the gene encoding type Fig. 4.31
VII collagen likely underlie differences in the phenotypic expression of this Recessive dystrophic EB (Hallopeau-Siemens): in this patient numerous large
disease.88 keratoses are evident. Many of these progress to squamous cell carcinoma. Courtesy
of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.
Recessive dystrophic EB, inversa
In this autosomal recessive form, lesions are present at birth and consist of
blisters, erosions, milia, and atrophic scarring, found particularly about the
flexural sites, including the inguinal regions, axillae, neck, and the lower Recessive dystrophic EB, centripetalis
back.89,90 Nail dystrophy is usually evident and sometimes scarring alopecia is This autosomal recessive localized form has been described in a single
seen. Severe oral and esophageal involvement (erosions and scarring) is patient. Presentation was at birth with widespread blisters. In adulthood,
characteristic.91 however, the distribution became acral. The blisters, milia, and severe scar-
ring with atrophy then showed a characteristic centripetal spread. Nail dys-
Recessive dystrophic EB, pretibial trophy and/or absence were also present. Despite the severe scarring,
The pattern of involvement is similar to the dominant form (see above), but contractures and deformities were not features.92 There were no extracuta-
can be more severe. neous manifestations.
Recessive dystrophic EB, pruriginosa Recessive dystrophic EB, bullous dermolysis of the newborn
The pattern of involvement is similar to the dominant form (see above), but The pattern of involvement is similar to the dominant form (see above), but
can be more severe. can be more severe.

The investigation of a patient with suspected EB should ideally include immu-
nofluorescence antigen mapping, ultrastructural, and molecular genetic
studies. In general, routine histopathology often contributes little, other than
to confirm the presence of a subepidermal blister.
Immunofluorescent antigen mapping of basement membrane determinants
is a method of identification of the plane of cleavage in the various types of
EB that can sometimes avoid the need for ultrastructural studies.100,101
Essentially, the location of three antigens – type IV collagen, laminin-332,
and bullous pemphigoid antigen-1 – is determined by standard indirect immu-
nofluorescence of lesional (either naturally occurring or mechanically induced)
skin:7
• In simplex variants, all three antigens are found along the floor of the blister.
• In junctional lesions, bullous pemphigoid antigen-1 is identified mainly in
the roof of the blister, whereas laminin-332 and type IV collagen are
present along the floor.
• In dystrophic EB, the plane of cleavage is below the lamina densa and
therefore all three basement membrane antigens are present in the roof of
Fig. 4.32 the blister.
Recessive dystrophic EB (Hallopeau-Siemens): in addition to severe scarring The immunofluorescent investigation of skin samples for a wide range of
accompanied by autoamputation of the fingertips, there is a large ulcerated squamous recognized basement membrane constituents known to be absent or
cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, diminished in the various subtypes of epidermolysis bullosa has proved to be
London, UK. particularly valuable, and has also been shown to be of use in antenatal
(16–18 weeks' gestation) diagnosis.102–104
The monoclonal antibody KF-1, which localizes to the lamina densa, shows
an absence of labeling in nonlesional skin from patients with the severe
recessive dystrophic form of EB, whereas in the dominant variant it is
reduced.105,106
The monoclonal antibodies AF1 and AF2, which recognize antigens in and
immediately below the lamina densa (probably constituents of anchoring fibrils),
show an absence of immunolabeling in both normal and lesional skin from the
recessive dystrophic form, but appear normal in dominant dystrophic EB.107
LH7:2 is a monoclonal antibody directed against the NC-1 globular
domain of type VII collagen, which binds to the lamina densa and attached
anchoring fibrils.108,109 Labeling is absent or markedly reduced in the severe
recessive dystrophic form, patchily reduced in mild or localized recessive dys-
trophic variants, and normal in the dominant dystrophic variant.110,111
Immunolabeling with the monoclonal antibody GB3, which recognizes
laminin-332 (nicein/kalinin/epligrin), is reduced or absent in the junctional
(Herlitz) form of EB. It may be normal, reduced or absent in the non-Herlitz
junctional variants.112,113 Laminin-332 is a major constituent of the anchoring
filaments, which stretch from the hemidesmosomes to the lamina densa.
Two further antibodies, 19-DEJ-1 and AA3, characteristically fail to label
Fig. 4.33 the basement membrane zone in all patients with junctional epidermolysis
Recessive dystrophic EB (Hallopeau-Siemens): in this patient there is a massive bullosa and are therefore of additional diagnostic value.114 19-DEJ-1, which
squamous carcinoma, which has destroyed much of the knee. Courtesy of R.A.J. recognizes uncein, has been recommended as the most reliable antibody for
Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK. evaluation and diagnosis of the major junctional variants.115,116
Bullous pemphigoid 180-kD antigen is demonstrably diminished or absent
as determined by immunofluorescence in many patients with generalized
Kindler syndrome atrophic benign EB.117
Kindler syndrome has been added to the EB classification scheme due to simi-
larities to EB, and the hope that patients with this disease may benefit from the EB simplex
greater molecular and pathogenetic understanding of EB as a whole. It does In EB simplex variants, blisters develop as a consequence of basal cell cytolysis
not readily fit into any of the EB types as the level of blistering separation can (Fig. 4.34). The plane of cleavage lies deep to the nuclei of the keratinocytes
be intraepidermal, junctional or below the lamina densa. This disease is caused such that wispy remnants of basal cell cytoplasm may be identified along the
by a mutation in the KIND1 gene that encodes the protein kindlin-1, a component floor of the blister cavity, which is therefore intraepidermal in location
of contact foci in basal keratinocytes.93,94 First described in 1954, more than (Figs 4.35, 4.36).118 In older lesions the blister often appears to be subepidermal
50 cases are now published in the literature.95,96 Significant heterogeneity is due to continued lytic changes of the residual keratinocyte cytoplasm
noted, but this rare autosomal recessive disease is associated with skin fragility (Fig. 4.37). By direct immunoperoxidase antigen mapping on paraffin-embedded
similar to other forms of EB associated with the symptoms of poikiloderma sections, keratin, laminin, and type IV collagen staining may be identified along
and photosensitivity not seen in other forms of EB. Trauma-induced blistering the floor of the blister, confirming its intraepidermal location (Fig. 4.38).
and photosensitivity often improve with age. Squamous cell carcinoma and Ultrastructural studies have shown that the earliest change is loss of keratin
transitional cell carcinoma of the bladder have been described.97 filaments (tonofilaments).118,119 As a consequence, there is structural instabil-
All types of hereditary epidermolysis bullosa (simplex, junctional, and ity and fragility of the keratinocytes. Keratin clumps similar to those described
dystrophic) may rarely present with large nevi that often simulate melanoma on in the Dowling-Meara variant (see below) have been a rare finding in EB simplex
clinical grounds. Histology, however, shows no evidence of malignancy.98,99 Koebner.120 Loss of keratin filaments is subsequently followed by dissolution
Fig. 4.34
EB simplex: the earliest histological feature in the development of a blister is Fig. 4.37
marked vacuolation of the basal keratinocytes, so-called cytolysis. EB simplex: old lesion; the features are those of a cell-free subepidermal blister and
are not specific.
Fig. 4.35
EB simplex: established lesion showing ‘subepidermal’ vesiculation.
Fig. 4.38
EB simplex: paraffin
immunoperoxidase
displays type IV collagen
along the floor of the
blister cavity (same case
as Fig. 4.37).
of the other keratinocyte cytoplasmic constituents. Suprabasal desmosomes

appear unaffected. The lamina densa and anchoring fibrils are normal. While
the hemidesmosomes generally appear normal, reduplication and increased
electron density have been described in a recent case report.121
The Dowling-Meara variant (including the subset with mottled pigmenta-
tion) is characterized by 1–5-μm homogenous intracytoplasmic clumps of
keratin filaments in addition to cytolysis (Fig. 4.39).122 These are present in
the basal keratinocytes and extend into the overlying prickle cell layer. They
may also be identified in the follicular outer root sheaths, dermal eccrine
sweat ducts, and sebaceous glands. The clumps are composed of keratins
5 (type II) and 14 (type I).122 In addition to intraepidermal vesiculation,
Fig. 4.36 intrakeratinocyte cleavage may also be found in the follicular infundibula.
EB simplex: basal keratinocyte cytoplasmic remnants are visible along the floor of The other skin appendage structures are not affected. The dermis may contain
the blister cavity. an infiltrate of lymphocytes and eosinophils.
Fig. 4.39
EB simplex (Dowling-Meara): (A) electron micrograph
showing intrakeratinocyte splitting; (B) close-up view of
A B tonofilament clumps. By courtesy of J.A. McGrath, MD, and
R.A.J. Eady, MD, Institute of Dermatology, London, UK.
The keratoderma shows hyperkeratosis and acanthosis. Clumps of keratin clusters on chromosomes 12 and 17.126–130 The gene for keratin 5 is carried on
may also be evident. chromosome 12q and that for keratin 14 is located on 17q. Truncated mutant
Ultrastructurally, the level of cleavage is low within the basal keratinocytes, just human keratin 14 gene induces the EB phenotype when introduced into trans-
above the level of the hemidesmosomes (Figs 4.40, 4.41). In addition to cytolysis, genic mice and similarly causes an identical keratin abnormality when
however, acantholysis may also sometimes be evident. The keratin filament expressed in transfected human keratinocytes.131,132 Specific missense muta-
abnormalities include irregular whorled bundles in addition to homogeneous tions or deletions have now been identified in patients with Dowling-Meara
clumps. They are present in normal skin in addition to lesional material (K5 and K14), localized (K5 and14), other generalized (K5 and14) subtypes,
(Fig. 4.42).122,123 Desmosomes may appear diminished in number in the keratinocytes and the the rare EB simplex subtypes with mottled pigmentation (K5), autosomal
showing tonofilament clumps. Basement membrane zone constituents are normal. recessive (K14), and migratory circinate (K5).133–138 The highly conserved end
In EB simplex superficialis the plane of cleavage is in the upper epidermis domains of the keratin rod are particularly susceptible to significant mutation
just beneath the stratum corneum.22 Additional clefts may also be evident in with resultant instability of the filament assembly and consequent fragility of
the lower third of the epidermis. basal keratinocytes following mild trauma.124
It is now apparent that the majority of EB simplex develop as a direct Plectin, which localizes to the inner plaque of the hemidesmosome, is a
consequence of keratin gene mutation, but mutations in desmoplakin, member of the plakin family and in concert with BP230 is believed to be of
plakophilin, plectin, and α6β4 integrin subunits are seen in some of the rare importance in keratin filament anchorage.10,14 Recently, mutation of the gene
subtypes (see Table 4.2).124,125 Following the initial discovery of keratin PLEC1 encoding this protein has been described in patients with the muscular
filament clumps in Dowling-Meara EB and their subsequent identification as dystrophy-associated, pyloric atresia, and Ogna subtypes.39 Plectin is associ-
keratins 5 and 14, it was shown that keratinocyte cultures from patients with ated with the Z-lines in the desmin cytoskeleton and this explains its
this disease exhibited an identical morphological abnormality.120 Genetic importance in myocyte adhesion and their role in the pathogenesis of EBS
linkage studies showed that EB simplex was associated with keratin gene with muscular dystrophy.139 Mutations in the genes encoding desmoplakin
and plakophilin-1, respectively, are associated with lethal acantholyic EB and
plakophilin deficiency.19,20
EB (both the simplex and junctional forms) associated with pyloric atresia
results from α6β4 integrin missense mutations resulting in premature termina-
tion codons with synthesis of defective or nonfunctional α6 or β4 subunits.140–142
As a result, hemidesmosomes are hypoplastic or reduced in number.10 Mutations
in the gene encoding plectin are also noted in the simplex form.48,143
Exceptionally, amlyoid has been described in the Weber-Cockayne type of
EB.144 Dyskeratosis has been reported as a histologic feature in Dowling-Meara
EB but not in other variants, including Koebner EB or Weber Cockayne EB.145
The sample in this study, however, was small and further investigation is
required to confirm the specificity of this finding.
Fig. 4.40
EB simplex (Koebner): the
M blister cavity forms within Junctional EB
the basal keratinocyte.
Note the cytoplasmic Junctional EB variants are also characterized by subepidermal blistering, usually
remnants along the unaccompanied by any substantial inflammatory cell infiltrate (Fig. 4.43).146
floor of the blister. Ultrastructurally, the site of cleavage is through the lamina lucida (Fig. 4.44). The
(M, melanosome.) hemidesmosomes may appear malformed, be diminished in number or
Fig. 4.41 Fig. 4.43

EB simplex (Koebner): this high-power view shows the floor of the blister cavity. Junctional EB: subepidermal cell-free blister.
Note the lamina densa (arrowed), hemidesmosomes (arrowheads) and basal
keratinocyte cytoplasm. (A, blister; B, cytoplasm; C, dermis.)
Fig. 4.42 Fig. 4.44

Epidermolysis bullosa simplex (Dowling-Meara): numerous tonofilament clumps are Junctional EB: lesional skin showing separation within the lamina lucida of the
present in the adjacent clinically normal skin (arrowed). By courtesy of J.A. McGrath, dermoepidermal junction. By courtesy of R.A.J. Eady, MD, Institute of Dermatology,
MD, Institute of Dermatology, London, UK. and M.J. Tidman, MD, Guy's Hospital, London, UK.
absent.147–150 Hemidesmosome alterations as detected by electron microscopy, Junctional EB, non-Herlitz (generalized and localized) is most commonly
however, are heterogeneous. In a morphometric study of numbers of hemidesmo- a result of BP180 mutations (BPAG2/type XVII collagen).161–163 Nonsense
somes per unit length of basement membrane, one of five patients with the Herlitz mutations or insertions/deletions with resultant premature termination
variant and two of three patients with non-Herlitz variants had normal results.151 codons result in absence of type XVII collagen. This is a transmembrane col-
The same authors recorded an association between junctional EB and a reduction lagen that is thought to contribute to the anchoring filaments via its carboxy-terminal
in the numbers of hemidesmosomes with associated sub-basal plates. segment.10 The amino-terminal globular domain resides within the cytoplasm
Junctional EB is characterized by mutations in the genes that encode the of the basal keratinocyte localizing to the outer plaque of the hemidesmo-
α3, β3 or γ2 chains of laminin-332 (laminin-5).152–158 Mutations resulting in some. Less often, laminin-332 mutations are responsible for this clinical
premature termination codons in the laminin-332 genes are present, for phenotype.
example, in all cases of the Herlitz lethal variant.7,10 Nonsense mutations,
out-of-frame deletions or insertions and splicing errors affect both alleles, Dystrophic EB
resulting in reduced synthesis and defective assembly of trimeric laminin-5 In the dystrophic variants the histological features are those of subepidermal
molecules.10 The majority of mutations have affected the LAMB3 gene vesiculation or blister formation in the absence of any significant inflamma-
although LAMA3 and LAMC2 gene abnormalities have also been docu- tory content (Fig. 4.45). The clinical subtypes show no particular distinguishing
mented. Non-Herlitz junctional EB variants, including some cases of general- features. The adjacent dermis is often markedly scarred due to previous epi-
ized atrophic benign EB, are associated with milder missense mutations or sodes of blistering.
deletions in the laminin-332 genes.152,159,160 Laminin-332 is located within The squamous carcinoma that develops in association with recessive dys-
anchoring filaments and in the lamina densa. The abnormal laminin-332 trophic EB is very often well differentiated (Fig. 4.46) and occasionally its
results in defective anchoring filaments with resultant instability at the base- appearance suggests a verrucous variant. Whether this latter form has the
ment membrane region. good prognosis usually evident with verrucous carcinoma is uncertain.
Fig. 4.45 Fig. 4.47

Dystrophic EB (Hallopeau-Siemens): in addition to obvious subepidermal blistering Dystrophic EB (Hallopeau-Siemens): lesional skin demonstrates cleavage
there is dermal scarring and chronic inflammation. immediately beneath the lamina densa of the dermoepidermal junction (arrowed).
By courtesy of R.A.J. Eady, MD, Institute of Dermatology, and M.J. Tidman, MD,
Guy's Hospital, London, UK.
Ultrastructurally, the site of cleavage is immediately below the lamina

densa (Fig. 4.47).164,165 In the autosomal dominant and some localized
recessive groups, anchoring fibrils are decreased in number, but may
appear morphologically normal, whereas in the generalized recessive
variants (and occasionally in severe dominant cases), the fibrils are very
sparse or more often absent.166–168 Frequently, thin wispy filaments imme-
diately adjacent to the lamina densa are all that are visible. In a recent
morphometric study of basement membrane in various dystrophic forms,
using nonblistered skin, anchoring fibrils were completely absent in gen-
eralized recessive dystrophic EB. Reduced numbers of morphologically
normal anchoring fibrils were found in localized recessive and dominant
dystrophic variants.169 Type VII collagen expression in dystrophic EB,
however, as determined by LH7:2 immunolabeling, is not an all-or-none
phenomenon. Even in the recessive variant, some positive staining of thin,
ill-formed filamentous structures may be seen immediately below the lam-
ina densa. Collagenolysis in the superficial dermis may also be seen in the
A more severe variants.
In transient bullous dermolysis of the newborn, in addition to reduced
numbers of anchoring fibrils, intracytoplasmic inclusions are seen in the basal
keratinocytes. These have a stellate appearance and represent retained type
VII and type IV collagen.170–172
Dystrophic EB variants are all caused by mutations in the type VII collagen
gene COL7A1.173–175 Over 100 distinct mutations have been identified.10 The
Hallopeau-Siemens severe recessive variant is characterized by nonsense
mutations, insertions, deletions or splicing errors, which cause premature ter-
mination codons affecting both alleles, resulting in very low levels of mRNA
and virtual absence of type VII collagen synthesis.10,172,173 Premature termina-
tion codon, missense, deletion, and substitution mutations have been identi-
fied in a number of the less severe dystrophic variants.7 Dominant dystrophic
EB is caused by a glycine substitution mutation resulting in a less severe vari-
ant in which type VII collagen, although defective, is still produced and
anchoring filaments are present albeit in reduced numbers.176,177 Transient
bullous dermolysis of the newborn also results from a mutation in
COL7A1.79,80
B Milia, which are most commonly seen in dystrophic EB, are small cysts within
the upper dermis, consisting of a mass of keratinized squames surrounded by a
Fig. 4.46 wall of squamous epithelium, thereby representing miniepidermoid cysts. They
(A, B) Dystrophic EB (Hallopeau-Siemens): biopsy from the forearm of a 30-year-old are not specific to epidermolysis bullosa, being found in a variety of conditions
patient showing a cell-free subepidermal blister. In addition, a well-differentiated associated with damage to the cutaneous adnexal structures (e.g., severe burns
squamous cell carcinoma extends into the subcutaneous fat. and porphyria cutanea tarda) and other blistering disorders.
Differential diagnosis (Fig. 4.51). Often they contain clear or bloodstained fluid. Any area of the
body may be affected, but the blisters are most commonly located about the
With the appropriate clinical information the histological diagnosis of EB
lower abdomen, the inner aspect of the thighs and on the flexural surfaces of
should not pose any problems. With the exception, however, of the
the forearms, the axillae, and groin (Fig. 4.52).14 Grouping of lesions as seen
Dowling-Meara variant, it is not usually possible to predict which subtype
the patient suffers from although, in specimens from early lesions, it is in dermatitis herpetiformis is not usually a feature and symmetry is character-
sometimes possible to identify the simplex variants of the basis of cytolysis. istically absent. A ‘cluster of jewels’ appearance of new blisters arising at the
Cell-free subepidermal blisters, however, may be seen in a variety of conditions edge of resolving lesions as seen in linear IgA disease may, however, occasionally
be a feature of bullous pemphigoid (Fig. 4.53).15 The lesions are often pruritic
including autolysis, EB acquisita, cell-free pemphigoid, suction blisters,
and a burning sensation is sometimes a feature. Nikolsky's sign is usually
bullous cutaneous amyloidosis, bullous lichen sclerosus, porphyria cutanea
negative. In contrast to mucous membrane pemphigoid, generalized bullous
tarda, and pseudoporphyria.
pemphigoid is not associated with scarring.
Because the genetic defects for so many of the EB subtypes are now known,
Reported mucosal involvement (frequently as ulcers) is highly variable,
prenanatal testing is possible.178 It is hoped that understanding of the molecu-
lar pathobiology of this disease may eventually lead to successful gene ther- ranging from 8% to 58%.16–18 In a series of 115 patients, 24% had oral
involvement and 7% had genital lesions.18 Lesions are found most often on
apy as was recently described for a patient with junctional EB using
the palate, the cheeks, lips, and tongue (Fig. 4.54). Other sites less commonly
transplanted epidermal stem cells genetically modified to express wildtype
involved include mucosae of the nose, pharynx, conjunctiva and, rarely, the
LAMB3.179,180
urethra and vulva (see below) (Fig. 4.55).17 In contrast to mucous membrane
pemphigoid, mucosal involvement in generalized bullous pemphigoid is not
associated with scarring.
Bullous pemphigoid
Clinical features
Bullous pemphigoid is not a single disease entity. Rather, there are many sub-
types, which have been classified into primary cutaneous and mucosal vari-
ants and into generalized and localized forms (Fig. 4.48).1–4 Bullous
pemphigoid (BP) is the most frequently encountered autoimmune bullous
dermatosis with an annual incidence of 6.6 new cases per one million of the
population.5,6
Generalized cutaneous pemphigoid

Any age group may be affected, but the generalized variant demonstrates
a predilection for the later years of life, showing a maximum incidence in
the seventh decade and over. Rarely, however, children and even infants
may be affected.7,8 The disease is associated with a worldwide distribu-
tion and shows no racial propensity. There are no significant human leu-
kocyte antigen (HLA) associations and the sex incidence is approximately
equal.
Prodromal events are numerous and include erythematous, urticarial and,
rarely, eczematous phases.9,10 Erythroderma, either preceding the bullous Fig. 4.49
phase or occurring simultaneously, is a very rare manifestation (erythroder- Erythrodermic BP: blistering has developed against a background of generalized
mic pemphigoid).11,12 Similarly, patients may present with a history of gener- erythroderma. By courtesy of the Institute of Dermatology, London, UK.
alized pruritus in the absence of visible skin lesions (pruritic pemphigoid). In
such circumstances, immunofluorescence investigations are essential to estab-
lish the correct diagnosis.13
The characteristic lesions of established disease are tense and often intact
blisters arising on normal or erythematous skin (Figs 4.49, 4.50). They may
measure up to several centimeters in diameter and are typically dome-shaped
Generalized
Vesicular
Polymorphic
Widespread Vegetans
Nodularis
Erythrodermic
Cutaneous
Seborrheic
Pretibial
Localized
Brunsting-Perry
Widespread Mucous Membrane

Mucosal
Desquamative Gingivitis
Localized
Oral
Fig. 4.50
Fig. 4.48 BP: early tense blister arising on an erythematous base. By courtesy of the Institute
Bullous pemphigoid: classification. of Dermatology, London, UK.
Fig. 4.51 Fig. 4.53

BP: tense, dome-shaped blisters. The flexures are typically affected. By courtesy of BP: new blisters arising at the edge of a healing lesion (‘cluster of jewels’ sign). Although
the Institute of Dermatology, London, UK. typically seen in childhood linear IgA disease, this is sometimes a feature of bullous
pemphigoid. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 4.54
Fig. 4.52 BP: oral erosions are an occasional finding. Intact blisters are rare. By courtesy of
BP: widespread, fluid- R.A. Marsden, MD, St George's Hospital, London, UK.
filled, hemorrhagic blisters
on the arms and legs
of an elderly female. By
courtesy of the late M.
Beare, MD, Royal Victoria
Hospital, Belfast, N.
Ireland.
Although bullous pemphigoid has been reported in association with a

variety of internal malignancies, this may just be coincidental, merely reflect-
ing the age incidence of these two diseases.19 In a series of almost 500 patients
from Sweden, no increased incidence of cancer was observed.20 Other stud-
ies, however, have shown that there may be a positive correlation between
internal malignancy and seronegative bullous pemphigoid patients.21
Generalized bullous pemphigoid is a serious condition with a significant
mortality ranging from 10% to 20%.1 Since the advent of steroid therapy and
immunosuppressive agents, patients are more at risk of developing severe iat-
rogenic disorders than of dying from their disease.22 Morbidity from this dis-
ease may be related more to the age and general state of health of the patient
than to the severity of blistering.23 Although mortality from the disease is low, Fig. 4.55
there has been a reported increase in mortality in the last 20 years of the BP: conjunctival injection is present. By courtesy of R.A. Marsden, MD, St George's
twentieth century.24 Hospital, London, UK.
Fig. 4.56 Fig. 4.57

Bullous pemphigoid: occasionally erythematous urticarial lesions may be the Bullous pemphigoid: close up view. By courtesy of R.A. Marsden, MD, St George's
presenting feature. Blisters may not evolve until several weeks later. By courtesy of Hospital, London, UK.
R.A. Marsden, MD, St George's Hospital, London, UK.
Clinical variants of generalized pemphigoid Dyshidrosiform pemphigoid is a rare variant of pemphigoid in which
Urticarial bullous pemphigoid presents with large persistent erythematous patients develop 1–2-mm, tense ‘sago-grain-like’ vesicles on the palms and
plaques, which sometimes display an annular or gyrate peripheral component soles resembling dyshidrosiform dermatitis (pompholyx).44–50 Lesions may be
(Fig. 4 56, 4.57).1 Rarely, small vesicles are also to be found. localized, or precede or occur simultaneously with generalized disease.
Vesicular pemphigoid is a rare clinical variant in which the cutaneous Overlap with pemphigoid nodularis has been described.51
manifestations show a striking overlap with dermatitis herpetiformis.25–28 Childhood pemphigoid exhibits lesions that are similar to their adult coun-
Patients present with numerous small tense vesicles that may be symmetrical, terparts, but there is some tendency for lesions to be localized around the
intensely pruritic, and therefore associated with conspicuous excoriation. face, lower trunk, thighs, and genitalia, reminiscent of linear IgA disease in
Polymorphic pemphigoid is a somewhat confusing entity, which is similar childhood (Fig. 4.60).7,8,52–61 Similarly, a ‘cluster of jewels’ appearance is
to vesicular pemphigoid, but probably shows overlap with linear IgA sometimes evident.7 Palmar, plantar, and oral lesions are often present and
disease.29–31 may be the sole site of involvement in infants (Fig. 4.61). The mucous mem-
Patients present with burning and itching lesions predominantly affecting branes may be affected but scarring is absent. A number of children with pri-
the extensor aspects of the limbs, back, and buttocks. Symmetry, grouping, mary localized penile and vulval lesions have also been described (Fig.
and a polymorphic clinical appearance of papules, vesicles, and variably sized 4.62).47,48,59,62,63 This is of particular clinical importance since it may be mis-
bullae emphasize a similarity to dermatitis herpetiformis. It has been sug- taken for evidence of sexual abuse. Childhood pemphigoid has a good prog-
gested that polymorphic pemphigoid is not an entity sui generis, but repre- nosis and, as in adults, is usually self-limiting. Although the etiology is
sents a potpouri of conditions including vesicular pemphigoid, linear IgA generally unknown, in some infant cases there appears to be a relationship to
disease, and mixed subepidermal bullous disease in which patients show both prior vaccination or immunization.59,64 Differences between childhood and
linear IgG and linear IgA or dermal papillary granular IgA on direct infant cases have been described, but the importance of further subdividing
immunofluorescence.30 this group is unclear.64
Pemphigoid vegetans is an exceedingly rare vegetative intertriginous vari-
ant that may be associated with chronic inflammatory bowel disease.32–39
Fewer than 10 cases have been documented. Patients present with vegetative, Localized cutaneous pemphigoid
crusted, purulent, and sometimes eroded lesions in the groin, axillae, neck, Although classical bullous pemphigoid not uncommonly presents initially as
hands, eyelids, inframammary, and perioral regions (Fig. 4.58). Vesicles and localized lesions that after a few months become generalized, occasional
bullae may also be evident. Scarring has been described.39 The etiology of the patients present with localized blisters that do not subsequently disseminate
vegetative lesions is unknown. (localized bullous pemphigoid).65 Traditionally, this group has been subdivided
Seborrheic pemphigoid is a variant in which the clinical features are sug- into two variants:
gestive of pemphigus erythematosus.31 • Brunsting-Perry pemphigoid predominantly affects the head and neck
Pemphigoid nodularis represents the extremely rare association of lesions and is associated with scarring.66
of bullous pemphigoid with intensely pruritic papules and nodules of nodular • Localized cutaneous nonscarring bullous pemphigoid (Eberhartinger and
prurigo predominantly affecting the trunk and extremities (Fig. 4.59).40–42 Niebauer variant)67 predominantly affects the lower legs (in particular the
The association of pemphigoid nodularis with immune dysregulation, poly- pretibial region) of females.
endocrinopathy, enteropathy, and X-linked (IPEX) syndrome is the subject of The former variant is considered in the section on mucous membrane
a single case report.43 pemphigoid. Although the latter nonscarring cutaneous form particularly
Exceptionally, patients may show immunofluorescent evidence of bullous affects the lower legs (Fig. 4.63), it may also present at a variety of other sites
pemphigoid in the absence of clinical blistering.42 The cause of this unusual including forearms and hands, breasts, chest, buttocks, and umbilicus. Lesions
phenomenon is unknown although in some patients at least, chronic scratch- in localized bullous pemphigoid may be related to trauma.67 This variant
ing probably damages the basement membrane region with exposure of shows a peak incidence in the sixth decade. As with generalized bullous pem-
bullous pemphigoid antigens. There is a female predilection (2:1).42 The age phigoid, patients present with tense, sometimes hemorrhagic, bullae that arise
range of this variant extends from 24 to 80 years but, as with classical bullous on normal or erythematous-appearing skin. Localized cutaneous nonscarring
pemphigoid, the majority of patients are elderly. bullous pemphigoid is generally associated with a good prognosis.67
Fig. 4.58
(A, B) Pemphigoid vegetans:
presentation as verrucous
lesions in the flexures
may result in considerable
diagnostic difficulties. By
courtesy of R.K. Winkelmann,
A B MD, The Mayo Clinic,
Scottsdale, Arizona, USA.
Fig. 4.60
Childhood BP: very rarely
this disease affects young
Fig. 4.59 children and infants.
Pemphigoid nodularis: in There is a widespread
addition to bullous lesions, distribution of bullae,
this patient also developed which characteristically
these pruritic nodules. arise on an erythematous
By courtesy of H. Shimizu, base. By courtesy of
MD, Keio University R.A. Marsden, MD,
School of Medicine, Tokyo, St George's Hospital,
Japan. London, UK.
Rare patients present with localized bullous pemphigoid at the site of manifestation of lichen planus, mucosal pemphigoid, and pemphigus.41 The
trauma without much evidence of disease elsewhere.68 diagnosis of localized oral pemphigoid depends upon the presence of a linear
band of immunoreactants at the epithelial basement membrane region on
Mucosal pemphigoid/desquamative gingivitis direct immunofluorescence.69 Clinical features include erythema, edema, erosions,
Localized oral pemphigoid is a recently described variant of desquamative gin- and ulcers.72 The oral lesions are nonscarring. Bullous pemphigoid-associated
givitis.69–71 The latter, of multifactorial etiology by definition, affects the mar- desquamative gingivitis may remain confined to the gingiva (the localized oral
ginal and attached gingivae. It shows a female predominance (9:1) and presents pemphigoid type), but approximately an equal proportion of patients goes on
most frequently in the middle aged. Desquamative gingivitis may also be a to develop full-blown cutaneous pemphigoid (Fig. 4.64).69
Fig. 4.63
Localized pemphigoid,
nonscarring variant:
lesions are found
particularly on the lower
Fig. 4.61 legs of females. The
Childhood BP: plantar involvement is sometimes the only site of disease. By courtesy prognosis is usually good,
of M. Liang, MD, The Children's Hospital, Boston, USA. but occasionally the
condition can become
generalized. By courtesy
London, UK.
Fig. 4.62
Childhood BP: note the perineal scarring and isolated blister. By courtesy of M. Liang,
MD, The Children's Hospital, Boston, USA.

The histological features of bullous pemphigoid depend to some extent upon Desquamative gingivitis: note the intense gingival erythema and retraction. Such
the age of the lesion biopsied. Early erythematous and urticarial lesions most features may also be seen in mucous membrane pemphigoid and pemphigus. By
often show upper dermal edema associated with a perivascular lymphohistio- courtesy of P. Morgan, FRCPath, London, UK.
cytic infiltrate accompanied by usually conspicuous eosinophils (Figs 4.65
and 4.66). Eosinophilic spongiosis is sometimes evident and occasionally, if
eosinophils are present in sufficient numbers, flame figures may be a feature. severe edema. An infiltrate of eosinophils and mononuclears surrounds the
Mild interface changes characterized by basal cell hydropic degeneration can blood vessels and extends between the adjacent collagen bundles.
be seen in early or prodromal lesions. Leukocytoclasis is not seen and features of vasculitis are absent. The adjacent
If the biopsy is taken from an established blister, the changes are most papillary dermis is often edematous and, very occasionally, eosinophil
often those of an inflammatory (cell-rich) variant.73 The blister, which is sub- microabscesses are a feature (Fig. 4.70). Exceptionally rarely, neutrophil
epidermal, is typically unilocular and covered by attenuated epithelium (Fig. microabscesses may be seen (see vesicular pemphigoid), raising diagnostic
4.67). In early lesions the roof epidermis may appear unaffected or show confusion with dermatitis herpetiformis. Eosinophilic spongiosis is also some-
occasional to even confluent necrotic basal keratinocytes. The blister contents times evident in the adjacent epidermis (Fig. 4.71).74
include coagulated serum, fibrin strands, and large numbers of inflammatory Cell-poor (noninflammatory) features are occasionally seen if biopsies are
cells including conspicuous eosinophils (Fig. 4.68). Variable numbers of neu- taken from lesions arising on noninflamed skin (Fig. 4.72). Because inflam-
trophils may be present. matory cells are sparse or, exceptionally, even absent in such cases, there may
A typical finding in bullous pemphigoid is retention of the dermal papil- be considerable problems with the differential diagnosis, particularly if ade-
lary outline (festooning) which project like sentries into the vesicle cavity quate clinical information and immunofluorescence findings are not
(Fig. 4.69). The underlying dermis is inflamed and usually shows widespread available.
Fig. 4.65 Fig. 4.68

Prebullous pemphigoid: there is upper dermal edema and a perivascular lymphohis BP: the blister cavity contains large numbers of eosinophils.
tiocytic infiltrate with conspicuous eosinophils.
Fig. 4.69
BP: preservation of the dermal papillary outline (festooning) is a characteristic
Fig. 4.66 feature.
Prebullous pemphigoid: there are numerous eosinophils.
Fig. 4.67 Fig. 4.70

BP: an established lesion showing a subepidermal tense, dome-shaped blister BP: the presence of eosinophil microabscesses in the dermal papillae is a useful
containing edema fluid, fibrin, and inflammatory cells. although rare diagnostic marker.
Fig. 4.71
BP: eosinophilic
spongiosis is sometimes
seen in the epidermis
adjacent to the blister.
Fig. 4.73
Vesicular pemphigoid: (A) low-power view showing a multilocular blister; (B) the
blister contains a neutrophil-rich infiltrate.
Localized nonscarring (pretibial) bullous pemphigoid usually shows the his-

tology of cell-rich bullous pemphigoid. Localized oral pemphigoid is typified by
a subepithelial vesicle (when present) and cannot be distinguished histologically
from oral involvement in mucous membrane pemphigoid (see below).
Ultrastructurally, in early lesions of bullous pemphigoid, the dermoepider-
mal cleavage is seen to have developed between the plasma membrane of the
Fig. 4.72 basal keratinocyte and the lamina densa, through the lamina lucida.75 The
Cell-poor pemphigoid: this is a very uncommon variant and is most often seen if a lamina densa is therefore located along the floor of the blister
very early lesion is sampled. The blister contains only a little edema fluid and there (Figs 4.77, 4.78). Degenerative changes in the basal cells, including villous
is a light chronic inflammatory cell infiltrate in the superficial dermis.
process formation, mitochondrial swelling, and cytoplasmic vacuolization,
are frequently found. Hemidesmosomes may appear reduced in number or
may even be absent.76 Intercellular edema between adjacent basal cells is a
Vesicular/polymorphic pemphigoid is characterized by subepidermal vesi- common finding.77 If specimens from established inflammatory lesions are
cles with features suggesting either bullous pemphigoid or dermatitis herpeti- examined, the lamina densa is sometimes fragmented or entirely absent.48
formis or both (Fig. 4.73). Neutrophil dermal papillary microabscesses, Bullous pemphigoid is characterized by a linear antibasement membrane
which are often regarded as pathognomonic of dermatitis herpetiformis, may zone antibody using the indirect immunofluorescent technique.78 Although
be seen in this variant (Fig. 4.74). IgG is invariably present (and most commonly of the IgG4 subclass), other
Pemphigoid vegetans is characterized by acanthosis, often with pseudoepi- immunoglobulins, including IgE, may be represented.79 Such antibodies are
theliomatous hyperplasia, papillary dermal edema with subepidermal clefting present in around 75–80% of patients.80–83 Sensitivity can, however, be
or frank vesicle formation and an inflammatory cell infiltrate of eosinophils, increased to 90% if split skin is used as substrate.18 Although the antibody
mononuclears, and occasional neutrophils. titer does not correlate with disease activity or severity, more recently it has
Pemphigoid nodularis exhibits pruriginous lesions which are characterized been shown that serum antibodies to the NC16A domain of BP180 (a subunit
by hyperkeratosis and acanthosis, and which may amount to pseudoepithe- of the bullous pemphigoid antigen) do correlate with disease activity (see
liomatous hyperplasia and dermal fibrosis (Fig. 4.75). In the dermis, a below).84,85
perivascular infiltrate of lymphocytes and eosinophils is present. The blisters Split skin indirect studies are essential in the investigation of a patient in
show typical features of bullous pemphigoid (Fig. 4.76). whom a linear IgG antibasement membrane antibody has been detected.86–88
A B
Fig. 4.74
Vesicular pemphigoid: (A) neutrophil microabscesses in the adjacent dermal papillae heighten the resemblance to dermatitis herpetiformis. It would be impossible to establish
the diagnosis of bullous pemphigoid without appropriate immuno-fluorescent findings; (B) preservation of the dermal papillae may be a clue to the correct diagnosis of
pemphigoid.
Fig. 4.75
Pemphigoid nodularis: this is a biopsy of a pruritic nodule showing hyperkeratosis,
irregular acanthosis, dermal chronic inflammation, and scarring.
Fig. 4.77
BP: electron micrograph showing the lamina densa lying along the floor of the
blister cavity.
Fig. 4.76
Pemphigoid nodularis: this subepidermal blister comes from the same patient as
shown in Figure 4.75. Pemphigoid nodularis is of particular importance because Fig. 4.78
the nodular lesions may precede clinical evidence of blistering. BP: high-power view of the lamina densa.
Such antibodies are also characteristic of mucous membrane pemphigoid, her-

pes (pemphigoid) gestationis, inflammatory epidermolysis bullosa, and bullous
systemic lupus erythematosus. The antibodies in pemphigoid variants (with the
exception of the anti-p105 and anti-p200 variants discussed below) bind to the
epidermal side of 1 M NaCl-split skin whereas those of inflammatory epider-
molysis bullosa and bullous systemic lupus erythematosus bind to the floor.
In those patients in whom indirect fluorescent studies are not available,
similar information may sometimes be obtained through the localization of
lamina densa constituents such as type IV collagen or laminin-1 using
paraffin-embedded direct immunoperoxidase techniques. In pemphigoid, the
staining is found along the floor of the blister, whereas in inflammatory
epidermolysis bullosa and bullous systemic lupus erythematosus it is located
along the roof (see Figs 4.7 and 4.8).
Bullous pemphigoid antibodies are capable of complement fixation in as
many as 75% of patients.89,90 Most of complement fixation in bullous pem-
phigoid antibody resides in the IgG4 subclass.91
Linear in vivo-bound immunoglobulin at the epidermodermal interface on
direct immunofluorescence is present in 90% or more of patients (Fig.
4.79).18,92 Complement (C3) is also usually present and is sometimes the sole
immunoreactant (Fig. 4.80).93 Other immunoglobulin subclasses including Fig. 4.80
BP: direct immunofluorescence showing C3 deposition (left), no staining is
IgM, IgA, and IgE may be detected occasionally.83,89,94 In addition to C3, the
seen in the negative control (right). By courtesy of B. Boghal, FIMLS, Institute of
other components of the classical complement pathway, in particular C5b-9 Dermatology, London, UK.
(the membrane attack complex) and members of the alternative complement
pathway, including properdin, factor B and B-1H-globulin, may also be iden-
tified.83,95 There is therefore evidence that both the classical and alternate rescent test for bullous pemphigoid antibody, while others may be positive for
complement pathways are involved in the pathogenesis of bullous pemphig- in vivo-bound complement, but negative on indirect examination.66,67,99 One
oid.96 The classical complement pathway, however, predominates. A recent series has shown that almost 70% of patients with localized pemphigoid have
mouse model underscores the necessity of an intact innate immune system, as circulating IgG antibodies in their sera and the presence of these can be rele-
depletion of complement or neutrophils or blockage of mast cell activation vant for serum-based testing, as discussed below.67,100 A caveat is that in one
prevents blister formation.97 study, antibodies were also detected in more than half of normal subjects who
The immunofluorescence findings in erythematous, pruritic, urticarial, did not subsequently develop the disease.101,102 This finding is further dis-
and eczematous prodromal lesions and childhood, dyshidrosiform, vesicular, cussed below.
nodular, and vegetans variants are similar to those seen in the conventional By direct immunoelectron microscopy, the immunoreactants (IgG and C3)
generalized disease.25–28,32–49,98,99 In polymorphic pemphigoid either linear IgG are seen to be located within the hemidesmosomal plaque and upper lamina
or IgA deposits may be identified along the basement membrane region.29–31 lucida (Fig. 4.81).103–107 Indirect immunoelectron microscopic studies show
The serum may contain either IgG or IgA antibodies.30 that the bullous pemphigoid antigen is most often detected intracellularly in
Immunofluorescence findings in localized cutaneous disease are variable. the region of the cytoplasmic face of the hemidesmosome (Fig. 4.82).104,108–110
In some reports, patients show positive direct immunofluorescence for IgG The immunoelectron microscopic observations in childhood bullous pem-
and C3 at the epidermodermal junction and a positive indirect immunofluo- phigoid, vesicular pemphigoid, polymorphic pemphigoid, pemphigoid nodu-
laris, pemphigoid vegetans, and localized pemphigoid are identical to those of
classic bullous pemphigoid.111,112
Two principal bullous pemphigoid antigens are recognized by Western
blot and immunoprecipitation studies: one is 230 kD (BPAG1) and the other
is approximately 180 kD (BPAG2) (Fig. 4.83).113–119 These represent products
of distinct genes.120–123
BP230 maps to the short arm of chromosome 6, locus 6p11-12.121 It
belongs to the plakin family and shows homology with plectin and the
desmogleins.122 It is wholly intracellular and localizes to the hemidesmosome.
BP230 is not involved in the early stages of the pathogenesis of blistering but
is of importance as a secondary event; antibodies against this antigen are not
required for blister formation in most cases.124–126
BP180 (collagen type XVII) is the major pathogenic antigen in bullous
pemphigoid. The BPAG2 (COLI7A1) maps to the long arm of chromosome
10, locus 10q24.3.121 It is a transmembrane adhesion molecule comprising an
intracytoplasmic N-terminal fragment, a transmembrane region, and a col-
lagenous extracellular C-terminal ectodomain.127 The latter constitutes part
of the anchoring filament and distally merges with the lamina densa. The
antibodies directed against BP180 in bullous pemphigoid most commonly
react with a short extracellular noncollagenous locus – NC16A (regions
MCW0-MCW3) – located within the upper lamina lucida proximal to the
collagenous segment (Fig. 4.84).127–130 It now appears that antibodies specific
Fig. 4.79
to this area are generally required for blister formation and, while antibodies
BP: direct
immunofluorescence of
may also target BP180 non-NC16A domains, these latter antibodies do not
perilesional skin showing appear to be pathogenic in most cases.124–26 This finding reconciles the fact
intense linear basement that antibodies to both BP180 and BP230 can be seen in a significant portion
membrane zone staining of the population without blister formation as these are not against the criti-
(IgG). cal NC16A region of BP180.84
Fig. 4.81 Fig. 4.83

BP: direct immunoperoxidase reaction using frozen tissue substrate showing BP: Western blot
electron-dense deposits in the lamina lucida. demonstrating the two
quite separate bullous
pemphigoid antigens.
By courtesy of M.M.
Black, MD, Institute of
More recently, two patients with a nonscarring, bullous pemphigoid-like

illness characterized by neutrophil-rich subepidermal blisters resembling
dermatitis herpetiformis and antibodies to a unique 105-kD protein – so-called
anti-p105 pemphigoid – have been documented.141–143 This antigen localizes
to the dermal side of split skin on indirect immunofluorescence. Its precise
nature has not yet been determined.
Anti-p200 pemphigoid is characterized by antibodies to a lower lamina
lucida basement membrane antigen.144–146 Patients generally present with a
Basal keratinocyte
HD plaque
NH2 Globular cytoplasmic domain

Fig. 4.82
BP: immunogold electron microscopic preparation. Note that the immunoreactant
NC16a
to BP180 and BP230 is particularly located on the hemidesmosomes (open arrows). Transmembranous domain Cell membrane
However, deposits are also present within the lamina lucida, black arrows. (BC,
basal cell; DER, dermis.) By courtesy of H. Shimizu, MD, Keio University School of
Medicine, Tokyo, Japan.
Lamina lucida Rod-like interrupted

Between 50% and 90% of patients with generalized bullous pemphigoid collagenous domain
have antibodies that react with BP230 and 35–50% have antibodies that
react with BP180 that are readily detected by immunoblotting.131 However,
the sera in 100% of patients react with BP180 NC16A domain recombinant
protein.131 This latter finding underscores the usefulness of recent testing for
anti-NC16A domain antibodies from peripheral blood to distinguish bullous
pemphigoid from other disorders.100,132–134 COL1
Flexible ‘tail’
Circulating antibodies against BP180 or BP230 have also been defined in
Lamina densa COOH
many of the other less common variants of bullous pemphigoid, including
localized and vesicular forms, pemphigoid vegetans, erythrodermic pemphig-
oid, and pemphigoid nodularis.131,135–139
In childhood pemphigoid, the antibodies also react against the same anti- Fig. 4.84
A schematic representation of the BP180 molecule showing the globular
gens.140 In addition, rarely there may also be antibodies that react with the
intracellular NH2 domain, the membrane proximal NC16A domain and the flexible
linear IgA 120-kD antigen.140 The BP180 antigen is most often targeted, and rod-like interrupted collagenous structure of the extracellular domain. (HD,
immunoblot analyses have shown that the antibodies react specifically with hemidesmosome). Collagen XVII/BP180: a collagenous transmembrane protein
the NC16A domain as in adult patients. In some children at least, the IgG and component of the dermoepidermal anchoring complex. (Powell AM,
subclasses differ from adult disease, consisting of all IgG subclasses or IgG2 Sakuma-Oyama Y, Oyama N, Black MM. Department of Immunodermatology,
in isolation.18 IgE antibodies are not a feature of c hildhood disease. St John's Institute of Dermatology, St Thomas' Hospital, London, UK.)
nonscarring bullous pemphigoid-like illness although linear IgA disease-like Successful differentiation depends upon careful clinicopathologic correlation
and dermatitis herpetiformis-like variants have also been reported.144 The dis- and immunofluorescent studies or, more recently, serum-based immunologic
ease has also been described in association with psoriasis.145 With split skin (ELISA) testing. Split skin indirect immunofluorescence or lamina densa anti-
indirect IMF, the antibodies bind to the floor of the blister cavity.144 With gen mapping by type IV collagen or laminin-1 direct immunoperoxidase is
indirect immunoelectron microscopy, the antibodies bind to the lower lamina essential to determine the level of the split. Although electron microscopy,
lucida.147,148 The identity of the 200-kD antigen has yet to be determined but immunoelectron microscopy, and immunoprecipitation or Western blotting
it is neither laminin nor type VII collagen.148 provide definitive information, such techniques are not necessary in the
Anti-p450 pemphigoid has been documented in a single patient. The anti- majority of cases.
gen, which has been localized to the basal keratinocyte, belongs to the plectin The cell-poor variant of bullous pemphigoid has a very wide range of differential
family.149 Its precise nature has yet to be determined. diagnoses including epidermolysis bullosa (congenital and acquired), porphyria
Exceptionally, bullous pemphigoid may be associated with antiplectin cutanea tarda, bullous amyloidosis, bullosa diabeticorum, and autolysis.
antibody.150
Bullous pemphigoid has been described following PUVA therapy for myco-
sis fungoides. More recently, a case arising in the setting of radiation therapy Pemphigoid gestationis
has also been noted, perhaps suggesting a role for tissue damage in the patho-
Pruritus is a very common symptom in pregnancy, occurring in up to 18% of
genesis of this disease.151
gravid females.1–4 When it occurs in the absence of significant cutaneous stig-
A mechanism for blister development in bullous pemphigoid has been pro-
mata it is known as pruritus gravidarum. This may occasionally be associated
posed by Jordon et al.80,152 and is outlined as follows. Following antibody–
with a cholestatic pathogenesis. The specific pregnancy eruptions have long
antigen interaction and complement fixation, various chemotactic agents
been a source of considerable confusion and controversy in the literature,
including C3a and C4a are produced.153 Mast cells degranulate under the
largely due to a diverse range of terminologies and classifications. Recently,
influence of the latter or IgE, and release ECF-A, NMW-NCF, ESM, hista-
Holmes has attempted to clarify the situation with the introduction of a new
mine, and enzymes.154 Eosinophils and neutrophils, so recruited, bind (possi-
and much simplified classification and others have proposed similar schemes.2,5
bly via C3b receptors) to the basement membrane region. By direct cytotoxic
Therefore the specific dermatoses of pregnancy may be divided into:
action (eosinophils are capable of antibody-dependent cellular cytotoxicity)
• polymorphic eruption of pregnancy, where the predominant lesions are
or via released proteases, particularly elastase, damage at the basement mem-
urticarial; in the United States, the term pruritic urticarial papules and
brane region results in the development of a vesicle. Lymphocytes elaborate
plaques of pregnancy (PUPPP) has achieved greater popularity;
histamine-releasing factor (HRF), which increases mast cell degranulation
• pregnancy prurigo in which the lesions consist of itchy papules;
and perpetuates the process. A broad range of cytokines are involved in this
• pemphigoid (herpes) gestationis, an autoimmune dermatosis belonging to
inflammatory reaction including interleukin (IL)-1, IL-4-IL-8, IL-10-IL-13,
the bullous pemphigoid group of diseases.
IL-15 and interferon gamma (IFN-γ).155 As yet, their relative importance and
Pemphigoid gestationis is a bullous dermatosis of pregnancy and the puer-
time sequences are unknown.
perium. It may be exacerbated by the use of oral contraceptives and rarely
Bullous pemphigoid is therefore a true autoimmune disease in which
complicates hydatidiform mole and gestational (but not nongestational) cho-
antigen–antibody reaction and complement fixation results in a character-
riocarcinoma. The current evidence implicates an autoimmune-mediated
istic and reproducible train of events, which is inevitably accompanied by
pathogenesis in which hormonal influences play a significant role.6,7
the development of subepidermal blister formation. The etiology or
initiator (other than those associated with drugs or PUVA therapy, which Clinical features
are the minority) is unknown. The question as to why self-tolerance breaks
down with the formation of symptomatic autoantibodies in patients with The term herpes (gestationis) is neither appropriate nor satisfactory. It is not
this d
isease is an important question for further investigation. of viral etiology, nor has it anything to do with creeping (Gr. herpes, to creep).
It was originally so named because of the tendency of the disease to show
‘progressive involvement by peripheral extension’.3 Because of its intimate
Differential diagnosis relationship to bullous pemphigoid, the designation pemphigoid gestationis is
The inflammatory cell-rich variant of bullous pemphigoid must be distin- preferred. As the major larger series have consisted of patients derived from a
guished from other subepidermal blistering dermatoses in which a heavy variety of sources, estimates of incidence have been very variable, ranging
inflammatory cell component is a typical finding. These include dermatitis from 1:3000 to 1:50 000 pregnancies.4,8–10 The more recent figures where
herpetiformis, linear IgA disease, inflammatory epidermolysis bullosa cases have had immunofluorescent confirmation would suggest that the latter
acquisita, and bullous systemic lupus erythematosus (see Table 4.5). figure is the most accurate.3
Table 4.5
Differential diagnosis of cell-rich pemphigoid
Parameter BP EBA BSLE LAD DH

DIMF Linear IgG, C3 Linear IgG, C3 Linear IgG, C3 Linear IgA Granular IgA
IIMF IgG antibodies 75–80% IgG antibodies 25–50% IgG antibodies 60% IgA antibodies 30% Antitransglutaminase antibodies
Split skin IMF Roof Floor Floor Roof or floor or both N/A
Type IV collagen Floor Roof Roof Roof or floor N/A
EM: site of split LL Sub-LD Sub-LD LL, sub-LD or both Papillary dermis
Western blot BP180 kD 290 kD 290 kD BP180 kD Antigen uncertain
BP230 kD (type VII collagen) (type VII collagen) BP230 kD
200/280 kD
285 kD
250 kD
290 kD
BP, bullous pemphigoid; BSLE, bullous systemic lupus erythematosus; DH, dermatitis herpetiformis; DIMF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; EM,
electron microscopy; IIMF, indirect immunofluorescence; IMF, immunofluorescence; LAD, linear IgA disease; LL, lamina lucida; sub-LD, sub-lamina densa.
Pemphigoid gestationis may present in the first or any subsequent preg-

nancy.3 It may first also rarely present in the postpartum period. In one series,
30% of patients were primigravidae.9 In addition to developing in pregnant
or postpartum patients, pemphigoid gestationis has rarely been described fol-
lowing a hydatidiform mole and gestational choriocarcinoma.11,12 It has not,
however, been reported in nongestational variants such as those occurring in
Fig. 4.86
the ovary, mediastinum, and testis, or complicating malignant teratoma. Pemphigoid gestationis:
Pemphigoid gestationis is predominantly a disease of white females, being the blisters are tense and
exceedingly rare in blacks.13,14 Presentation is usually in the second or third dome-shaped.
trimester, most often developing in the sixth or seventh month, but the range By courtesy of R.C.
is variable from 2 months to 4 days postpartum.10,15 Although the disease Holmes, MD, Warneford
may rarely completely remit before delivery, most patients (up to 75%) Hospital, Oxford, UK.
develop an exacerbation, which is frequently severe, in the immediate puerpe-
rium when progesterone levels have fallen.15,16 Exceptionally, the infant may
contain clear fluid, but at times the fluid may become hemorrhagic (Fig.
show transient urticated erythema and blistering.4
4.86). They typically heal without scarring.
Pemphigoid gestationis usually complicates subsequent pregnancies, fre-
The umbilicus is frequently the site of initial involvement; spread to the
quently presenting earlier on and with more severe symptomatology.10
trunk and extremities then follows (Figs 4.87, 4.88).3 Surprisingly, lesions on
Sometimes, however, it may skip intervening pregnancies.3 This may be
the face and mucous membranes are distinctly uncommon. Eventually palmar
related to a change in paternity, or else due to compatibility at the HLA-D
and plantar manifestations may appear. Other than pruritus, symptoms are
locus.
usually mild, with stinging, burning, and pain being relatively infrequent.10
Pemphigoid gestationis may develop into a very protracted ‘postpartum’
illness associated with considerable morbidity and lasting up to 12 years.17,18
In the majority of patients, however, the disease resolves by about 6 months
postpartum.4 The disease may first present following a change in sexual part-
ner.3,19 Alternatively, recurrent disease may persist even when there has been
a change of sexual partner.7 This obviously calls into question the role of spe-
cific paternal antigens.
Exacerbation following the use of the oral contraceptive is a common
complication,10,20–23 affecting 20–50% of patients.3 Estrogens in particular
have been implicated.22 The condition may also relapse during menstruation
for some weeks or months postpartum and the return of symptoms (pruritus)
has also been noted to coincide with ovulation (again suggesting an estrogen
influence), although this is rare.3,10,22
Evidence has been published relating the duration of symptoms postpar-
tum to the practice of breast-feeding. Bullous lesions lasted only 5 weeks in
those who breast-fed compared to 24 weeks in those who bottle-fed. Although
hormonal factors must be implicated, the precise pathogenetic implications
underlying this observation are not fully understood.22
Pemphigoid gestationis is associated with intense pruritus, which may be
present for days or weeks before the onset of typical cutaneous manifesta-
tions.1 The dermatosis is characteristically polymorphous, consisting of ery-
thematous or urticarial papules and plaques, some with a polycyclic pattern,
and later vesicles and bullae develop at the periphery of spreading erythema-
tous plaques (Fig. 4.85).3,10,24 When fully evolved, the blisters are tense and
Fig. 4.87
Fig. 4.85 Pemphigoid gestationis: slightly raised erythematous lesions with a propensity to
Pemphigoid gestationis: prebullous phase showing erythema and small papules. cluster on the abdomen. By courtesy of R.C. Holmes, MD, Warneford Hospital,
By courtesy of the Institute of Dermatology, London, UK. Oxford, UK.
Fig. 4.89
Pemphigoid gestationis: early erythematous lesion showing marked edema of the
Fig. 4.88 papillary dermis and conspicuous eosinophils.
Pemphigoid gestationis: umbilical involvement is a common mode of presentation.
Occasionally, the presence of target or iris lesions may mimic erythema mul-
tiforme.25 Less commonly, features may initially suggest classical bullous
pemphigoid.25 Very occasionally, there is clinical overlap with dermatitis
herpetiformis.
Pemphigoid gestationis is not associated with pre-eclamptic toxemia and
there is no related maternal mortality.
Pemphigoid gestationis is accompanied by a significant increased risk of
developing Graves' disease and an increased risk of autoantibodies.26
The literature concerning the incidence and nature of fetal morbidity and
mortality is a source of some confusion. Kolodney therefore considered that
there was no evidence of an increased incidence of stillbirths or abortions;
however, his report predates the immunofluorescence era.5 An investigation
by Lawley et al.20 of a large series of cases where immunofluorescent confir-
mation was available, suggested that there was an increased risk of fetal mor-
bidity and mortality. More recently, evidence has been presented that patients
with pemphigoid gestationis are liable to deliver low weight and small-for-
dates infants, prematurely.27 In contrast, however, Shornick et al. failed to
show any evidence of significant fetal complications.7 It has been shown that Fig. 4.90
the onset of the disease in the first and second trimester and the presence of Pemphigoid gestationis: early erythematous lesion showing eosinophilic
blisters is associated with higher morbidity including premature birth and spongiosis.
low birth weight children.28 Morbidity, however, still remains low. The anti-
body can cross the placenta and, in approximately 5% of cases, this may be
associated with a mild and transient vesiculobullous eruption.29–32

The histopathologic features seen in biopsies from patients with pemphigoid
gestationis are variable, depending upon whether early erythematous lesions,
urticarial papular lesions, or fully established vesicles and bullae are
studied.33
In early lesions, the major pathological features are seen in the superficial
dermis where there is a perivascular inflammatory cell infiltrate consisting of
lymphocytes, histiocytes, and typically very large numbers of eosinophils.
This is associated with edema of the papillary dermis, which when marked
may result in a ‘teardrop’ appearance (Fig. 4.89).33 Sometimes there is accom-
panying spongiosis and this may be associated with large numbers of eosino-
phils (eosinophilic spongiosis, Fig. 4.90). Occasionally the infiltrate of
lymphocytes, histiocytes, and eosinophils is present in a linear distribution
along the dermoepidermal junction.3
Vacuolar degeneration of the basal keratinocytes, sometimes accompa-
nied by individual cell necrosis, may be a feature of the early lesions, but is
often more evident in the fully established vesicular or bullous stage.33 In the
latter, the blister is subepidermal in location and frequently contains large Fig. 4.91
numbers of eosinophils (Figs 4.91, 4.92).33 The underlying and adjacent Pemphigoid gestationis: established subepidermal blister.
Fig. 4.92 Fig. 4.93

Pemphigoid gestationis: the blister cavity contains a heavy eosinophil infiltrate. Pemphigoid gestationis: indirect complement immunofluorescence showing linear
deposition of IgG.
dermis is edematous and contains a predominantly perivascular lympho/his- same NC16A domain as described in bullous pemphigoid.55–62
tiocytic infiltrate with large numbers of eosinophils. Leukocytoclasis and This can be detected in serum using the same test employed for bullous
eosinophil dermal papillary microabscesses are only rarely identified.33,34 pemphigoid.60–62 Antibodies that recognize the 230-kD bullous pemphigoid
Ultrastructural studies show that the cleavage plane lies within the lamina antigen are present in 10–26% of cases.56,57 Experimental models indicate that
lucida.33,35 antibodies against the NC16A domain of BP180 are the pathogenic antibodies
Direct immunofluorescence of perilesional skin in pemphigoid gestationis in pemphigus gestationis just as they are for bullous pemphigoid 7,62
shows a linear basement membrane zone deposition of C3 in all patients.3,36–41 Patients with pemphigoid gestationis have an increased incidence of HLA-
About 30–50% of cases also have an IgG band (less frequently IgM or IgA).36 B8 (43–79%), HLA-DR3 (61–80%) and HLA-DR4 (52–53%). The paired
They are present in nonlesional (perilesional) as well as in lesional skin.36 haplotypes HLA-DR3 and -DR4 are present in 54% of patients compared
Recently, it has been suggested that demonstration of linear C3d deposition with 3% in the general population.1,3,22,63,64 The phenotype, however, does not
at the dermoepidermal junction may be a useful tool in the diagnosis of the appear to correlate with the clinical features of pemphigoid gestationis.3,65
disease.42 The authors of this study used immunohistochemistry in paraffin- Patients with pemphigoid gestationis also have a high incidence (100%) of
embedded, formalin-fixed material with good results. Complement pathway anti-HLA cytotoxic antibodies, particularly directed against the paternal
components including properdin and properdin factor-B may also be identi- antigens.36,63–66 These are, however, found in 25% of normal multiparous
fied.1 IgG and complement can often be detected along the amniotic basement women and therefore their possible role in the pathogenesis of pemphigoid
membrane region using direct immunofluorescence.38,43,44 Pemphigoid gesta- gestationis is uncertain.26
tionis antigen has been detected in the placenta from early in the second The pathogenesis of pemphigoid gestationis relates to antibody-associated
trimester onwards.45 The antibody may also be found in the skin of infants of complement fixation with the production of leukocyte chemotactic factors,
affected mothers.29 Interestingly, serologic evidence of pemphigoid gestationis mast cell degranulation, and associated dermoepidermal separation.36
without manifestation of the disease may be seen, An exceptional case of neo- The presence of pemphigoid gestationis antigen in both skin and amnion
natal pemphigus in a child whose mother had clinical and serologic evidence raises the possibility that an initial antiplacental antibody cross-reacts with
of pemphigus vulgaris but only serologic evidence of pemphigoid gestationis skin, giving rise to the clinical features of pemphigoid gestationis.29 Support
has been described.46 for this theory has been the discovery that the HLA antigens -DP and -DR are
Circulating complement-fixing (via the classical pathway) IgG antibodies consistently expressed in the placentas of patients with this condition.64,67 The
(pemphigoid (herpes) gestationis (HG) factor) can be detected in 50–75% of main antigen present in both the skin and placenta seems to be collagen type
cases by indirect complement immunofluorescence (Fig. 4.93).20,36,47–51 The so- XVII and this, associated with genetic predisposition and specific HLA
called HG factor is nothing more than a low titer IgG complement-fixing genotype, appears to trigger the disease.68
antibasement membrane antibody.36 The antibody can be of any IgG subclass;
IgG1 and IgG4 have been reported as predominent.38,51 If monoclonal antibod-
ies directed against IgG are used, 100% of patients can be shown to possess Differential diagnosis
circulating HG factor.38 Approximately 25% of patients have antibasement The differential diagnosis includes epidermolysis bullosa acquisita, dermatitis
membrane zone antibodies detectable by conventional techniques.51 These bind herpetiformis, linear IgA disease, and bullous systemic lupus erythematosus (see
to the roof of 1 M NaCl-split skin.36 The antibody also reacts with amnion and Table 4.4). Pemphigoid gestationis must also be distinguished from pruritic urti-
chorion basement membrane.42,44 The autoantibodies in the disease are directed carial papules and plaques of pregnancy (PUPPP) and pregnancy prurigo.
against collagen XVII which is the BP 180-kD protein (BPAG2). The latter PUPPP is predominantly a disorder of first pregnancies. Lesions particu-
plays a major role in cell adhesion and signaling. It has been demonstrated that larly develop around abdominal striae, and periumbilical sparing is a charac-
collagen XVII is present in the epithelial cells of the amniotic membrane and in teristic feature (Fig. 4.94). Eosinophilic spongiosis and subepidermal
syncitial and cytotrophoblastic cells.52 Although the exact pathogenetic mecha- blistering may be seen in established lesions and therefore, in the absence of
nism of the disease is still unknown (see below), the presence of collagen XVII clinical details and immunofluorescence findings, distinction from pemphig-
in these tissues seems to play a major role in the mechanism of the disease. oid gestationis may be impossible.
With immunoelectron microscopy the immunoreactants are deposited Pregnancy prurigo, which typically develops in the third trimester, presents
within the upper lamina lucida where they are most probably associated with with pruritic papules and nodules (Fig. 4.95). Blisters are not a feature.
the sub-basal dense plate.53,54 In pemphigoid gestationis the antibody recog- Histologically, the changes are those of a low-grade, non-specific spongiotic
nizes BPAG2 (collagen type XVII) on Western immunoblot and localizes to the dermatitis.
Lichen planus pemphigoides 131
Fig. 4.94
Pruritic papules and plaques of pregnancy: note the erythematous papules
particularly related to the abdominal striae, and characteristic umbilical sparing. Fig. 4.96
By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK. Lichen planus pemphigoides: typical lichenoid papules are present on the anterior
aspect of the wrist. By courtesy of M.M. Black, MD, Institute of Dermatology,
London, UK.
Fig. 4.95
Pregnancy prurigo: there are erythematous papules and excoriations. Blisters are
not a feature of this condition. By courtesy of R.A. Marsden, MD, St George's
Fig. 4.97
Lichen planus pemphigoides: note the blisters and erosions arising on an erythematous
base. Atypical target lesions are present. By courtesy of M.M. Black, MD, Institute of
Lichen planus pemphigoides Dermatology, London, UK.
Clinical features
Lichen planus (lichen ruber) pemphigoides (Kaposi) must be distinguished Pathogenesis and histological features
from the vesicles occasionally seen in lichen planus as a consequence of severe The lichenoid lesions show the typical histopathological and immunofluores-
hydropic degeneration (lichen planus vesiculosis).1,2 Rarely, lichen planus is cent changes of lichen planus, but the bullae have features more suggestive of
associated with a generally benign, bullous pemphigoid-like disease: lichen bullous pemphigoid (Fig. 4.99). A variety of findings have been described.
planus pemphigoides. This represents a heterogeneous condition characterized Early erythematous lesions show intense dermal edema with a dense
by basement membrane antibodies directed towards a number of antigens. perivascular and interstitial eosinophil infiltrate; eosinophilic spongiosis may
Clinically, the pemphigoid-like lesions are usually preceded by typical also sometimes be evident. Established blisters are subepidermal and both
lichen planus although rarely the blisters may develop first (Fig. 4.96). The inflammatory (cell-rich) and cell-poor variants have been documented (Figs
bullae, which are most numerous on the extremities, may arise on normal 4.100, 4.101).5 Eosinophils are variably present but often may be numerous.
skin, in areas of erythema or on lichenoid papules (Figs 4.97 and 4.98). Immunofluorescent examination of biopsies from peribullous skin reveals
In some patients the blisters are generalized. Exceptionally, the blisters are linear deposition of IgG and complement.10–13 The serum contains an IgG
localized with typical lichen planus-like lesions elsewhere. A case with single antibasement membrane antibody in up to 50–60% of patients. With NaCl-split
blisters on the soles has been described.3 They are tense, dome-shaped and skin, the antibody generally labels the roof of the blister cavity. Ultrastructural
hemorrhagic or contain clear fluid. Evolution to pemphigoid nodularis-like investigations have shown that the level of separation is usually through the
lesions has been described.4 Lichen planus pemphigoides more commonly lamina lucida. By immunoelectron microscopy, the immunoreactants typically
affects males and presents most often in the fourth and fifth decades.5,6 localize to the hemidesmosome and lamina lucida.5,13,14 Mucous membrane
Exceptionally, however, cases have been documented in childhood.7–9 All pemphigoid and epidermolysis bullosa acquisita (EBA)-like variants have,
races may be affected. however, also been documented.15
Fig. 4.98
Lichen planus pemphigoides: note the intact dome-shaped tense blister. By courtesy
of M.M. Black, MD, Institute of Dermatology, London, UK.
Fig. 4.100
Lichen planus
pemphigoides: there is a
subepidermal blister.
Fig. 4.99
Lichen planus
pemphigoides: the
lichenoid papules show
typical features of lichen
planus.
A number of antigens have been recognized in lichen planus pemphigoides Fig. 4.101
including BP180, BP230, and an as yet uncharacterized 200-kD protein of Lichen planus
keratinocyte derivation.1,15–23 The segment of the NC16A domain recognized pemphigoides: the blister
in lichen planus pemphigoides differs from BP, localizing to MCW-4 (the contains eosinophils.
more C-terminal end of the domain) as opposed to MCW-0 to MCW-3.24,25
Type VII collagen has also been implicated in the EBA-like variant although
the immunoblot was negative.15 planus pemphigoides might be associated with internal malignancy but the
Although the pathogenesis of lichen planus pemphigoides has not been diagnosis lacked substantiation by immunofluorescence studies.36 Two addi-
fully unraveled, it is likely that the basement membrane zone damage associ- tional cases involving a patient with multiple keratoacanthomas and colonic
ated with lichen planus results in antigen exposure with subsequent autoanti- adenocarcinoma indicating a Torre-Muir-like syndrome and association with
body production and resultant bullous disease. So far, it is uncertain why only retroperitoneal Castleman disease have been noted more recently.37,38
a small percentage of patients with lichen planus are affected. The pathogen-
esis in those patients in whom the blisters develop first is unknown although a Differential diagnosis
different antigen may be involved. Exceptionally, cases have been documented Lichen planus pemphigoides differs from typical bullous pemphigoid clini-
as an adverse drug reaction (e.g., to angiotensin-converting enzyme inhibitors, cally by its earlier age of presentation and predilection for the lower limbs. In
complicating PUVA therapy, or in a patient taking paracetamol, ibuprofen, those cases associated with antibodies to BP180, epitope mapping may make
and having narrowband UVB).26–35 There has been a suggestion that lichen the distinction.
Mucous membrane pemphigoid (cicatricial pemphigoid) 133
Mucous membrane pemphigoid (cicatricial

pemphigoid)
Mucous membrane pemphigoid represents a spectrum of diseases (e.g., ocular
pemphigoid, oral pemphigoid, benign mucous membrane pemphigoid) which
affect the mucosa and skin.1–4 With the advent of molecular studies identifying
the antigens involved, it is becoming clear that there are a number of relatively
well-defined clinicopathological variants that arise as a consequence of auto-
immune diseases directed against a number of different basement membrane
antigens. Although multiple systems are often affected, there is increasing
evidence that pure ocular and oral variants may also be encountered.1,2
Clinical features
Mucous membrane pemphigoid is a rare blistering disorder in which mucosal
lesions predominate and in which scarring is a characteristic feature (although
not generally in the oral lesions).1,2,5 It is often associated with severe morbid-
ity, largely due to the effects of the scarring. As ocular and oral lesions pre-
dominate, many patients come to the attention primarily of the dental and
Fig. 4.103
oral surgeons or ophthalmologists rather than dermatologists.
Mucous membrane pemphigoid: in addition to erosions, intact blisters are evident.
The incidence is estimated as being between 1:12 000 and 1:20 000 of the By courtesy of P. Morgan, FRCPath, London, UK.
population per year.2 It is associated with a female preponderance (2:1) and it
not uncommonly presents in the seventh decade. Very rare instances of child-
hood involvement have been reported.3,6–10 Mucous membrane pemphigoid is
a chronic disease and is rarely self-limiting. It shows no racial or geographic Ocular lesions, which occur in approximately 64% of patients, are a
predilection. source of considerable morbidity.17–19 The eye (in particular the conjunctiva)
Oral lesions occur in 85–95% of patients and commonly follow mild may be a sole site of involvement.14 Early symptoms are those of a non-spe-
trauma.11 Bullae, erosions, and erythema most commonly affect the gingival cific conjunctivitis. In more advanced lesions, subconjunctival fibrosis
or buccal mucosa, but the hard and soft palate, tongue, and lips are also fre- develops.20,21 Patients may therefore present with fibrous bands (sym-
quently involved (Figs 4.102, 4.103). Desquamative gingivitis is the most blephara) stretching between the fornices and the globe (Fig. 4.104).
common manifestation.12,13 Patients with this condition present with painful, Eventually, contractures may obliterate the conjunctival sac. An essential
swollen, erythematous lesions of the gums, which may be associated with feature of ocular cicatricial pemphigoid is the production of an abnormal
bleeding, blistering, erosions, and ulceration.14 Most cases of desquamative tear film. This develops because of diminished lacrimal gland secretion (due
gingivitis have lichen planus and only in a low percentage, around 9%, is the to ductal stenosis), impaired goblet cell mucus secretion and ocular exposure
process a manifestation of mucous membrane pemphigoid.15 Lesions limited due to impaired eye closure.20 The end result is ocular drying and eventual
to the oral cavity is a distinctive subset, usually associated with a good keratinization of the ocular surface epithelium. Other important sequelae
prognosis although characterized by chronicity.1 Pharyngeal (19% of patients) include entropion, trichiasis (maldirected eyelashes, which can result in cor-
and esophageal (4% of patients) lesions may be complicated by scarring, neal abrasion), erosions and perforation, corneal neovascularization and
resulting in stenoses. Aspiration pneumonia is sometimes a fatal complica- scarring with opacification (Figs 4.105, 4.106). Primary corneal bullae have
tion. Nasal lesions, which may occur in up to 15% of patients, lead to obstruc- been described but are very rare, and erosions are more typical.11 Corneal
tion and occasionally cicatricial stenoses and septal perforation.16 Laryngeal lesions manifest as foreign body sensation, photophobia, and eventual
involvement, which occurs in 8% of patients, is sometimes complicated by blindness, which may be bilateral, occurring in up to 16% of patients.9
such severe stricture formation and edema that tracheotomy may be a life- Ocular involvement may be classified into a number of stages of progression
saving necessity.14 (modified Foster staging system).22
Fig. 4.104
Fig. 4.102 Mucous membrane pemphigoid: there is a dense fibrous adhesion (symblepharon)
Mucous membrane pemphigoid: there is erosion of the buccal mucosa. By courtesy between the conjunctiva lining the eyelid and that covering the globe. By courtesy
of P. Morgan, FRCPath, London, UK. of the Institute of Dermatology, St Thomas' Hospital, London, UK.
Fig. 4.105 Fig. 4.107

Mucous membrane pemphigoid: in this advanced case there is entropion and Mucous membrane
trichiasis (inwardly directed eyelashes). By courtesy of D. Kerr-Muir, MD, pemphigoid: in addition to
St Thomas' Hospital, London, UK. erosions, marked scarring
of the vulva is present. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.
Fig. 4.106
Mucous membrane pemphigoid: here there is dense corneal scarring with complete
opacification. By courtesy of D. Kerr-Muir, MD, St Thomas' Hospital, London, UK.
Fig. 4.108
Mucous membrane
pemphigoid: note the
Ocular involvement should not be confused with drug-induced pemphig- localized blistering and
oid (pseudo-ocular mucous membrane pemphigoid).2 This is a self-limiting erosion with scarring on
unilateral scarring disease of the eye, which most commonly develops as a the lower leg of an elderly
consequence of long-term use of eyedrops containing pilocarpine, echothio- female. By courtesy
phate iodide, idoxuridine, timolol, and adrenaline (epinephrine) in the treat- of R.A. Marsden, MD,
ment of glaucoma.23,24
London, UK.
Lesions of the female genitalia, which occur in 20% of patients, predomi-
nantly affect the labia majora and minora.14 Scarring is common and may
occasionally be associated with labial fusion (Fig. 4.107). In males, genital In the Brunsting-Perry variant of localized mucous membrane pemphig-
lesions most often affect the prepuce and the glans penis and are occasionally oid, scarring lesions are found predominantly on the head and neck
complicated by urethral stricture formation. Anal lesions affect up to 4% of (Fig. 4.109).25,26 This condition shows a male predominance (2:1) and pres-
patients and sometimes cause stenosis.14 ents most often in the sixth decade. The lesions are slowly enlarging, atrophic
Cutaneous lesions are found in approximately 25–33% of patients with or scarred plaques measuring several centimeters or more in diameter and
mucous membrane pemphigoid and most often affect the scalp, face, and showing vesiculation and/or bullae formation, both centrally and at the
neck.2,14,15 In some patients, presentation is similar to that of bullous pemphi- enlarging margin.27 The anterior portion of the scalp, the face (forehead,
goid, and fibrosis is not a feature.2 Lesions are generally few in number and temporal regions, and cheeks), and the anterolateral aspects of the neck are
present as itchy, sometimes burning, tense bullae situated on an erythematous most often affected.27 In some patients, lesions are few in number and,
or urticated base (Fig. 4.108). They tend to recur on previously affected sites. because of crusting, they may be clinically treated as actinic keratosis,
Rarely, patients may suffer from a transient generalized bullous eruption.14 thereby delaying the diagnosis. Transient mucous membrane lesions may be
Nikolsky's sign is negative.21 a feature, but scarring is not seen.25
Mucous membrane pemphigoid (cicatricial pemphigoid) 135
Fig. 4.110
Fig. 4.109 Mucous membrane pemphigoid: in this example of a recurrent lesion, the
Brunsting–Perry localized pemphigoid: there is extensive alopecia in addition to subepidermal blister is cell free and there is dermal scarring.
multiple erosions with scarring. By courtesy of R.A. Marsden, MD, St George's
An exceptional case of anti-BP180 mucous membrane pemphigoid

resenting with concomitant pemphigus vulgaris limited to mucosal surfaces
p
Autoimmune blistering diseases are very rarely associated with HIV infec-
tion and only a single exceptional case of mucous membrane pemphigoid has
been reported in association with HIV.29

Mucous membrane pemphigoid has been described as a complication of
D-penicillamine therapy for rheumatoid arthritis, practolol and clonidine.14,30
Immunologically, characteristic cicatricial pemphigoid has also been described
following acute, severe, ocular inflammation in patients with Stevens-Johnson
syndrome.31 Although the results of HLA associations have been variable, an
increased frequency of HLA-DR4 and -DQw3 (DQB1*0301) correlates with
a heightened risk of developing ocular disease.32
The cutaneous lesions of mucous membrane pemphigoid are often indis-
tinguishable from those of cell-rich (inflammatory) bullous pemphigoid, com-
prising a subepidermal vesicle containing fibrin, edema fluid, and variable
numbers of inflammatory cells. Although eosinophils are usually evident, Fig. 4.111
they tend to be much less numerous than in generalized bullous pemphigoid. Mucous membrane
The dermis contains a perivascular lymphohistiocytic infiltrate, sometimes pemphigoid: high-power
with conspicuous plasma cells and accompanied by neutrophils and eosino- view of a similar lesion
phils. In older or recurrent lesions, scarring may be a feature (Fig. 4.110).
Less commonly, a cell-poor subepidermal blister is seen (Fig. 4.111). In late
lesions all that may be observed is a band of scarring in the superficial dermis
with or without a subepidermal split. If the latter is present, this is a good clue
to the diagnosis, especially in localized variants where the diagnosis is not
suspected on clinical grounds.
The histopathology of lesions in antilaminin 332 mucous membrane pemphi-
goid has been studied in a small number of cases.33 The features are nondiagnos-
tic and do not allow distinction from other autoimmune blistering diseases. There
is subepidermal blistering and a mild to moderate, superficial mixed inflamma-
tory cell infiltrate composed of lymphocytes, histiocytes, and neutrophils and/or
eosinophils. Scarring is not often seen as biopsies are taken from early lesions.
Oral lesions may rarely be characterized by vesiculation developing
between the stratified squamous epithelium (mucosa) and lamina propria
(Figs 4.112, 4.113). The latter is usually edematous and contains a mixed
inflammatory cell infiltrate consisting of lymphocytes, histiocytes, plasma
cells, and varying numbers of eosinophils and neutrophils (Fig. 4.114). More
commonly, however, the features seen are those of erosions or ulcers lined by
granulation tissue or fibrous tissue and showing non-specific acute or chronic
inflammation. The histology is frequently modified by intense acute inflam- Fig. 4.112
matory changes due to secondary infection. Mucous membrane pemphigoid: oral lesion showing an intact subepithelial blister.
Fig. 4.113 Fig. 4.115

Mucous membrane pemphigoid: note the preservation of the papillae. Mucous membrane pemphigoid: this specimen of conjunctiva shows complete
squamous metaplasia. Neovascularization of the lamina propria is evident. By
courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.
Fig. 4.114
Mucous membrane pemphigoid: in this example the infiltrate consists of Fig. 4.116
lymphocytes and histiocytes. Eosinophils are not a feature. Mucous membrane pemphigoid: section of cornea. The overlying pannus shows squamous
metaplasia, chronic inflammation, and neovascularization. Blood vessels are also present in
the cornea. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.
Conjunctival vesicles or bullae are very rarely seen in ocular cicatricial
pemphigoid. Although erosions may be a feature, more commonly one may
anticipate conjunctival squamous metaplasia with foci of hyperkeratosis and
parakeratosis accompanied by goblet cell depletion (Fig. 4.115).14 The lam-
ina propria is infiltrated by a mixed inflammatory cell population consisting
of lymphocytes, plasma cells, mast cells, and occasional eosinophils and neu-
trophils.21 Granulation tissue may be seen in early lesions, but dense scarring
is a feature of the later stage. In more severely affected patients, a variety of
intraocular manifestations, including iridocyclitis, rubiosis iridis, and the
development of synechiae, may be seen (Figs 4.116–4.118).
Laryngeal, pharyngeal and esophageal lesions occasionally show subepithe-
lial bullae, erosions, ulcers, inflammatory changes, and fibrosis are more likely
to be seen (Fig. 4.119). Chronic involvement may result in serious stenosis.
The histological features of the localized cutaneous scarring (Brunsting-
Perry) variant are indistinguishable from those of mucous membrane
pemphigoid.27
Electron microscopic observations are variable. In some patients, the split is in
the lamina lucida with the lamina densa lining the floor of the blister cavity
whereas in others, lamina densa is found along the roof of the blister, and occa-
sionally the lamina densa may be split, lining the roof and the floor.2,34 Fig. 4.117
Direct immunofluorescent findings in cicatricial pemphigoid are similar to Mucous membrane pemphigoid: this section shows iris impaction with anterior
those found in generalized bullous pemphigoid. Therefore a linear deposit of synechiae. Iritis and posterior synechiae are also present. By courtesy of A. Garner,
IgG (and sometimes IgA) and C3 is found at the basement membrane region MD, Institute of Ophthalmology, London, UK.
Epidermolysis bullosa acquisita (dermolytic pemphigoid) 137
in from 50% to 100% of cases with active disease.48,49 Although the majority
of sera have reacted with the epidermal side of the split, some have labeled the
floor (dermal side, subsequently shown to be due to antilaminin 332 antibod-
ies: see below), and exceptionally both the roof and the floor have been
labeled.45–49 There is also variation in indirect immunofluorescence findings
depending upon the predominant site of involvement. Thus, for example,
split skin indirect immunofluorescence may be positive in up to 81% of
patients with combined skin and mucosal disease whereas much lower figures
have been found in patients with mucosal disease only (18%) or isolated ocu-
lar disease (7%).2,50
The immunofluorescent findings in the Brunsting-Perry variant are the
same as those described for mucous membrane pemphigoid.51–54
Immunoelectron microscopic observations in mucous membrane pemphi-
goid have revealed two patterns of immune reactant deposition. IgG and C3
may be localized to the lower lamina lucida and lamina densa or else identified
overlying the hemidesmosome.55–61 There is no involvement of the sublamina
densa region. The variation can be explained by the different target antigens
involved, i.e., BP180, laminin 332 or β4 integrin.
In the Brunsting-Perry variant of localized chronic pemphigoid the immu-
Fig. 4.118 noreactants are localized within the lamina lucida and on the undersurface of
Mucous membrane pemphigoid: this field shows anterior uveitis. There is
basal keratinocytes.62 In a single case it was demonstrated that the antibodies
inflammation of the iris and ciliary body. By courtesy of A. Garner, MD, Institute of
Ophthalmology, London, UK.
in the serum reacted with the C-terminal domain of the BP180 (BPAG2) pro-
tein.63 Additionally, however, the complement components C3 and C4 may
also be detected within the lamina densa and the upper papillary dermis. It is
suggested that this latter finding might account for the scarring characteristic
of this disease process.62
A number of subsets of cicatricial pemphigoid have been delineated by
antigen analysis including variants characterized by antibodies to BP180,
laminin-332, and β4 integrin.43,47,57,64–74 Traditionally, this group of diseases
has been classified together, but the increasing demonstration of autoimmune
reactions to different cell adhesion molecules will likely ultimately lead to
subtyping of this disease similar to the cutaneous forms. For now, since the
clinical features are more uniform than those seen in the skin, these mucosal
cases are considered together. BP180 (collagen XVII) antibodies react with at
least two different sites on the extracellular domain of BP180. One is located
on the noncollagenous domain NC16A; the other is located within the
carboxy-terminal region.68,75–78 Antilaminin-332 (also called epiligrin) antibodies
to the γ3 subunit (sometimes accompanied by antilaminin type-6 antibodies)
are present in a minority of cases and, although the antibodies are usually
IgG, IgA, and IgE, antibodies against laminin-332 may also be found in a sub-
set of patients.79 Patients with antilaminin-332 antibodies have been classified
as having antiepiligrin mucous membrane pemphigoid (AEMMP). Some of
such cases are associated with internal malignancies (including lung, colon,
endometrium, stomach, ovary, pancreas, prostate, non-Hodgkin's lymphoma,
cutaneous T-cell lymphoma, and acute myeloblastic leukemia).80–84 Integrin
Fig. 4.119 has been implicated in patients with ocular disease and an as yet unidentified
Mucous membrane
45-kD antigen, which binds to the epidermal side on split skin immunofluo-
pemphigoid: postmortem
specimen showing
rescence, has been identified in some patients with IgA antibodies.70,72,73
laryngeal erosion, Autoantibodies to type VII collagen is of importance in some cases of
ulceration, and scarring. Brunsting-Perry cicatricial pemphigoid (these patients might be better classi-
fied within the epidermolysis bullosa acquisita spectrum, see below).85
of perilesional mucosa (the site of choice) or perilesional skin in approxi- Differential diagnosis
mately 80–97% of patients.35–39 The presence of IgA at the basement mem-
Apart from the presence of scarring in older lesions, mucous membrane pem-
brane region accompanied by IgG and C3 is a diagnostic pointer towards
phigoid is indistinguishable from bullous pemphigoid.
cicatricial pemphigoid.2 Examination of the oral mucosa is also of value in
the diagnosis of ocular disease.2 Direct immunoperoxidase of paraffin-embed-
ded tissue can be a satisfactory alternative if a specimen has not been taken
for direct immunofluorescence studies.40 Epidermolysis bullosa acquisita (dermolytic
Circulating antibasement membrane zone autoantibodies (IgG and/or IgA) pemphigoid)
are sometimes present (26–36%) and are usually of low titer.36,41,42 Substitution
of normal buccal mucosa as substrate does not increase the yield of circulat- Epidermolysis bullosa acquisita (dermolytic pemphigoid) is a rare, chronic
ing antibodies.41 The antibody consists predominantly of IgG4 and IgG1 blistering disease, which is characterized by variable clinical presentations
subclasses, the presence of the latter conferring complement-fixing ability.43 and which may therefore be mistaken for a number of other blistering disor-
The presence of IgA may be linked to the mucosal membrane distribution of ders including congenital epidermolysis bullosa and the other acquired auto-
this disease.44 immune bullous dermatoses.1,2 Annual incidence figures from France and
Investigations of cicatricial pemphigoid antibodies using 1 M NaCl-split Central Germany are 0.17–0.26 per million of the population.3,4 In contrast
skin have yielded variable results.45–47 Circulating antibodies may be detected to its congenital counterpart, epidermolysis bullosa acquisita (EBA) usually
develops in adult life although cases in childhood have been documented.5,6 e pidermolysis bullosa. Scarring may then be extreme with resultant contrac-
Initially it was characterized as a porphyria cutanea tarda-like mecha- tures and syndactilism. Rarely, esophageal involvement has been documented
nobullous dermatosis. More recently, however, patients have been described with resultant stricture formation.10,13,14
in whom the disease has presented as a generalized inflammatory bullous der-
matosis.1 For many decades the diagnosis of EBA was one of exclusion. As a Bullous pemphigoid-like EBA
result of immunofluorescence and immunoultrastructural techniques This is the most commonly encountered inflammatory variant.15 On the basis
combined with immunoblotting and immunoprecipitation, EBA is now of split skin indirect immunofluorescence (see below) it has been suggested
recognized as an autoimmune dermatosis, type VII collagen (290 kD) repre- that a BP presentation may account for up to 50% of cases of EBA and that
senting the target antigen.1,8 A 145-kD antigen is also sometimes identified. 10–15% of patients diagnosed as BP, in fact, have EBA.15 Other authors,
This represents a cleavage product of the 290-kD antigen. however, have found that EBA is very rare compared to BP, the relative inci-
dence being approximately 25–50 cases of BP for every one case of EBA
Clinical features diagnosed.16,17
EBA was defined in 1971 by Roenigk and colleagues5 as follows: Patients present with a generalized eruption of large tense blisters, which
are often associated with erythema and show a predilection for the flexural
• clinical lesions resembling dystrophic epidermolysis bullosa (blisters
developing on the hands, feet, elbows, and knees following mild trauma and intertrigenous areas.18,19 Pruritus is common.15 Skin fragility is typically
and complicated by atrophic scarring, milia formation and nail dystrophy), absent and scarring and/or milia are not usually features unless the patient
concomitantly shows or evolves towards a mechanobullous phase.1,15
• an adult onset,
Infrequently, the clinical manifestations may resemble dermatitis herpetiformis
• a negative family history of epidermolysis bullosa,
(Fig. 4.122). Exceptionally, prurigo nodularis-like lesions may be seen.20
• exclusion of all other recognized bullous dermatoses including porphyria
cutanea tarda, bullous pemphigoid, dermatitis herpetiformis, pemphigus,
erythema multiforme, and bullous drug reactions.9
It has a wide age incidence ranging from 11 to 77 years, with a mean age
of 47 years. It is associated with a slight female predominance.
In addition to the mechanobullous classical form of EBA, inflammatory
variants, including bullous pemphigoid-like, mucous membrane pemphigoid-
like, and linear IgA disease-like variants, may also be encountered.1,10,11
A case of familial EBA has been described.12
Classical variant
The classical variant is the most commonly encountered variant of EBA.
Patients present with a porphyria cutanea tarda-like illness showing extreme
skin fragility, developing erosions, blistering and crusting in response to mild
trauma including shearing forces.5 Lesions are located on the backs of the fin-
gers and hands in particular and at other sites that are susceptible to trauma,
including the knees, elbows, and buttocks, but virtually any site may be
affected (Fig. 4.120).1,5 The blisters are characteristically noninflammatory,
painless, and tense, and may contain clear or bloodstained fluid.
Healing is usually associated with postinflammatory hyperpigmentation,
considerable scarring, and atrophy. Milia are frequently conspicuous, and
nail changes, including distal onycholysis, dystrophy, and anonychia with Fig. 4.121
nail bed scarring, are common complications (Fig. 4.121). More widespread Epidermolysis bullosa acquisita: conspicuous milia are present on the back of the
involvement may resemble dominant or more often recessive dystrophic hand. By courtesy of the Institute of Dermatology, London, UK.
Fig. 4.122
Fig. 4.120 Epidermolysis bullosa acquisita: in this patient with the dermatitis herpetiformis-like
Epidermolysis bullosa acquisita: there is a tense fluid-filled blister on the ankle. An inflammatory variant, blisters, erosions, and erythematous plaques are evident on
old lesion is also evident. By courtesy of the Institute of Dermatology, London, UK. the elbow. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Mucous membrane pemphigoid-like variant

Some patients present with a mucous membrane pemphigoid-like variant,
characterized by mucous membrane involvement. The oral cavity is commonly
affected. Erosions, ulcers, and blisters may be seen on the tongue, gums, palate,
and buccal mucosa.11 Rarely, the larynx and esophagus are affected with
resultant stricture formation.10 The anus, vulva, vagina, and bladder can very
occasionally be involved.21 Conjunctival lesions are an important, but infre-
quent, cause of morbidity.10,11,22 Symblepharon, epiphora, and even blindness
may occur. Alopecia is sometimes an additional feature.7,13
Brunsting-Perry variant
Some patients with the Brunsting-Perry variant of mucous membrane pem-
phigoid (characterized by blistering and scarring confined to the head and
neck) have antibodies against type VII collagen and therefore might better be
classified within the epidermolysis bullosa acquisita spectrum.7,23,24 Facial
involvement predominates.24,25 A very unusual localized case with periorbital Fig. 4.123
papulovesicular blisters has been reported.26 Epidermolysis bullosa acquisita (classical variant): there is a cell-free subepidermal
vesicle. Note the dermal scarring.
Linear IgA disease-like variant (IgA-EBA)
Epidermolysis bullosa acquisita may also present as a linear IgA disease-like
variant in which both adult and childhood patients have IgA autoantibodies
directed against type VII collagen (see below).27–29 In adults, ocular involve-
ment is often severe and blindness is not uncommon.28
Childhood EBA
Childhood EBA is extremely rare. Mucosal disease is often severe, and clini-
cal manifestations have included classical bullous pemphigoid and linear IgA-
like variants.6,8,30–33
Systemic disease
Epidermolysis bullosa acquisita has long been known to be associated with a
number of systemic illnesses, many with an immunologically mediated patho-
genesis. Most important are inflammatory bowel disease and diabetes melli-
tus.2,10,15,34–45 Approximately 30% of patients with EBA manifest inflammatory
bowel disease, predominantly Crohn's disease.42,46 Control of this improves
the skin condition in some patients. Interestingly, although up to 68% of
patients with inflammatory bowel disease have antibodies against collagen
type VII, only very few develop EBA.47 Presentation as a paraneoplastic phe-
Fig. 4.124
nomenon in association with internal malignancy has also on occasion been
Epidermolysis bullosa acquisita (classical variant): high-power view. There is fibrin
described.48,49 along the floor of the blister cavity. Note the absence of inflammatory cells.

The histological features are somewhat variable depending upon whether a keratinocytes appear normal. Anchoring fibrils have been variably reported
mechanobullous or an inflammatory lesion is biopsied. as reduced in number or absent.47–53
The mechanobullous lesion is characterized by a bland, ‘cell-free’ An occasional finding is the presence of electron-dense, amorphous granu-
subepidermal vesicle containing only a few erythrocytes and a little fibrin lar material within the superficial papillary dermis close to, but separated
(Figs 4.123, 4.124). Usually, no significant inflammatory cell infiltrate is from, the lamina densa (Fig. 4.128).9,35 When present, the split is usually
present either within the blister cavity or in the adjacent or underlying dermis. below the electron-dense amorphous material, which is therefore located
Sometimes, however, a small number of neutrophils, histiocytes, and eosino- within the roof of the blister.
phils may be present. The basement membrane lines the roof of the blister. By direct IMF, IgG and C3 are present in a linear distribution along the
Marked scarring of the adjacent dermis is often a feature and milia are basement membrane region (identical to BP) in a very high proportion of
frequently identified. cases of EBA (Fig. 4.129).9,10,36 Less commonly, IgM, IgA, properdin, and fac-
The inflammatory variant is characterized by a subepidermal vesicle tor B may also be identified.1,52,53 In linear IgA disease-like patients, IgA may
accompanied by a mixed inflammatory cell infiltrate comprising lympho- be present in the absence of IgG.27–29 Positive direct immunofluorescence has
cytes, histiocytes with prominent neutrophils, and eosinophils. Neutrophils also been reported at a variety of other sites including the oral mucosa, con-
are usually the predominant cell type and in incipient lesions they may be junctiva, cornea, esophagus, duodenum, and bladder.9,28,34
identified in a linear distribution adjacent to the epidermodermal junction.15 IgG antibasement membrane antibodies may be identified in 25–50% of
Occasionally, however, eosinophils predominate.24 Such inflammatory lesions patients, thereby increasing the similarity to BP.2,47,51,54 In many patients the
may resemble bullous pemphigoid or dermatitis herpetiformis (Figs 4.125, antibasement membrane antibodies are associated with complement-fixing
4.126).2,50 Oral lesions show similar features of submucosal vesiculation with properties.55 With split skin indirect IMF, which is more sensitive than con-
an erythrocyte and inflammatory cell content. ventional indirect IMF, the immunoreactants line the floor of the induced
By direct immunoperoxidase using paraffin-embedded material, type IV blister cavity.56–59
collagen is found in the roof of the blister cavity (see Fig. 4.8). Direct and indirect immunoelectron microscopic studies have determined
Ultrastructurally, the level of the split in EBA is situated within the super- that the immunoreactants lie on or below the lamina densa, corresponding to
ficial dermis immediately below the lamina densa (Fig. 4.127).51–53 The basal the site of the electron-dense amorphous material mentioned above
A
A
B
B
Fig. 4.125
Fig. 4.127
(A, B) Inflammatory epidermolysis bullosa acquisita: in this bullous pemphigoid-like
(A, B) Epidermolysis bullosa acquisita: electron micrograph showing the lamina
variant, subepidermal blistering is associated with an eosinophil-rich infiltrate.
densa in the roof of the blister. (BC, blister cavity.)
Fig. 4.126
Inflammatory
epidermolysis bullosa
acquisita: dermatitis Fig. 4.128
herpetiformis-like variant, Epidermolysis bullosa acquisita: occasional deposits of finely granular electron-
with a neutrophil-rich dense material (immunoreactant) as seen in this field may be a useful diagnostic
infiltrate. pointer.
Fig. 4.129 Fig. 4.131

Epidermolysis bullosa acquisita: (left) direct immunofluorescence shows linear Epidermolysis bullosa acquisita: immunogold preparation showing localization of
IgG deposition along the basement membrane region; (right) with split skin the the immunoglobulin to the anchoring fibrils. By courtesy of H. Shimizu, MD, Keio
immunoreactant lines the floor of the induced lesion. By courtesy of Department of University School of Medicine, Tokyo, Japan.
Immunofluorescence, Institute of Dermatology, London, UK.
Fig. 4.132
Fig. 4.130 Epidermolysis bullosa
Epidermolysis bullosa acquisita: direct immunoelectron microscopy showing acquisita: there are two
reactant deposition below the lamina densa. distinct antigens: one the
290-kD major antigen; the
other the 145-kD minor
(Fig. 4.130).1,51,52,60,61 Immunogold labeling confirms that the immunoglobu- antigen. By courtesy of I.
lin deposits are related to the anchoring fibrils (Fig. 4.131).62 As a conse- Leigh, MD, Royal London
quence of these additional observations, a modified set of criteria for the Hospital Trust, London, UK.
diagnosis of EBA has been recommended:1,63
• clinical lesions of trauma-induced bullae occurring over the joints of the
hands, feet, elbows and knees, atrophic scars, milia and nail dystrophy, through the lamina densa to the connective tissue constituents of the adjacent
or else presentation as a clinically inflammatory bullous or mucous dermis and is composed of three identical alpha-chains (each 290 kD). It is
membrane pemphigoid-like process, synthesized by both human keratinocytes and fibroblasts in culture, and is
• postinfancy onset of the disease, found in other mammalian skin including dog, cat, guinea pig, rat, mouse,
• no family history of EBA, and hamster, but not in avian, reptilian, amphibian, or fish skin.69–72 Type VII
• exclusion of other bullous diseases, collagen has also been identified within the esophagus, mouth, anus, and
• IgG at the basement membrane zone on direct immunofluorescence, vagina. It has a high affinity for fibronectin, which is thought to be respon-
• demonstration of blister formation beneath the lamina densa, sible (at least in part) for adhesion between cells and matrix within the der-
• demonstration of IgG associated with anchoring fibrils beneath the basal mis.73 The interaction between the EBA antibody and type VII collagen is
lamina by immunoelectron microscopy, thought to somehow upset this delicate relationship with consequent der-
• localization of the immunoreactants to the floor of 1 M NaCl-split skin moepidermal separation.74 Passive transfer of human EBA autoantibodies to
by direct and or indirect immunofluorescence. mice and immunization of mice with type VII collagen both lead to EBA dis-
The EBA antigen (290 kD) is the globular (noncollagenous) carboxyl ter- ease models, confirming the importance of this autoantibody.75–78 An animal
minus of type VII procollagen (Fig. 4.132).64–68 Type VII collagen is the major model and human antibody characterization indicate that the pathogenic
constituent of anchoring fibrils which anchor the basement membrane antibodies of epidermolysis bullosa acquisita are often against the cartilage
matrix protein subdomain of the N-terminal noncollagenous domain of type

VII collagen.79 In some cases of inflammatory EBA the antibodies react against
epitopes in the triple-helical collagenous domain.80
The parallel between EBA and BP is obvious and it is tempting to extrapo-
late a similar downstream pathogenesis after autoantibody binds to its pro-
tein target.81 Although the current concept for EBA points to such a similarity,
additional confirmatory evidence is required. Recent studies have shown that
the pathogenesis is related, at least in part, to neutrophil recruitment medi-
ated by complement activation, and the generation of complement-derived
chemotactic activity (C5A) at the epidermal basement membrane region.74
Experimental models in which immune complexes are produced by treating
normal skin in organ culture with EBA complement-fixing antibodies has
been shown to result in complement-dependent neutrophil migration to the
basement membrane region and eventual dermoepidermal separation.55,82
Lack of complement-fixing function in the autoantibodies does not result in
tissue injury in one model.83 The precise mechanism whereby such blisters
evolve is unknown, but it has been suggested that leukocyte-derived proteases
and reactive oxygen intermediates may be important.54
The pathogenesis of the ‘cell-free’ mechanobullous variant is poorly under-
stood. It is also associated with antibasement membrane antibody, but there is Fig. 4.133
Bullous systemic lupus erythematosus: West Indian female with perioral blistering.
little if any evidence for neutrophil chemotactic activity. It has been proposed
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
that separation at the dermoepidermal junction may result from an abrogation
of affinities between the type VII collagen and laminin-332 in addition to matrix
proteins such as fibronectin due to a direct effect of autoantibody deposition at
that site.1,84–86 An additional potential mechanism proposed is a direct effect of both sexes may develop the disease (Fig. 4.133).4,6–11 Presentation in children
the autoantibody on type collagen VII antiparallel dimer assembly leading to is exceptional.12,13
diminished anchoring fibril formation.1,87 The finding of domain specificity in Patients present with a widespread, sometimes pruritic, tense, vesicu-
EBA autoantibodies will direct focus toward the function of this cartilage matrix lobullous eruption that may affect both sun-exposed and nonsun-exposed
protein subdomain.81 It is intriguing that the pathogenetic autoantibodies in skin (Figs 4.134–4.136). The eruption can precede the onset of SLE or
EBA are against type VII collagen, the same protein genetically interrupted in develop subsequently.8,14 Lesions develop on flexural and extensor surfaces,
dystrophic epidermolysis bullosa, leading to nonfunctional anchoring fibrils. and mucosal (mouth and pharynx) lesions have been documented.4,8,15
Nonetheless, the clinical presentation of EBA is broad and includes features not A predilection for involvement of the upper trunk and supraclavicular
seen in dystrophic EB, such as bullous pemphigoid-like lesions. regions has been reported.4 Lesions may arise against a background of
erythema or less commonly urticaria. Unlike EBA with which this disease
shares much in common, mechanobullous lesions are not seen, nor is there
Differential diagnosis evidence of scarring.4 Milia formation, although rare, has been recorded on
‘Cell-free’ EBA must be distinguished from congenital EB, porphyria cutanea two occasions and in both instances affected children.9,10 Postinflammatory
tarda, pseudoporphyria, and cutaneous bullous amyloidosis. Diagnosis can hyperpigmentation is a not uncommon complication. Surprisingly, patients
be achieved easily with the use of immunofluorescence. with bullous SLE do not usually develop other cutaneous manifestations of
Inflammatory EBA can be distinguished from bullous pemphigoid, mucous lupus. Bullous SLE has been recorded in a patient whose primary disease
membrane pemphigoid, and linear IgA disease by split skin IMF and, when developed as a consequence of hydralazine therapy and identical features
necessary, by Western blot (see Table 4.4). (including immunological) have been recorded in a patient with mixed
It is also important that dermoepidermal separation due to autolysis is not connective tissue disease.16
confused with in vivo blister formation. In autolysis the epithelium typically
shows marked eosinophilia and the nuclei are often lost.
Bullous systemic lupus erythematosus

Blisters may rarely develop as a manifestation of systemic lupus erythemato-
sus (SLE). They can therefore arise in a background of vasculitis or compli-
cate sunburn and photosensitivity.1,2 Occasionally vesicles form after extreme
basal cell hydropic change and consequent dermoepidermal separation.3
Patients with SLE manifest a wide range of antibodies resulting in numer-
ous complications, which include the development of autoimmune bullous
dermatoses such as bullous pemphigoid, dermatitis herpetiformis, pemphigus
vulgaris, pemphigus foliaceus, linear IgA disease, and epidermolysis bullosa
acquisita.4,5 More recently, an apparently unique dermatosis comprising a
widespread vesiculobullous eruption characterized by a dermatitis herpeti-
formis-like histology, linear basement membrane zone antibody deposition
(reacting with type VII collagen), and a striking response to dapsone has been
described in patients with SLE.6 This c onstitutes bullous SLE.

Bullous SLE – also termed bullous eruption of SLE, vesiculobullous SLE, SLE Bullous systemic lupus erythematosus: in this example there is a conspicuous
with herpetiform blisters – tends to present in the second and third decades inflammatory background. By courtesy of the Institute of Dermatology,
and although young black women are most often affected, all ages, races, and London, UK.
Bullous systemic lupus erythematosus 143
Fig. 4.135 Fig. 4.137

Bullous systemic lupus erythematosus: numerous erosions are present over the Bullous systemic lupus erythematosus: this shows the typical features of a
chest, shoulders, and upper arms. By courtesy of R.A. Marsden, MD, St George's subepidermal, neutrophil-rich vesicle.
Fig. 4.138
Bullous systemic lupus
erythematosus: the
Fig. 4.136 presence of a neutrophil
Bullous systemic lupus abscess in the papillary
erythematosus: tense dermis increases the
bullous pemphigoid-like histological similarity of
lesions. By courtesy of the this condition to dermatitis
Institute of Dermatology, herpetiformis.
London, UK.
Using direct immunofluorescence, the disease is characterized by the pres-

Pathogenesis and histological features ence of immunoglobulin and complement at the epidermal basement mem-
Patients with bullous SLE (and EBA) have a significantly higher incidence of brane region of both lesional and perilesional skin. Immunoglobulins are
HLA-DR2 compared to the normal population.4 This is thought to be associ- frequently multiple: IgG is present in 100% of patients, IgA in 67%, and IgM
ated with an increased risk of developing autoimmune diseases.17 in 50%.4,7,8,17,18 Two patterns are recognized: granular in 40% of cases and
The histological features of bullous SLE (BSLE) are those of a subepidermal linear in 60%.8 Sometimes immunoreactants are also present within the walls
vesicle, often indistinguishable from dermatitis herpetiformis. The roof is usu- of the upper dermal vasculature, particularly venules.4 Indirect immunofluo-
ally intact and the blister cavity contains fibrin with large numbers of neutro- rescence using 1 M NaCl-split skin as substrate shows the presence of a low
phils and karyorrhectic debris (Fig. 4.137). Occasionally lymphocytes, titer antibasement membrane antibody in those patients who demonstrate
histiocytes, and eosinophils are also evident.4 The adjacent, nonbullous skin linear positive direct IMF (type 1 BSLE).1,4,8,15,16,19–22 The antibodies generally
characteristically shows subepidermal neutrophil microabscesses (Fig. 4.138). label the floor of the blister cavity although a roof (epidermal) variant has
The upper dermis contains a perivascular mixed inflammatory cell infiltrate rarely been described.8 Those that are negative on indirect IMF have been
consisting of neutrophils, occasional eosinophils, lymphocytes, and histio- classified as type 2 BSLE.4 Type 3 BSLE refers to those cases in which the
cytes. Sometimes the features of a leukocytoclastic vasculitis are also present target antigen is an epidermal rather than dermal epitope.6
(Figs 4.139–4.141). Direct immunoelectron microscopy shows that the immunoreactants are
Electron microscopy shows that the site of the split is below the lamina densa.4 present on and immediately below the lamina densa, obscuring the anchoring
fibrils, and also occasionally somewhat deeper in the papillary dermis similar
to those seen in nonbullous SLE.4, 23–25 The antibody binds to the lamina
densa and sublamina densa in a manner identical to that seen in epidermoly-
sis bullosa acquisita.4,24
Western immunoblot has shown that these antibodies bind to antigens of
290 kD and 145 kD as described for EBA (i.e., type VII collagen).19 Recently,
rare patients with SLE have been shown to have circulating antibodies to type
VII collagen in the absence of blisters, and occasional patients with bullous
SLE have been shown to have antibodies which bind to both the roof and the
floor of NaCl-split skin, suggesting that a number of different basement mem-
brane antigens may be involved.1,4 The target antigen in the epidermal variant
of bullous SLE has not yet been identified although bullous pemphigoid anti-
gen 1 was identified in addition to type VII collagen and laminins-332 and -311
in one patient with combined epidermal and dermal staining on NaCl-split
skin indirect IMF, most likely representing a manifestation of postinflamma-
tory epitope spreading.25
The bullous SLE antibodies are associated with complement activation
activity, which results in neutrophil migration and adherence to the basement
membrane region.4 Neutrophil enzyme release is associated with basement
Fig. 4.139 membrane damage and subsequent dermoepidermal separation.
Bullous systemic lupus erythematosus: this scanning view shows a central focus
of subepidermal vesiculation. Striking inflammatory changes outline the dermal
vasculature. Differential diagnosis
Bullous SLE shows obvious overlap with EBA. There are, however, a number
of discriminatory features. Bullous SLE is not associated with a mecha-
nobullous pathogenesis and scarring is not a feature. It develops most often
in a younger age group than EBA. The dermatitis herpetiformis-like histologi-
cal features are rarely seen in EBA and probably of greatest importance;
bullous SLE responds dramatically to dapsone therapy, but EBA does not.3
Dermatitis herpetiformis
Clinical features
Dermatitis herpetiformis and celiac disease are highly interrelated conditions
and best regarded as variable expressions of a common inherited tendency to
autoimmune disease.
Dermatitis herpetiformis (Duhring-Brocq disease) is a widespread, intensely
pruritic, papulovesicular eruption affecting all ages, but particularly people in
their second to fourth decades.1–4 The male to female ratio is 2:1.
The incidence of dermatitis herpetiformis is highest in Northern Europe,
Fig. 4.140 Scotland, and Ireland.2,5,6 It is less frequently seen in the United States.
Bullous systemic lupus erythematosus: this view shows florid leukocytoclastic Caucasians are mainly affected, the disease being rare in Asians and blacks.
vasculitis.
Case clustering is common and familial involvement (either dermatitis
herpetiformis or celiac disease), possibly autosomal dominantly inherited, has
been documented in up to 10.5% of cases.2,7 Relatives of patients with
dermatitis herpetiformis have an increased risk of developing celiac disease.2
The lesions, which may be symmetrical, are grouped mainly on the
posterior scalp, shoulders, back, buttocks, and extensor aspects of the limbs
(Figs 4.142, 4.143). Scratching is often severe and therefore excoriation and/
or lichenification typically predominate with intact vesicles rarely being seen.
However, occasionally, larger blisters similar to those found in bullous
pemphigoid may be evident. Patients sometimes present with urticarial
plaques and crusted erosions.2 Oral involvement is rare.3 Rarely, the initial
presentation may be with localized lesions in areas such as the scalp.8 The lat-
ter is not infrequently involved in more generalized disease. In one patient,
the presenting symptom was petechiae on the fingertips.9
The clinical response to dapsone (50–200 mg/day) is dramatic; therefore,
the drug is commonly administered for diagnostic as well as therapeutic
purposes. Relief from pruritus occurs within a few hours of commencing
treatment and is soon followed by clearing of the rash. The eruption returns
2–3 days after dapsone is discontinued. The disease persists for many years
and is usually lifelong. A gluten-free diet may result in prolonged remission in
Fig. 4.141 some patients or lowering of the daily dapsone requirement in others.
Bullous systemic lupus erythematosus: this is a close-up view of the subepidermal At least 65–75% of patients with dermatitis herpetiformis show histological
vesicle shown in Figure 4.139. evidence of celiac disease (gluten-sensitive enteropathy, GSE). However, only
Dermatitis herpetiformis 145

Patients with dermatitis herpetiformis (and celiac disease) have a high
incidence of HLA-B8 (80–90%), HLA-DR3 (90–95%) and HLA-DQ2
(95–100%) compared to a normal control population (21%, 23%, and
40%, respectively).3,24–27 More recent studies, however, have demon-
strated that the increased incidence of HLA-B8 and -DR3 are due to
positive linkage disequilibrium. 28 The most current data suggest that the
significant positive HLA association in dermatitis herpetiformis lies with
the class II antigen DQ2.2,29 These HLA associations can be helpful
diagnostically.30
All patients with dermatitis herpetiformis have granular deposits of IgA
in the dermal papillae of perilesional skin, and many also show in vivo-
bound fibrin (Fig. 4.144).31,32 IgA has also been identified in the oral
mucosa.33 A granular linear pattern may be seen and it seems to be more
common than previously reported.34 In patients with a linear pattern, careful
attention should be paid to the presence of granularity to avoid a misdiagno-
sis of linear IgA disease. Recently, a fibrillar pattern has also been docu-
Fig. 4.142 mented.35 Two of the three patients reported with this pattern had clinical
Dermatitis herpetiformis:
features of dermatitis herpetiformis but lacked antitransglutaminase and
excoriations are present
on the elbow and back of antiendomysial antibodies. Other immunoglobulins are not usually found,
the arm. Intact blisters are but C3 is often present.36 This is associated with formation of the membrane
uncommon in dermatitis attack complex (C5–C9), which is thought to result in neutrophil chemo
herpetiformis because of taxis and the evolution of subepidermal vesiculation.3,37 Cutaneous IgA
the intense pruritus. By
courtesy of the Institute of
Fig. 4.143
Dermatitis herpetiformis: the buttocks are frequently affected. By courtesy of the
about 20% have clinical manifestations of malabsorption, these being usually

mild.10–15 The actual incidence of celiac disease is likely to be higher because the
mucosal abnormality in dermatitis herpetiformis is patchy and may be missed
unless multiple jejunal biopsies are taken.16–18 Interestingly, patients who appar-
ently do not have enteropathy may develop the condition when challenged with
large doses of gluten (latent GSE).13 It is therefore believed that all patients with
dermatitis herpetiformis have GSE to a greater or lesser extent.1–3 Relatives of
patients with dermatitis herpetiformis may show no evidence of the skin dis-
ease, but can have subclinical or overt s ymptoms of the enteropathy.
Patients with dermatitis herpetiformis may have antigastric parietal cell
antibody (10–25%), gastric hypochlorhydria (50–90%), and gastric atrophy
(50–70%).3 They may also have antithyroid antibodies and show an increased B
incidence of thyroid disease, insulin-dependent diabetes mellitus, and connec-
tive tissue diseases including systemic lupus erythematosus and Sjögren's syn- Fig. 4.144
drome.19,20 As with isolated celiac disease, there is an increased risk of Dermatitis herpetiformis: direct immunofluorescence showing (A) deposits of granular
intestinal lymphoma.21 IgA in the dermal papillae; (B) fibrin deposition in the dermal papillae. (A) By courtesy
Exposure to iodine may trigger or flare the disease.22,23 of the Department of Immunofluorescence, Institute of Dermatology, London, UK.
deposits may still be detected after dapsone therapy. They do, however, many levels of the biopsy will have to be examined before a microabscess is
sometimes disappear after a prolonged gluten-free diet.2 Cutaneous IgA found.
deposition is not seen in patients with celiac disease.2 Abscess evolution depends upon the initial presence of fibrin and
Electron microscopy reveals electron-dense, amorphous granular deposits polymorphs within the tips of the dermal papillae (Fig. 4.146), both of
in the superficial dermis showing no particular relationship with the base- which are associated with degenerative changes of the collagen and the
ment membrane region or any other specific structure.38,39 development of edema. Development of small subepidermal microvesicles
Immunoelectron microscopic observations initially suggested that the IgA follows, leading on to the formation of multilocular subepidermal
deposits were associated with elastic-containing microfibrillar bundles, but blisters.
more recently published work using antifibrillin antibodies has discounted Typically, the blister cavity contains edema fluid, a reticular network of
this theory.38,40 fibrin, and numerous polymorphs (Figs 4.147, 4.148). In contrast to bullous
Antigliadin antibodies, which are often used to assess celiac disease status, pemphigoid, the floor of the blister cavity usually shows effacement of the
are of limited value in the diagnosis of dermatitis herpetiformis.13 They have dermal papillary outline.
high specificity, but low sensitivity.13 Anti-smooth muscle endomysial anti- Within the dermis is a mixed inflammatory cell infiltrate consisting of lym-
body correlates with the gluten-sensitive state and appears before the devel- phocytes, histiocytes, and abundant neutrophils. Leukocytoclasis (nuclear
opment of any small intestinal histological abnormality in patients with dust, Fig. 4.149) is characteristic. Although blood vessels frequently show
dermatitis herpetiformis.13,41,42 Such endomysial antibodies are present in up endothelial swelling, there is no evidence of vasculitis. Occasionally, eosino-
to 70% of patients and are highly specific; they react with tissue transglu- phils are quite numerous in the infiltrate, but usually they are late arrivals,
taminase (tTG) (antitransglutaminase antibodies).43 Antibodies against epi- appearing 24–48 hours after the neutrophils. On occasions, biopsies from
dermal transglutaminase are found more frequently than the latter. typical dermatitis herpetiformis may show acantholysis, a cause of consider-
Antitransglutaminase antibodies, particularly those to epidermal tranglutam- able confusion (Fig. 4.150).
inase, seem to be the most sensitive serological marker of dermatitis herpeti-
formis.33,44 Patients with high levels of IgA and IgG transglutaminase
antibodies usually have more prominent mucosal villous atrophy and more
severe clinical disease.45 Gliadin is an important substrate for tissue transglu-
taminase forming gliadin–gliadin or gliadin–tTG complexes.46 Circulating
IgA antibodies to tTG are pathognomonic of dermatitis herpetiformis and
celiac disease.47 The gut subtype of transglutaminase is TG2 while that in the
skin is TG3. Cross-reactivity between these homologous proteins or antigenic
drift may underlie some of the mucosal and cutaneous features of this condi-
tion.48,49 Whatever the underlying mechanism, the IgA in some way ‘fixes’ in
the skin, resulting in complement activation via the alternative pathway.50–52
Neutrophil chemotaxins are then released and the ensuing inflammatory
reaction leads to dermal papillary edema, fibrin deposition, and eventual
vesiculation. There may be a role for cell-mediated immunity in this disease
as well, perhaps involving γ/δ T cells.53
The histological hallmark of dermatitis herpetiformis is the dermal papil-
lary neutrophilic microabscess, best seen in early erythematous lesions or well
away from the blister in an established eruption (Fig. 4.145).54–56 Occasionally,
Fig. 4.146
Dermatitis herpetiformis: in this early lesion, there are thin strands of fibrin visible
above the neutrophilic infiltrate.
Fig. 4.145
biopsy from an early
lesion showing Fig. 4.147
conspicuous neutrophil Dermatitis herpetiformis: an established subepidermal blister. Although early lesions
microabscesses. are usually multilocular, by 24–48 hours the lesion becomes unilocular.
Linear IgA disease 147
Fig. 4.148
floor of the blister in
Figure 4.147 showing
an intense neutrophil
infiltrate.
Fig. 4.150
(A, B) Dermatitis herpetiformis: in this example acantholysis may result in
diagnostic confusion with pemphigus. Note that the blister is subepidermal.
Linear IgA disease

Linear IgA disease of adults by definition presents after puberty. It is
characterized by the development of a sometimes self-remitting dapsone or
sulfonamide-responsive dermatosis typified by subepidermal vesicles and
Fig. 4.149 blisters in association with in vivo deposition of linear (homogeneous) IgA at
Dermatitis herpetiformis: nuclear debris (karyorrhexis) within the dermis is a the basement membrane region on direct immunofluorescence of normal or
characteristic feature. perilesional skin.1–3 Childhood linear IgA disease (chronic bullous dermatosis
of childhood) is almost identical to the adult counterpart; however, there are
differences in clinical presentation and therefore these particular aspects are
described separately.
Jejunal biopsy may reveal villous blunting, intestinal crypt elongation, Linear IgA disease of adults is a rare disease, which was originally thought
flattening of surface epithelial cells with loss of microvilli, and intraepithe- to represent a variant of dermatitis herpetiformis4–6 or bullous pemphigoid.7,8
lial γ/δ lymphocytic infiltration to a degree ranging from partial to subtotal Some cases were reported under the rubric polymorphic pemphigoid (see
villous atrophy.57 If gluten is withheld from the diet, these changes revert to above) or intermediate (mixed) forms of bullous disease.9,10 More recently,
normal. particularly following the application of immunoelectron microscopic and
immunoblotting techniques, it has been confirmed as a disease (or at least a
Differential diagnosis disease spectrum) sui generis.11–15
A neutrophil-predominant subepidermal vesicle accompanied by neutrophil Its approximate incidence in the south of England is 1:250 000.16 In France
dermal papillary microabscesses in addition to dermatitis herpetiformis may and central Germany, the incidence is 0.5 per million of the population.17,18 In
also be seen in the following conditions: vesicular pemphigoid, bullous sys- Singapore, the incidence has been estimated at 0.26 per million population.19
temic lupus erythematosus, inflammatory epidermolysis bullosa, and linear Although data for the United States are limited, the incidence in Utah has
IgA disease. Distinction depends upon clinical information and the results of been reported as 0.6 per 100 000.20 Some consider that this disease is
immunofluorescent studies (see Table 4.4). underdiagnosed.
Clinical features
Linear IgA disease of adults affects the sexes equally and, while the age distribu-
tion is wide, there are peaks in teenagers and young adults and in patients in
their sixties.1 It may present as a somewhat atypical bullous eruption showing
features suggestive of dermatitis herpetiformis or more commonly bullous pem-
phigoid (Fig. 4.151). Occasionally, it may initially resemble and be mistaken
clinically for erythema multiforme.21 Pruritus and/or a burning sensation are
common manifestations and early lesions may include urticarial, annular,
polycyclic, and targetoid eruptions.15,22 The established dermatosis may be
vesicular or more often frankly bullous; blisters arising at the edge of erythema-
tous annular lesions (‘string of beads’ sign) are said to be characteristic.15
Sites affected in decreasing order of frequency include the trunk, limbs,
hands, scalp, face, and perioral region. The perineum and vagina may also be
affected with erosions and blisters.1 Mucous membrane involvement, which
is common, is of particular importance because it can be associated with scar-
ring. Important sites that may be affected include the eyes (conjunctivitis,
symblepharon, trichiasis, corneal opacification, and rarely blindness; Fig.
4.152), the mouth (erosions, blisters, and chronic ulceration), nasal cavity
(crusting and bleeding) and the pharynx (hoarseness).1,23–25 When these Fig. 4.152
mucosal symptoms are severe there is clinical overlap and diagnostic confu- Adult linear IgA disease: there is marked conjunctival injection and blepharitis.
sion with mucous membrane pemphigoid. By courtesy of the Institute of Dermatology, London, UK.
Childhood linear IgA disease (chronic bullous disease of childhood) not
uncommonly develops after an upper respiratory tract illness, often following
treatment with penicillin.26–29 Females are affected more often than males
(1.6:1) (Fig. 4.153). The average age of onset is 6 years, but very rare cases
in neonates have been described.30
Lesions, which can be pruritic or burning in the early stages, may be
urticated, annular or polycyclic in appearance and usually arise on normal
skin. Vesicles and large bullae (sometimes hemorrhagic) then predominate,
and although the perioral regions and genitalia are particularly affected, the
face, ears, trunk, limbs, hands, and feet are also often involved (Fig. 4.154).
Usually, the new lesions appear around those that are resolving (the ‘cluster
of jewels’ sign, Fig. 4.155). In older and black African children the clinical
appearances can suggest bullous pemphigoid. Healing is sometimes associ-
ated with postinflammatory hyper- or hypopigmentation. Mucous membrane
lesions are common (64%). Ocular symptoms of pain, grittiness, discharge
and redness are found in 40% of children; conjunctival scarring is present in
approximately 21%; oral lesions are found in up to 57%.
Fig. 4.153
Childhood linear IgA
disease: in this case
widespread erosions
on an erythematous
background are present
on the buttocks and legs.
Occasional intact vesicles
are also evident. By
London, UK.
Although linear IgA disease in children was originally thought to be self-

limiting, it is now appreciated that symptoms may last over 5 years (25%)
and occasionally extend beyond puberty into adult life. Exceptionally, an
association with IgA nephropathy may be seen.31
Linear IgA disease is associated with increased expression of HLA-Cw7,
-B8, -DR2, -DR3 and -DQ2.32 The incidence of HLA-B8 association is vari-
able, with reported figures varying from 28% to 56% (normal range
Fig. 4.151 20–25%).15,22 There is no evidence of an increase in HLA-B12.15 Linear IgA
Adult linear IgA disease: disease is also associated with HLA-Cw7 and -DR3.1
in this example the clinical
Although in the earlier literature as many as 24% of patients with linear
appearances of excoriated
lesions are suggestive of
IgA disease were thought to have associated gluten-sensitive enteropathy, the
dermatitis herpetiformis. incidence is almost certainly considerably lower.1 There are, however,
By courtesy of the occasional recent references documenting occasional patients with linear IgA
Institute of Dermatology, disease with clinical and histological evidence of gluten-sensitive enteropathy
London, UK. in the presence of antiendomysial and antitransglutaminase antibodies.33,34
Fig. 4.154
Childhood linear IgA disease: groups of blisters are present on the vulva and inner
thighs. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 4.156
(A, B) Linear IgA disease: in this example the features are those of a neutrophil-rich
subepidermal vesicle reminiscent of dermatitis herpetiformis.
A homogeneous linear deposition of IgA along the basement membrane

region is found by direct immunofluorescence in 100% of patients (Fig.
4.158).26,41–43 Uninvolved skin (particularly of the back) is suitable.1 Oral
mucosa and conjunctiva may also show IgA deposition.1 The linear IgA anti-
gen is present in all stratified squamous epithelia and amnion but, in contrast
Fig. 4.155 to the bullous pemphigoid antigen, is not found in bladder mucosa.42 IgG
Childhood linear IgA
may also be demonstrable in up to 25% of cases.12,15 IgM and C3 are occa-
disease: the arrangement
of blisters called the sionally present.43
‘cluster of jewels’. By A low titer circulating IgA antibasement membrane zone antibody is pres-
courtesy of R.A. Marsden, ent in approximately 30% of patients.1 Use of conjunctiva as substrate may,
MD, St George's Hospital, however, substantially increase this figure (up to 50%).23 Circulating IgG or
London, UK. C3-binding antibasement membrane antibodies are seen only in those patients
with overlap syndrome.44 The IgA antibody is of pathogenetic significance
since it causes dermoepidermal separation after incubation with whole skin
It is possible that these cases represent dermatitis herpetiformis with linear cultures.45 Passive transfer of antibodies into a mouse model with human skin
granular deposits of IgA in which the granularity has not been detected. graft also produces characteristic lesions.46 Blister fluid is also satisfactory for
There are a number of reports documenting an association between linear indirect IMF.1
IgA disease and internal malignancy, including lymphoma and leukemia, With split skin immunofluorescence, the titer may be higher and sensitiv-
although whether this has significance is uncertain.35–38 ity is increased. The IgA antibasement membrane zone antibody variably
labels the epidermal side, the dermal side or both sides of the artificial blister
Pathogenesis and histological features cavity.47–49 Immunoelectron microscopy has shown similar results, with IgA
Histologically, linear IgA disease is characterized most frequently by dermati- being present within the lamina lucida or below the lamina densa in associa-
tis herpetiformis-like features (Fig. 4.156).26,39,40 Occasionally, however, the tion with anchoring fibrils, and sometimes in both locations
histological changes suggest bullous pemphigoid or sometimes a mixture of (Fig. 4.159).50–55
both diseases (Fig. 4.157). Eosinophilic spongiosis may rarely be a feature.26 Studies by Western immunoblotting indicate that linear IgA disease is a
Ultrastructurally, the site of cleavage may be through the lamina lucida or heterogeneous condition. Thus, in those cases associated with dermal binding
below the lamina densa.21 on indirect NaCl-split skin IMF, the dermal antigens include 285-kD and
A B
Fig. 4.157
(A, B) Linear IgA disease: in this field the presence of eosinophils is more suggestive of bullous pemphigoid.
Fig. 4.158
Linear IgA disease: direct Fig. 4.159
immunofluorescence Linear IgA disease: direct immunoperoxidase reaction using frozen tissue substrate.
showing linear IgA There is an abundance of granular IgA beneath the basal lamina.
deposition. By courtesy
of the Department of
Immunofluorescence, clinical features of these various autoimmune bullous disorders. LAD1 has
Institute of Dermatology, been identified as ladinin localizing to the extracellular domain of BP180 kD.69
London, UK. Those patients with mixed IgA and IgG antibody-mediated disease also target
BP180.44 Recent reports suggest that antibodies against the NC16A domain
may be more important than those against the LAD1 cleavage product of
250-kD proteins and type VII collagen.14,49,56,57 Epidermal binding antibodies BP180, but not all cases contain the anti-NC16A antibodies.70–72
react with BP230 (BPAG1), BP180 (BPAG2), and 200/280-kD antigens dis- Drug-induced linear IgA disease is considered in chapter 14.
tinct from either of the BP antigens.58–60 The antigens 120 kD (LAD1) and
97 kD described in earlier reports represent proteolytic cleavage products of
BP180.61–64 Linear IgA disease 180-kD antibodies recognize the NC16A Differential diagnosis
domain of collagen XVII (BPAG2) also critical for bullous pemphigoid, pem- The diseases from which linear IgA disease must be differentiated are derma-
phigoid gestationis, mucous membrane pemphigoid, and lichen planus pem- titis herpetiformis, bullous pemphigoid, and inflammatory epidermolysis
phigoides described above.65–68 This fact is remarkable considering the variable bullosa. Points of distinction are considered in Table 4.4.
Chapter
See
for references and
additional material
Acantholytic disorders
5
Introduction 151 Paraneoplastic pemphigus 163 Linear Darier's disease 173
IgA pemphigus 165 Transient acantholytic dermatosis 174
Pemphigus 151 Acantholytic dermatosis of the genitocrural area 176
Drug-induced pemphigus 167
Pemphigus vulgaris 152
Contact pemphigus 167 Warty dyskeratoma 176
Pemphigus vegetans 156
Familial dyskeratotic comedones 177
Pemphigus foliaceus 157 Acantholytic dermatoses with dyskeratosis 167 Acantholytic acanthoma 178
Endemic pemphigus foliaceus (fogo selvagem) 160 Hailey-Hailey disease 167
Acantholytic dyskeratotic acanthoma 179
Pemphigus herpetiformis 162 Relapsing linear acantholytic dermatosis 169
Focal acantholytic dyskeratosis 179
Pemphigus erythematosus 162 Darier's disease 169
Table 5.1
Introduction Antigens targeted in the pemphigus variants
The term acantholysis derives from the Greek akantha, a thorn or prickle, and Pemphigus variant Autoantigen
lysis, a loosening. In its simplest definition, the term is used to reflect a primary Pemphigus vulgaris Dsg3 (mucosal), Dsg1 (cutaneous),
disorder of the skin (and sometimes the mucous membranes) characterized desmocollins, pemphaxin, α9-acetylcholine
by separation of the keratinocytes at their desmosomal junctions (Fig. 5.1). receptor
A wide range of conditions are characterized by this feature, from inherited Pemphigus vegetans Dsg3, Dsc1, and Dsc2 in some patients
disorders such as Darier's disease and Hailey-Hailey disease in which a cal-
Pemphigus foliaceus Dsg1
cium pump gene mutation results in desmosomal instability through to the
autoimmune pemphigus group of diseases whereby autoantibodies directly Pemphigus erythematosus Dsg1
damage desmosomes with resultant keratinocyte separation and blister for- Fogo selvagem Dsg1, rarely also Dsg3
mation (Table 5.1). Desmosomes may also be damaged by secondary phe-
IgA pemphigus Dsc1, Dsg1 or Dsg3
nomena, for example following severe edema, either intercellular (spongiosis)
or intracellular (e.g., ballooning degeneration as is seen in various viral infec- Herpetiform pemphigus Dsg1, rarely also Dsg3
tions). Such processes, however, are not included in the acantholytic category Paraneoplastic pemphigus Desmoplakins I and II, envoplakin,
periplakin, BP230, plectin, Dsg1, and Dsg3
Drug-induced pemphigus Dsg1 or Dsg3
Dsc, desmocollin; Dsg, desmoglein. Modified from Martel, P., Joly, P. (2001)
Pemphigus: autoimmune diseases of keratinocyte's adhesion molecules. Clinical
Dermatology, 19, 667.
and are discussed elsewhere. The histological features of the conditions

described in this chapter show considerable overlap. The diagnosis is there-
fore dependent upon adequate clinical information and the results of immu-
nofluorescence investigations.
Pemphigus
Pemphigus (Gr. pemphix, blister) refers to a group of chronic blistering dis-
eases which develop as a consequence of autoantibodies directed against a
variety of desmosomal proteins.1–5 The condition as a whole is rare, with an
annual incidence ranging from 0.1–0.7 per 100 000 of the general population.2
Fig. 5.1 It is commoner in the Jewish population in which the annual incidence rises
Acantholysis: the keratinocytes are rounded and separated from each other to form to 1.6–3.2 per 100 000.6 Ashkenazi Jews are the most frequently affected.6
an intraepidermal blister. Villi formed from the underlying dermal papillae typically The incidence in India also appears to be higher than in other countries.7
project into suprabasal cavities. There is no sex predilection.
152 Acantholytic disorders
The clinical features and, therefore, classification of these disorders blisters spread to involve the skin.12–15 Oral lesions most commonly affect the
depends upon the level of separation within the epidermis: buccal, palatine, and gingival mucosae.1,15–17 Pemphigus vulgaris is only rarely
• In pemphigus vulgaris (p. vulgaris) and pemphigus vegetans (p. vegetans) confined to the skin.18,19
the blisters are suprabasal. The typical skin lesion is a fragile, flaccid blister, which develops on nor-
• In pemphigus foliaceus (p. foliaceus), pemphigus erythematosus (p. erythe mal or erythematous skin, and readily ruptures, leaving a painful, crusted,
matosus) and fogo selvagem, the blisters are situated more superficially. raw, bloody erosion (Figs 5.4, 5.5). Lesions are most often seen on the
Pemphigus vulgaris is by far the most common variant, accounting for scalp, face, axillae, and groin, although in some patients they are generalized
80% of cases.8,9 (Figs 5.6–5.8).1–3,20 Blisters can be induced by rubbing the adjacent, appar-
In addition to affecting humans, pemphigus has been described in a variety ently normal skin with a finger – the Nikolsky sign. Direct pressure applied
of animals including dogs, cats, goats, and horses.10 to the center of the blister is also followed by lateral extension – the Asboe-
Hansen sign.2 Healing is often accompanied by postinflammatory hyperpig-
Pemphigus vulgaris mentation but scarring is not a feature.2
Before the introduction of corticosteroid therapy, the lesions usually became
more extensive and in the past often led eventually to death. Treatment with
Clinical features
high doses of corticosteroids, immunosuppressants, such as azathioprine and
Pemphigus vulgaris (p. vulgaris) particularly affects the middle aged (onset more recently biologicals has significantly reduced the mortality to 5–15%
typically at 40–60 years of age) although occasionally (up to 2.6%) children and prolonged remissions without treatment are now being reported.2 A con-
are affected.1–7 Self-limiting neonatal disease through transplacental transfer siderable proportion of the deaths that do occur, however, are due to the
of maternal autoantibodies has also rarely been documented (see pathogene- side effects of therapy and include staphylococcal infections and, to a lesser
sis).8–11 The disease begins in the mouth (Figs 5.2, 5.3) in 50–70% of patients extent, pulmonary embolism.2 Severe opportunistic infections due to a wide
with painful erosions or bullae and, after a period of weeks or months, the range of organisms including listeria, nocardia, enterococci, herpes virus,
cryptococcus and candida may further complicate the disease.21–27
Fig. 5.2
Pemphigus vulgaris: painful erosions are present on the buccal mucosa. By courtesy Fig. 5.4
of R.A. Marsden, MD, St George's Hospital, London, UK. Pemphigus vulgaris: since the blisters are superficial, erosions are more commonly
encountered. By courtesy of the Institute of Dermatology, London, UK.
Fig. 5.3
Pemphigus vulgaris: in this patient there is an intact blister on the floor of the Fig. 5.5
mouth. Pemphigus commonly presents in the mouth. By courtesy of the Institute Pemphigus vulgaris: extensive erosions and blisters are present on the shin. By
of Dermatology, London, UK. courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Pemphigus 153
Fig. 5.6
Pemphigus vulgaris: umbilical lesions showing intact blisters as well as raw
erosions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. Fig. 5.8
Pemphigus vulgaris:
extensive disease can
be very disfiguring. By
documented in as many as 63–87% of patients.46,47 Erosions and ulcers are

t ypically found and intact blisters are rare. Exceptionally, the whole mucosa
may be affected with subsequent sloughing – esophagitis dissecans superfi-
cialis.48 Ocular lesions are usually restricted to the conjunctiva, presenting as
conjunctivitis or small vesicles that rapidly rupture.2,49,50 Very rarely, scarring
may develop and corneal ulceration with perforation has been described.51
Vulval, vaginal, and cervical lesions are well recognized.52–56 Exceptionally,
the vagina may be the sole site of involvement.57 Penile lesions most com-
monly affect the glans.58 They are not usually followed by any significant
sequelae.
The development of pemphigus may be associated with a variety of dis-
orders including other autoimmune bullous dermatoses, particularly bullous
pemphigoid, lupus erythematosus, thymoma, and myasthenia gravis as
well as Hashimoto's thyroiditis, vitiligo, minimal change nephropathy, and
ulcerative colitis.59–66 It has also been described in a patient with the 1p36
deletion syndrome.67 As in the many other diseases with an immunological
Fig. 5.7 pathogenesis, pemphigus is accompanied by an increased incidence of inter-
Pemphigus vulgaris: nal malignancy including thymoma, lymphoma, and multiple myeloma (see
extensive trauma-induced paraneoplastic pemphigus).68,69 It has also been reported in association with
blisters. By courtesy
Kaposi's sarcoma.70
of the Institute of
Pemphigus is an immunologically mediated disease.71,72 Examination of per-
Nail involvement seems to be more common than previously reported. ilesional skin by direct immunofluorescent techniques reveals in vivo-bound
Patients may present with hemorrhagic paronychia, chronic paronychia, immunoglobulin (usually IgG) and often complement (C3) in the intercel-
trachyonychia, onycholysis or onychomadesis.17,28 Paronychia and onycho- lular region of the epidermis (Fig. 5.9).73 Abundant antigen in the follicular
madesis are the most common nail changes encountered. Nail involvement is outer root sheath and germinal matrix may account for the marked scalp
more common in the nails of digits affected by periungual blisters and also in involvement typical of pemphigus, and plucked hair follicles may serve as an
patients with large number of skin blisters.29 adequate substrate for direct immunofluorescence analysis.74,75 The in vivo-
Occasional modes of presentation include linear lesions and pemphi- bound IgG is mainly of the IgG1 and IgG4 subclasses.76
gus arising after surgery, burns, vaccination, and radiation therapy.30–39 Indirect immunofluorescent techniques show that the serum of patients
Development after exposure to pesticides and a possible association with with pemphigus contains an IgG antibody that reacts with the intercellular
cocaine snorting has also been reported.40,41 A very exceptional case has been region of normal squamous epithelium – the intercellular substance (pemphi-
described in which blisters were initially confined to melanocytic nevi.42 gus) antibody.77 This antibody is, however, not entirely specific as it may be
P. vulgaris may also be rarely induced by a variety of drugs. found in a variety of other conditions, such as severe burns, penicillin drug
In addition to oral and cutaneous involvement, lesions have been described reactions, and following radiation therapy.78–80 Presumably, pemphigus anti-
at a wide variety of sites including the nasopharynx, larynx, ear, esophagus, gens are released into the circulation following such trauma with resultant
eye, external genitalia, urethra, and anal and colonic mucosa.1,43–45 Esophageal antibody production. Circulating antibodies are predominantly of the IgG1
lesions, although originally thought to be rare, have more recently been and IgG4 subclasses; IgG3 is identified much less often.81
vegetans, pemphigus herpetiformis, and paraneoplastic pemphigus.111,115,116

Furthermore, so-called IgG/IgA pemphigus may show an atypical clinical
presentation, histological features more reminiscent of IgA pemphigus,
and the presence of IgA antibodies against desmocollins in a subset of
patients.114,117–123
The pathogenesis of the acantholysis is uncertain. Direct binding of
antibody to the desmosomal cadherins is of major importance and results
in internalization of Dsg3 and degradation by the endolysosomal path-
way.71,114,124 Plakoglobin has been implicated in mediating intracellular
events following IgG binding to Dsg3.125,126 In particular, the role of pla-
koglobin is signal transduction to the nucleus.125,127 There is also some evi-
dence to suggest that the process may involve, at least secondarily, the
action of local proteolytic enzymes.70 Pemphigus antibody induces expres-
sion of plasminogen activator receptor on the surface of keratinocytes.128
Binding of plasminogen activator to its keratinocyte cell membrane recep-
tor results in plasminogen activation with resultant production of plas-
min.129,130 This latter has non-specific proteolytic activity, which may
be responsible at least in part for the dissolution of the desmosomes.71
P. vulgaris antibodies stimulate production of keratinocyte phospholipase
Fig. 5.9 C, inositol 1,4,5-triphosphate, and increase intracellular calcium. Protein
Pemphigus vulgaris: direct immunofluorescence. By courtesy of the Institute of
kinase C activation results in release of keratinocyte plasminogen activa-
tor and increased expression of plasminogen activator receptor.131–133 Other
factors, however, must be of greater importance since p. vulgaris IgG can
Circulating IgG is pathogenic.71,72 The level of the antibody titer closely induce acantholysis in plasminogen activator knockout mice.134 An addi-
parallels the clinical state of the disease.82–85 IgG4 titers diminish during tional phenomenon is rapid phosphorylation of heat shock protein 27 and
remission whereas circulating IgG1 may continue to be present.72,83 Relapse is p38MAPK resulting in reorganization and collapse of the cytoskeleton as
commonly preceded by rising IgG4 antibody titers.83 a result of IgG binding to Dsg3.135,136 This process is mediated by upstream
P. vulgaris very occasionally may be evident in a neonate born of a mother events involving EGF receptor kinase and src.137 Complement appears not
with active pemphigus vulgaris.8,86 Such autoantibodies cross the placenta, to be essential for acantholysis and it is thought that any involvement is
inducing disease in the infant. The condition is, however, short lived, with secondary, perhaps accelerating or extending the process.71 Although it has
lesions disappearing, as the maternal antibodies are catabolized. Passive been suggested that apoptosis may be induced by p. vulgaris IgG, and that
transfer of IgG4 into neonatal mice results in the development of blisters.87 this mechanism may be important in the pathogenesis of the disease, a
Purified IgG from pemphigus induces acantholysis in human skin explants recent study has shown that apoptosis is not a prerequisite for blistering
and keratinocyte cultures.88,89 and may be a secondary phenomenon.138
The pemphigus antibody binds to the full thickness of the epidermis. T cells are also critical to the development of the antibody-mediated
Compared with p. vulgaris, immunofluorescence studies on the sera of acantholysis.70 CD4+ memory T cells are predominantly involved and both
p. foliaceus patients tend to show more staining in the superficial epidermis, T-helper 1 (Th1) and Th2 Dsg3-specific subtypes are represented.139,140 Th1
correlating with the level of the split.90,91 Conversely, the sera from patients T-cell-derived interferon-γ stimulates production of IgG1, and Th2 cells
with p. vulgaris show more affinity for the lower epidermis. Despite these produce interleukin (IL)-4 and IL-13 which are responsible for secretion
trends, we generally do not base diagnoses on these (often subtle) differences of B-cell-derived IgG4.141 Both populations are therefore of importance in
in immunofluorescence staining distribution. stimulating production of p. vulgaris antibody.72 In addition, there is evi-
The p. vulgaris antibody is directed at the extracytoplasmic domain of dence that tumor necrosis factor 1 (TNF-1), Fas-ligand and IL-1 are also of
the 130-kD epithelial desmosomal cadherin, desmoglein 3 (Dsg3), which importance in the development of acantholysis.142 Knockout mice for both
forms a complex with plakoglobin (85 kD).92–98 The p. vulgaris antibody, these cytokines show diminished acantholysis in passive antibody transfer
however, does not recognize the latter. Many patients also have antibod- experiments.143
ies that bind to the p. foliaceus antigen, desmoglein 1 (Dsg1), a 160-kD There is considerable evidence of a genetic background influencing suscep-
polypeptide.99,100 Dsg3 is expressed primarily in the oral mucosa and, there- tibility to pemphigus as shown by strong associations with human leukocyte
fore, antibodies directed against this antigen result in mucosal pemphigus. antigen (HLA)-DRβ1*0402, HLA-DRβ1*1401 and HLA-DQβ1*0503.144–147
In contrast, Dsg1 is a cutaneous antigen and, therefore, antibodies directed Perhaps surprisingly, however, there are only occasional documented reports
against it result in lesions affecting the skin but not the mucosa (cutaneous of familial occurrence.148–151
pemphigus).90 Anti-Dsg1 antibodies also show cross-reactivity against Dsg4, Pemphigus blisters rupture easily. It is therefore essential to biopsy an
a recently identified member of the desmoglein family.101,102 While patient early lesion to establish the correct diagnosis. The characteristic acantho-
sera contain antibodies against nonconformational epitopes of Dsg3, active lysis develops because of damage to the intercellular bridges. Acantholytic
disease correlates with the presence of antibodies directed against the NH2- cells are rounded and have intensely eosinophilic cytoplasm, pyknotic
terminal aspect of Dsg3, in particular ectodomains 2–4.103–105 Oral disease is nuclei, and perinuclear halos. An early lesion of p. vulgaris shows a slit-
particularly associated with reactivity to ectodomains 1-4, which is reduced like suprabasal cleft or vesicle containing occasional acantholytic cells. The
in cutaneous pemphigus.103 established blister contains acantholytic cells in clumps and in isolation
Antibodies reactive to a number of other proteins including desmoplakin, (Figs 5.10 and 5.11). Characteristically, the floor of the cavity is lined by
desmocollins, pemphaxin, and acetylcholine receptor have also been demon- a single layer of intact basal cells, the so-called ‘tombstone’ pattern (Fig.
strated in the sera of p. vulgaris patients.106–110 5.12).152
Sera from patients with pemphigus vulgaris not infrequently contain The acantholytic process frequently involves the epithelium of the adn-
additional IgA antibodies, in particular against Dsg1 and Dsg3.111–113 exae, which can be a useful diagnostic clue in those lesions which lack the
Although the combination of both IgG and IgA antibodies has in some roof of the blister (Fig. 5.13).153 The dermal papillary outline is usually main-
instances been referred to as IgG/IgA pemphigus in the literature, this tained and, frequently, the papillae protrude into the blister cavity. Sometimes
appears to be an ill-defined and heterogeneous disease group.111,114 In addi- the features of eosinophilic spongiosis are seen on biopsy, particularly in
tion to pemphigus vulgaris, the additional presence of anti-Dsg IgA anti- early lesions.154 The blister cavity often contains a few inflammatory cells
bodies has also been demonstrated in pemphigus foliaceus, pemphigus (notably eosinophils) and, in the dermis, there is a moderate perivascular
Pemphigus 155
Fig. 5.10 Fig. 5.12

Pemphigus vulgaris: established blister showing marked acantholysis and scattered Pemphigus vulgaris: cell-free example showing a linear palisade of intact basal
neutrophils. The dermal papillae project into the cavity as villi. keratinocytes – the so-called ‘tombstone’ appearance.
Fig. 5.13
Pemphigus vulgaris:
follicular involvement
distinguishes pemphigus
from Hailey-Hailey disease
in which it is not a feature.
chronic inflammatory cell infiltrate with conspicuous eosinophils, although

sometimes these are scanty or even absent. Mucous membrane lesions show
similar histology.
Ultrastructurally, there is dilatation of the intercellular space with conse-
quent stretching of the desmosomal attachment points (Figs 5.14, 5.15).155
With progression, these separate and eventually disappear, residual cell
membranes often showing a pseudovillous morphology. Hemidesmosomes
are morphologically normal. Immunoelectron microscopy confirms that the
immunoreactants are located within the intercellular space.
Endemic pemphigus vulgaris

Patients with clinical and histological presentation of pemphigus vulgaris
Fig. 5.11
Pemphigus vulgaris:
but epidemiological features of fogo selvagem were identified in the Goiania
(A) perianal mucosa and Brasilia regions of Brazil, known endemic areas of pemphigus foliaceus.
showing acantholysis and These patients demonstrate classical mucocutaneous disease and antibodies
B conspicuous villi; (B) high- to both Dsg1 and Dsg3, but are remarkable for early onset of disease, fre-
power view. quently before the age of 20.156
or without immunofluorescence studies, it may be impossible to establish a

definitive diagnosis. Darier's and Hailey-Hailey diseases are not associated
with immunoreactants.
Dyskeratosis in the form of corps ronds and grains is typical of Darier's dis-
ease, but is rarely seen in Hailey-Hailey disease, and is not a feature of pemphigus.
In Hailey-Hailey disease, the perivesicular epithelium is likened to a dilapidated
brick wall, an effect sometimes seen in p. vulgaris. More frequently, however, the
epithelium overlying and adjacent to the blister is essentially intact.
Acantholysis involving the follicular epithelium is often seen in pemphi-
gus, but usually not in Hailey-Hailey disease. The pemphigus-like variant
of Grover's disease is histologically indistinguishable from pemphigus, but
the clinical history, minute size of the lesions as viewed by the microscope,
and negative immunofluorescence findings make distinction relatively easy.
Extreme degrees of acantholysis in acantholytic solar keratosis may on rare
occasions be confused with the previously mentioned acantholytic disorders.
Similarly, it is important not to misinterpret the trivial finding of incidental
focal acantholytic dyskeratosis in a skin specimen removed or biopsied for an
unrelated finding.
Fig. 5.14
Pemphigus vulgaris: electron photomicrograph of an early lesion showing suprabasal,
Pemphigus vegetans
intraepidermal vesiculation. Residual cytoplasm of basal keratinocytes lines the floor
of the blister. The lamina densa is clearly visible. Clinical features
Pemphigus vegetans (p. vegetans), a chronic variant of p. vulgaris, has a
somewhat better prognosis than p. vulgaris with occasional cases associated
with spontaneous remission documented.1–3 It accounts for 1–2% of all cases
of pemphigus.1 As with the vulgaris variant, p. vegetans typically presents in
adults. There has, however, been a small number of cases described in child-
hood including a dapsone-responsive IgA-mediated variant.4–7 The lesions,
which present as blisters and erosions, are particularly prolific in the flexures,
especially the axillae, the groin, the inframammary region, the umbilicus and
at the margins of the lips. The scalp is also said to be a site of predilection.8,9
Soon thereafter, patients characteristically develop hypertrophic vegetations
and pustules at the blistered edges (Fig. 5.16).1
The oral cavity is commonly affected and a cerebriform or ‘scrotal’ tongue
is said to be a diagnostic clue in cases of early involvement.10–13 An exceptional
case of the disease restricted to the tongue has been reported.14 Esophageal
involvement presenting as erosions and white plaques has been described in
a number of patients and the nasal mucosa, larynx, vulva, vagina, penis, and
anus may also be affected.7,15–19 Nail involvement including onycholysis and
pustules is sometimes seen.20 Acral involvement can clinically be mistaken for
acrodermatitis continua suppurativa.21 A case has been described developing
after and restricted to a split-thickness skin graft.22 A further exceptional case
Fig. 5.15 developed in association with intranasal heroin abuse and was restricted to the
Pemphigus vulgaris: electron photomicrograph of an early lesion showing marked nasal mucosa.23 Peripheral blood eosinophilia is commonly present.
dilatation of the intercellular space. Cytoplasmic ‘villus’ formation is conspicuous Two clinical subtypes are recognized:24,25
and only occasional desmosomes are apparent. • In the Neumann variant (the more serious form), lesions usually begin
as described in p. vulgaris, but the ensuing erosions develop vegetations.
The course of this variant is similar to that of p. vulgaris.
Differential diagnosis • In the Hallopeau variant (‘pyodermite vegetante’), the eruption begins as
The differential diagnosis of p. vulgaris includes a variety of conditions such pustular lesions that rapidly evolve into verrucous vegetating plaques.2
as Darier's disease, Hailey-Hailey disease, and transient acantholytic derma- Bullae are usually not seen. This is a milder variant in which spontaneous
tosis (Grover's disease) (Table 5.2). In the absence of clinical information remission is not uncommon.
Table 5.2
Differential diagnosis of suprabasal pemphigus
Pemphigus vulgaris* Darier's disease* Hailey-Hailey disease*

Types of lesion Intraepithelial bullae Suprabasal clefts Intraepithelial bullae
Adjacent epithelium Intact Intact Disintegrating
Involvement of adnexae Yes Yes No
Corps ronds and grains No Yes Rarely
Dermal inflammation Mononuclears, eosinophils Mononuclears Mononuclears
IMF Positive Negative Negative
*The lesions of Grover's disease may histologically mimic any of these and can only be distinguished by immunofluorescence.
Pemphigus 157
Fig. 5.17
Fig. 5.16 Pemphigus vegetans: the epidermis is hyperplasic and there are scattered abscesses.
Pemphigus vegetans:
axillary ulceration and
vegetative lesions. From
the slide collection of the
late N.P. Smith, MD, The
London, UK.

Support for the thesis that p. vegetans is a variant of p. vulgaris is based on
the finding that both subtypes are associated with IgG and C3 deposition in
the epidermal intercellular space on direct immunofluorescence, and circu-
lating ‘pemphigus’ antibody.25 P. vegetans is characterized by an antibody
directed at the desmosomal cadherin, desmoglein 3.26–28 Antibodies against
desmocollins 1 and 2 as well as periplakin have also been documented.29,30
Rarely, additional IgA antibodies to Dsg3 may also be detected.31
Precipitating factors for this variant of pemphigus are largely unknown.
Exceptionally, however, p. vegetans has been linked with the angiotensin-
converting enzyme (ACE) inhibitors, captopril and enalapril.32,33 Lesions
localized to the nasal mucosa in a patient with longstanding nasal heroin
abuse have been reported and an association with human immunodeficiency
virus (HIV) infection documented.19,34,35 There are few reports relating p. veg-
etans with an underlying malignancy and in one patient a p.vegetans-like
Fig. 5.18
lesion was a manifestation of paraneoplastic pemphigus.33,36–40
Pemphigus vegetans:
Although a variant of p. vulgaris, p. vegetans shows strikingly different follicular involvement is
histological features. Suprabasal acantholysis is present but is often subtle, seen on the right.
being masked by an exuberant proliferation of squamous epithelium which
may sometimes show pseudoepitheliomatous hyperplasia (Fig. 5.17). The
epithelial proliferation involves both the epidermis and the infundibular folli-
hyperplasia and microabscesses may be confused with p. vegetans. In par-
cular epithelium. Characteristically, there is an intense inflammatory cell infil-
ticular, pyostomatitis vegetans must be excluded in patients presenting with
trate containing numerous eosinophils, and intraepidermal microabscesses
oral involvement. The latter is usually associated with inflammatory bowel
are often seen (Figs 5.18, 5.19). Eosinophilic spongiosis is a feature.41,42 The
disease and although it may mimic p. vegetans clinically and histologically,
inflammatory changes and epithelial proliferation are sometimes so marked
direct immunofluorescence is invariably negative. Halogenoderma may also
that the true nature of the lesions is obscured. Very occasionally, 10–40-μm
show similar histological features.
eosinophilic hexagonal Charcot-Leyden crystals have been described within
the eosinophil-rich microabscesses.32,43 The diagnosis of p. vegetans is eas-
ily overlooked and is made only by the pathologist with a high index of Pemphigus foliaceus
suspicion.
Clinical features
Differential diagnosis Pemphigus foliaceus (p. foliaceus) is considerably more uncommon than
Since early lesions may be similar, or identical, to p. vulgaris, the same differ- p. vulgaris and although it most often affects the middle aged and elderly,
ential diagnosis as discussed for that variant should be considered. In estab- it has a very variable age of onset, sometimes affecting younger adults and
lished lesions associated with squamous epithelial hyperplasia, the suprabasal even, occasionally, children.1–8 Very exceptionally, maternal antibodies have
cleft formation is often focal and easily overlooked. Infections, particularly been known to cross the placenta, resulting in neonatal disease.9–11 In general,
fungal and bacterial, that are associated with pseudoepitheliomatous nonendemic p. foliaceus in children is relatively benign and of short duration.6
Fig. 5.21
Pemphigus foliaceus:
crusted lesions are evident
Fig. 5.19 on the back of this young
Pemphigus vegetans: male. From the collection
there are numerous of the late N.P. Smith,
eosinophils. Note the MD, The Institute of
acantholysis. Dermatology, London, UK.
The superficial blisters of p. foliaceus are exceedingly fragile and there-

fore much less obvious; erosions and large leafy scales or crusts are often
predominant (Figs 5.20–5.22). The lesions may remain localized to the
scalp, nose, face, and trunk for many months or years, leading to a mistaken
diagnosis of seborrheic dermatitis, seborrheic keratosis, or even lupus
erythematosus. Sometimes the eruption involves the entire surface of the body
or produces a clinical resemblance to exfoliative dermatitis (erythroderma)
(Fig. 5.23).12,13 Mucous membrane involvement is rare.1 Exceptionally,
patients may present with localized disease, typically restricted to the face.14,15
The development of pustular lesions is exceptional.16 P. foliaceus often has
a much more benign course than p. vulgaris, although patients with severe
Fig. 5.20
Pemphigus foliaceus:
multiple erosions
are present with B
background erythema
and postinflammatory Fig. 5.22
hyperpigmentation. Pemphigus foliaceus: (A) there are numerous crusted lesions on the lower
Courtesy of The Institute of abdomen and in the groin, (B) high-power view. From the slide collection of the late
Dermatology, London, UK. N.P. Smith, MD, The Institute of Dermatology, London, UK.
Pemphigus 159

Similar to other variants of pemphigus, p. foliaceus is an immunologically medi-
ated disease. Examination of perilesional skin by direct immunofluorescent
techniques reveals in vivo-bound immunoglobulin (usually IgG) and often
complement (C3) in the intercellular region of the epidermis.1 Abundant anti-
gen in the follicular outer root sheath and germinal matrix may account for
the marked scalp involvement typical of pemphigus.35
Indirect immunofluorescent techniques show that the sera of patients with
p. foliaceus contain an IgG antibody that reacts with the intercellular region
of normal squamous epithelium.36 IgG4 predominates followed by IgG1.37,38
IgG3 is also sometimes present. This may be of importance since IgG3 is
the most efficient activator of complement.37 Some 60–70% of patients have
positive indirect immunofluorescence.39
The p. foliaceus antibody binds to a 160-kD desmosomal cadherin, des-
ignated desmoglein 1 (Dsg1).40,41 The sera of p. foliaceus patients bind to
the extracellular amino terminal domain of bovine Dsg1 whereas sera from
both p. vulgaris and p. vegetans patients react with the intracellular domain
of Dsg1.42,43 Compared with p. vulgaris, immunofluorescence studies on the
Fig. 5.23 sera of p. foliaceus tend to show more staining in the superficial epidermis,
Pemphigus foliaceus: in this patient, there is generalized erosion with scaling correlating with the level of the split.44,45 Conversely, the sera from patients
and erythroderma. By courtesy of R.A. Marsden, MD, St George's Hospital, with p. vulgaris show more affinity for the lower epidermis. Anti-Dsg1 anti-
London, UK. body is pathogenic.46 Injection of purified anti-Dsg1 antibodies from sera of
patients with p. foliaceus into neonatal mice induces subcorneal acantho-
lysis in a pattern typical of p. foliaceus.47 Acantholysis is thought to be the
isease, requiring corticosteroid and immunosuppressant therapy, still have
d result of an antibody-mediated cellular response rather than purely the result
an appreciable mortality. The disease may be complicated by Kaposi's vari- of steric hindrance.48 Internalization of nonclustered Dsg1 has been put for-
celliform eruption.17 ward as a possible mechanism resulting in lack of newly formed desmosomes
Very occasionally, patients may develop p. foliaceus during or after a pre- rather than a disruption of pre-existing structures.49 Increasing evidence sug-
vious episode of p. vulgaris and vice versa.18–20 The development of bullous gests that the blistering is the result of the activation of p38 mitogen-acti-
pemphigoid following an episode of p. foliaceus has also been described.21,22 vated protein kinase-dependent signaling by the p. foliaceus IgG antibodies.50
This is accompanied by an antigen shift, possibly as a result of intermo- Rarely, patient sera contain additional IgG antibodies directed against des-
lecular epitope spreading.19,23–25 A case of a blistering disorder displaying moglein 3 (Dsg3) and the presence of additional IgA antibodies against Dsg1
features of bullous pemphigoid and pemphigus foliaceus has been described as well as Dsg3 has also been detected.3,51,52 Furthermore, three patients have
in association with consumption of Spirulina algae.26 The coexistence of both been reported with clinical and histological features of p. foliaceus but direct
p. vulgaris and p. foliaceus in one patient has also been reported.27 A fur- immunofluorescence findings reminiscent of p. erythematosus. Antibodies
ther case of paraneoplastic pemphigus with concomitant clinical features of recognizing bullous pemphigoid antigen1 (BP230) as well as a 190-kD
pemphigus foliaceus and the presence of antibodies against desmoglein 1 was protein co-migrating with periplakin were detected in these patients in addi-
recently reported.28 tion to anti-Dsg1 antibodies.53 The use of D-penicillamine may be associated
In addition to idiopathic p. foliaceus, drug-induced variants, notably due with the acquisition of a pemphigus-like antibody and the development of
to penicillamine, may also be encountered (Fig. 5.24). A localized form p. foliaceus.54
may also be associated with topical drugs such as imiquimod and has been Since the blisters of p. foliaceus are superficial, they are therefore fragile
reported following radiation therapy.29–32 Pemphigus foliaceus is rarely asso- and it is often very difficult to obtain an intact lesion for diagnosis. Patients
ciated with an underlying malignancy including non-Hodgkin's lymphoma commonly have erosions without blisters, and frequently the clinician does
and esophageal cancer.33,34 not suspect a bullous disorder. Usually, the cleft or blister lies within the
A B
Fig. 5.24
Pemphigus foliaceus: (A) in this patient, the eruption was induced by penicillamine therapy; (B) close-up view of intact blisters, erosions and crusting. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.
A B
Fig. 5.25
Pemphigus foliaceus: (A) in this example, there is a cell-free, subcorneal blister; (B) occasional acantholytic cells are present adjacent to the roof.
g ranular layer or beneath the stratum corneum (Fig. 5.25). The roof of the Table 5.3
fragile blister is often not present, having sloughed either before or after Differential diagnosis of superficial pemphigus: conditions characterized by
biopsy. Acantholysis is frequently difficult to detect, but usually a few acan- subcorneal pustules
tholytic cells can be found attached to the roof or floor of the blister. In those
Superficial pemphigus
cases where the blister is missing, a careful inspection of the hair follicles IgA pemphigus
may reveal focal acantholysis. Sometimes the blister contains numerous acute Subcorneal pustular dermatosis
inflammatory cells (Fig. 5.26), particularly neutrophils, which can make dis- Pustular psoriasis
tinction from subcorneal pustular disorders, including bullous impetigo, a Reiter's syndrome
dermatophyte infection, candidiasis, pustular psoriasis, and subcorneal pus- Pustular drug reaction
tular dermatosis especially difficult.55,56 Eosinophilic spongiosis may also be Bullous impetigo
seen.57 Staphylococcal scalded skin syndrome
Pustular fungal infection
The histological features in the superficial forms of pemphigus may be eas-
ily overlooked and, since bullae are often not appreciated by the clinician,
the unwary pathologist may not consider a bullous disorder when evaluat-
Endemic pemphigus foliaceus (fogo
ing the biopsy. A high index of suspicion is therefore critical. The differential selvagem)
diagnosis of superficial pemphigus includes bullous impetigo, staphylococcal
scalded skin syndrome, IgA pemphigus, and subcorneal pustular dermatosis Clinical features
(Table 5.3). Distinction depends upon a careful consideration of the clinical
Fogo selvagem (Brazilian pemphigus foliaceus, ‘wild fire’, endemic pemphigus
information, the results of bacterial culture, and immunofluorescent studies.
foliaceus) is endemic in regions of Brazil and has also been documented in other
areas of Central and South America including Colombia, El Salvador, Paraguay,
Venezuela, and Peru.1–11 An endemic area has also been described in Tunisia.12,13
The condition is associated with poverty and malnutrition and particularly
affects children and young adults. Results from a more recent epidemiological
study demonstrated disease manifestation also in patients of higher socioeco-
nomic class and urban areas.14 There is a striking familial incidence.4 Most cases
are found along major rivers, and people especially at risk include farmers and
workers involved in land clearing and road construction.2 It appears that the
majority of patients live at an altitude of between 500 and 800 meters, and that
their homes are generally within 10–15 kilometers of running fresh water and in
the path of prevailing winds, thus suggesting a likely insect vector.4,15 In support
of this, a case-controlled epidemiological study has provided evidence that bites
by the black fly (family Simuliidae) are a significant risk factor for development
of the disease and it has been proposed that a component of the saliva may trig-
ger an antibody response in susceptible individuals.16–18 Simulium nigrimanum,
which is found in the same areas in which Brazilian fogo selvagem occurs, has
been identified as being the likely species involved.17
The clinical presentation of fogo selvagem has been divided into a number
of categories including localized and generalized forms:2,4
• Localized disease presents in a variety of ways including small blisters
Fig. 5.26 and erosions or violaceous papules and plaques distributed mainly in the
Pemphigus foliaceus: in this example, the blister cavity contains numerous neutrophils. seborrheic areas. Such lesions may be clinically misdiagnosed as discoid
Acantholytic cells are conspicuous. lupus erythematosus.
Pemphigus 161
were detected.32,33 Patients have circulating CD4+ memory T cells with a Th2
cytokine profile that proliferate in response to the extracellular domain of
Dsg1 and are thought to be of importance in the initiation and progression of
the disease by stimulating B-cell production of autoantibodies.34–36 The sys-
temic kinin system appears to be activated in patients with fogo selvagem but
the significance of this finding and its mechanism of action in blister forma-
tion are unclear.37
Patients often share the HLA phenotype DRB1*0102 and lack DQB1*0201
which is thought to represent a dominant protective gene found in unaffected
persons living in endemic regions.38,39 HLA-DRB1*0404, *1402 and *1406
may also confer susceptibility.4,28,34
The histological changes of fogo selvagem are identical to the other forms
of superficial pemphigus (p. foliaceus and p. erythematosus).40 Since the blis-
ters are superficial, often only nonbullous erosions are present for histologi-
cal examination. It is very difficult to obtain an intact lesion for diagnosis.
Typically, the cleft or blister lies within the granular layer or beneath the stra-
tum corneum. Acantholysis is frequently subtle but usually a few acantho-
lytic cells can be found attached to the floor of the blister. The blister roof is
often missing. Blisters may contain numerous inflammatory cells, particularly
Fig. 5.27 neutrophils. This feature may cause confusion with infection or other sub-
Brazilian pemphigus foliaceus: this woman with chronic disease shows very severe
corneal pustular disorders. Eosinophilic spongiosis is also sometimes present,
scaling. Blisters are not apparent. By courtesy of S.A. Pecher, MD, Amazonas, Brazil.
particularly if biopsies of early lesions are examined (Figs 5.28, 5.29).
• Generalized presentation includes bullous exfoliative, exfoliative

erythrodermic, and disseminated plaque and nodular (resembling nodular
prurigo) variants (Fig. 5.27).4
With resolution, patients may sometimes develop hyperpigmentation.19
The antibody does not cross the placenta and therefore neonatal disease is
not a feature.20 Patients with fogo selvagem appear to have no increased risk
for other concomitant autoimmune disorders.21
In contrast to Brazilian fogo selvagem, endemic disease in the area of El
Bagre, Colombia, shows several unusual and distinguishing features.22 The dis-
ease affects an older population with a strong male predilection and clinical fea-
tures reminiscent of pemphigus erythematosus. In addition to the more classical
presentation, patients develop hyperkeratotic plaques on the face, chest, and
back reminiscent of discoid lupus erythematosus as well as an erythematous
macular lesion in a butterfly-like distribution in the central face.22 Active dis-
ease is also accompanied by conjunctivitis. The disease also shows characteris-
tic immunological and histological changes, which are discussed below.

The immunological features of fogo selvagem are similar to p. foliaceus.
Indirect immunofluorescent techniques show that the sera of patients with Fig. 5.28
Brazilian pemphigus foliaceus: in this example of an early lesion, the features of
fogo selvagem contain an IgG4 antibody that reacts with desmoglein 1.15,23
eosinophilic spongiosis are evident.
Passive transfer of this antibody to BALB/c neonatal mice results in acan-
tholysis and subcorneal blistering clinically indistinguishable from that of
human disease.24–26 Low-titer IgG1 and IgG2 antibodies may also be pres-
ent and nonpathogenic IgG1 antibodies are present in unaffected individuals
and in the preclinical stages of patients from endemic areas.15,24 IgG antibod-
ies may be accompanied by IgM antibodies, a finding seen more frequently
in individuals from rural rather than urban areas. Furthermore, additional
IgM antibodies are detected more frequently associated with fogo selvagem
than pemphigus foliaceus.27 Fogo selvagem is otherwise histologically and by
immunofluorescence indistinguishable from nonendemic foliaceus and, like
the latter, the antibody recognizes epitopes in the ectodomain of Dsg1.28,29
Epitope recognition is conformation specific and calcium dependent, and
recently intramolecular epitope spreading has been implicated in the patho-
genesis of the disease. Epitope spreading appears to be related to onset of dis-
ease as well as disease modulation with remission and relapse.30 Specifically,
it has been shown that sera from patients in the preclinical stage or in remis-
sion recognize epitopes in the COOH-terminal region of the ectodomain of
Dsg1 while antibodies against epitopes in the NH2-terminal region of the
ectodomain are detected at disease onset.15,30 Interestingly, a study has sug-
gested that the presence of serum IgG4 antidesmoglein-1 in asymptomatic
individuals may suggest preclinical disease.31 A subset of patients may also Fig. 5.29
have antibodies to Dsg3, and in up to 36% of sera from individuals from Brazilian pemphigus foliaceus: there is superficial dermal edema and a perivascular
the Terena reservation of Liao Verde, Brazil, additional anti-Dsg3 antibodies inflammatory cell infiltrate with conspicuous eosinophils.
The verrucous plaques and nodules seen occasionally in localized or t argets a different epitope although this has yet to be confirmed. Recently, two
chronic fogo selvagem show acanthosis, hyperkeratosis, parakeratosis, and patients with neutrophil-rich histology were shown to co-localize pemphigus
papillomatosis.41 Acantholysis is invariably present. antibody and the neutrophil chemoattractant IL-8. In addition, circulating
The hyperpigmentation characteristic of remission is a direct result of IgG antibody up-regulated cultured keratinocyte IL-8 expression, thereby
pigmentary incontinence. offering an explanation for the neutrophil recruitment.20,21
The histological findings in the endemic form described in the El Bagre The biopsy findings are variable and often non-specific. Although eosino-
area in Colombia are identical to those of fogo selvagem in active disease. philic spongiosis is most typical, spongiosis associated with either a mixed
In addition, liquefactive degeneration of the epidermal basal cell layer is eosinophilic and neutrophilic, or a neutrophil-predominant infiltrate may
observed in a quarter of biopsies.22 By direct immunofluorescence, a posi- also be encountered.4,22 Intraepidermal vesicles and pustules, also of variable
tive lupus-band test is detected in 40% of patients in addition to IgG depo- composition, are often present and dermal papillary neutrophil microab-
sition on the surface of keratinocytes. Reactive antibodies are of the IgG4 scesses have been described.2,6,16 Acantholytic cells are usually (but not invari-
subtype with Dsg1 being the major antigen. Sera from patients also contained ably) identified. A requirement for multiple biopsies before a diagnosis can be
additional antibodies against antibasement membrane zone as well as further established is a common theme in the literature.
IgG1 anticell-surface antibodies, which may represent desmoplakin1, envo-
plakin, and periplakin.42 Differential diagnosis
Recently, criteria have been proposed to establish a diagnosis of fogo There is both clinical and histological overlap with IgA pemphigus and
selvagem as distinct from nonendemic p. foliaceus:4 dermatitis herpetiformis. Immunofluorescence allows for distinction between
• clinical evaluation, these entities. It should also be noted that, exceptionally, dermatitis herpeti-
• presence of subcorneal acantholysis, formis may histologically show occasional acantholytic cells in the absence of
• positive direct and indirect immunofluorescence and/or any evidence of pemphigus herpetiformis.
immunoprecipitation or ELISA assays, In those cases where eosinophilic spongiosis is the predominant histologi-
• confirmatory epidemiological data. cal feature, the differential diagnosis also includes hypersensitivity reactions
and infection (bacterial and fungal). Immunofluorescence studies and special
Differential diagnosis stains for microorganisms will eliminate these possibilities.
As with p. foliaceus, the histological features in fogo selvagem may be easily
overlooked and a high index of suspicion is critical to making the diagno- Pemphigus erythematosus
sis. The differential diagnosis includes p. foliaceus, p. erythematosus, bullous
impetigo, staphylococcal scalded skin syndrome, and subcorneal pustular
Clinical features
dermatosis. Careful clinical correlation, immunofluorescence studies, and
sometimes bacterial culture are necessary to establish a definitive diagnosis. Pemphigus erythematosus (p. erythematosus, Senear-Usher syndrome) is
a mild localized form of superficial pemphigus with the histological and
immunofluorescent findings of p. foliaceus combined with features of lupus
Pemphigus herpetiformis erythematosus.1–6 In general, the latter is subclinical, being suggested only
by laboratory findings, but there are also rare reports of full-blown systemic
Clinical features disease being present.4 The condition shows a worldwide distribution and a
Pemphigus herpetiformis (p. herpetiformis, herpetiform pemphigus, acantho- slight female predominance.5 Exceptionally, it has been described in children
lytic dermatitis herpetiformis) is a variant of pemphigus which shows clinical although immunological confirmation of the diagnosis is available in only
features resembling dermatitis herpetiformis with the histology and immu- one case.7–10
nofluorescent findings of pemphigus.1–6 It is rare, accounting for only up to Clinically, it is commonly confined to the head, neck, and upper trunk, and
7.3% of cases of pemphigus.2 The sexes are affected equally and there is a typically resembles p. foliaceus. Lesions are erythematous, scaly, and crusted,
wide age range varying from 31 to 83 years.3 with or without superficial vesicles, blisters or erosions. Facial involvement
Patients typically present with intensely pruritic, grouped, erythematous often shows a butterfly distribution reminiscent of lupus erythematosus
papules and plaques, vesicles and blisters, sometimes associated with mucous or seborrheic dermatitis (Fig. 5.30).1 Mucous membrane involvement is
membrane involvement.2 Urticaria may also be a presenting feature.7 The exceedingly rare.2
Nikolksy sign is variably present. Although lesions are often generalized,
there is a tendency for the extensor surfaces of the extremities to be par-
ticularly involved. Exceptionally, herpetiform pemphigus may be associated
with psoriasis, systemic lupus erythematous or with an underlying malig-
nancy including prostate and lung cancer (see paraneoplastic pemphigus).8–12
Although in some patients the clinical manifestations remain herpetiform
throughout, in others, the features evolve into more typical p. foliaceus,
fogo selvagem and, less commonly, p. vulgaris.2,4–6 Contrariwise, patients
with typical p. foliaceus and p. vulgaris may go on to develop a herpetiform
eruption.13 IgA pemphigus may also present with herpetiform lesions.14,15 In
general, p. herpetiformis has a benign course, most patients responding well
to sulfones or steroids.2,3,16

Immunofluorescence testing shows IgG in an intercellular pattern char-
acteristic of the pemphigus group of disorders on both direct and indirect
techniques.1,2,4,16 In most patients, Dsg1 (p. foliaceus antigen) is the tar-
get autoantigen.4,6,17,18 However, in some patients, antibodies against Dsg3
(p. vulgaris antigen) have also been documented.18,19 A single patient has been
reported with both IgG as well as IgA antibodies against Dsg1 in addition to
anti-Dsc (desmocollin) 3 IgG.15 Why antibodies to Dsg1 in patients with Fig. 5.30
p. herpetiformis often fail to induce appreciable acantholysis compared with Pemphigus erythematosus: there is scaliness and erythema affecting both cheeks.
p. foliaceus is uncertain. It is postulated that the p. herpetiformis antibody By courtesy of the Institute of Dermatology, London, UK.
Pemphigus 163
There are reports of p. erythematosus developing after treatment with a the latter deposits are found within sun-exposed skin but in some patients
number of drugs, notably D-penicillamine, and there are also instances attrib- normal, nonsun-exposed skin may also be positive.2 Pemphigus antibody is
uted to therapy with propranolol, captopril, pyritinol, thiopronine, ceftaz- generally present on indirect immunofluorescence, and antinuclear factor
idime, and cefuroxime.11–15 P. erythematosus has also been described as a may also be identified.20,21 Anti-DNA antibodies and antibodies to extract-
complication of heroin abuse.16 able nuclear antigens are negative except in those patients with features of
P. erythematosus may rarely be associated with thymoma.3,17–19 Typically, systemic lupus erythematosus.4 In common with p. foliaceus, the antibody
the thymoma precedes the onset of cutaneous lesions, which often present reacts with Dsg1.22
following thymectomy.18 Most tumors have been benign but one malignant P. erythematosus has histological changes that are identical to those seen in
variant has been documented.19 P. erythematosus may also be a manifestation p. foliaceus and fogo selvagem. As the blisters are superficial, it is often very
of paraneoplastic pemphigus.3 difficult to obtain an intact lesion for diagnosis. Usually, the cleft or blister
lies within the granular layer or beneath the stratum corneum. As with the
Pathogenesis and histological features other forms of superficial pemphigus, acantholysis is frequently difficult to
Pemphigus erythematosus, in addition to intercellular staining, also shows detect, but usually a few acantholytic cells can be found attached to the roof
granular deposition of IgG and complement along the basement mem- or floor of the blister. The blister may contain numerous acute inflammatory
brane region (positive lupus band test) (Figs 5.31 and 5.32).2,20,21 Typically cells, particularly neutrophils, which can make distinction from subcorneal
pustular disorders especially difficult.
The differential diagnosis includes the other forms of superficial pemphi-
gus (p. foliaceus and fogo selvagem), bullous impetigo, and staphylococ-
cal scalded skin syndrome, in addition to subcorneal pustular dermatosis.
Distinction depends upon a careful consideration of the clinical information,
the results of bacterial culture, and immunofluorescence studies.
Paraneoplastic pemphigus
Clinical features
Paraneoplastic pemphigus is a variant of pemphigus, quite distinct from
p. vulgaris and p. foliaceus.1 Paraneoplastic pemphigus may be associated
with a variety of tumors, such as B-cell lymphoproliferative disorders and
hematopoietic malignancies, Castleman's disease, Waldenström's macro-
globulinemia, thymoma (occasionally with myasthenia gravis), Hodgkin's
Fig. 5.31 lymphoma, carcinomas (e.g., carcinoma of bronchus, pancreas, liver, uterus,
Pemphigus breast, and liver), and sarcomas (including dendritic follicular cell sarcoma,
erythematosus:
round cell liposarcoma, leiomyosarcoma, and inflammatory myofibroblas-
typical intercellular
immunofluorescence with
tic tumor).2–47 We have seen an exceptional association with systemic mas-
granular staining (IgG) at tocytosis. Lymphoma is most often the coexistent neoplasm.1 In a case of
the basement membrane a patient with non-Hodgkin's lymphoma, the disease developed only after
region. By courtesy six cycles of fludarabine, raising the possibility of an association with the
of B. Bhogal, FIMLS, medication.48 In a further exceptional case, a patient presented with a dis-
Institute of Dermatology, ease fulfilling the diagnosis of paraneoplastic pemphigus by histology, immu-
London, UK. noblotting, and immunoprecipitation. However, no neoplasm was found in
8 years of follow-up.49
Paraneoplastic pemphigus has been defined by Sapadin and Anhalt as
follows:50
• painful mucosal erosions and a polymorphous skin eruption in the
context of an occult or confirmed neoplasm (Fig 5.33),
• histopathological changes of keratinocyte necrosis, intraepidermal
acantholysis, and vacuolar-interface dermatitis,
• direct immunofluorescence showing intercellular IgG and complement
accompanied by linear or granular complement at the dermal–epidermal
junction (Fig 5.34),
• indirect immunofluorescence showing circulating antibodies to simple,
columnar, and transitional epithelia in addition to a more typical
pemphigus pattern of binding to skin and mucosa,
• circulating autoantibodies that immunoprecipitate a high molecular
weight complex of polypeptides from keratinocyte extracts weighing
250, 230, 210, 190, and 170 kD.
Although the disease may develop in a wide age range (7–83 years), the
majority of patients have been in the fifth to eighth decades and there is a
male predominance.5 Exceptionally, children may be affected.4,51–54 Lesions
are seen in both the mucosa and the skin. Patients present with refractory,
Fig. 5.32 painful, persistent erosions of the oral mucosa and vermilion border of the
Pemphigus erythematosus: immunoelectron micrograph showing immunoreactant lips. In addition, the tongue, gingiva, floor of mouth, palate, oropharynx,
beneath the lamina densa in addition to occupying the intercellular space. By and nasopharynx can be affected.5 Manifestation confined to the skin or oral
courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK. mucosa is exceptional.22,55,56 Esophageal disease has been described and the
and periplakin (both cornified envelope constituents) is believed to be highly

specific for paraneoplastic pemphigus and the linker domain of plakins may
be of particular significance.72,73 There are also antibodies to an as yet unde-
termined 170-kD antigen.66 Antibodies to Dsg1 and 3 are also usually pres-
ent and plectin (another plakin family member) antibodies may be found.74,75
Anti-Dsg antibodies are thought to be of particular importance in the ini-
tiation of lesions, disrupting the cell membrane and thereby exposing des-
mosomal and hemidesmosomal plakin proteins with resultant autoantibody
formation.68,76
Direct immunofluorescence shows IgG deposition affecting the whole
thickness of the epidermis whereas C3 is found only on the lower layers.68,77–79
Characteristically, the intercellular staining is often focal and faint.77,78
In addition, complement is present along the basement membrane region.
Immunoglobulin deposition in the respiratory epithelium has also been docu-
mented.57–59 Indirect studies confirm the presence of a circulating antibody
although the membrane deposition is often masked by strong cytoplasmic
labeling.68 This latter can be reduced or abolished by serum dilution.68
In paraneoplastic pemphigus, in addition to binding to stratified squamous
epithelium, the antibody labels transitional epithelium, pseudostratified
Fig. 5.33 respiratory epithelium, small and large intestinal mucosa, and thyroid epi-
Paraneoplastic pemphigus: there are numerous erosions and crusted lesions.
thelium.78 It also reacts with myocardium and skeletal muscle. Rat bladder
Courtesy of The Institute of Dermatology, London, UK.
epithelium is said to be highly specific for paraneoplastic pemphigus.79 Up to
25% of cases, however, are negative.80
Recently, there has been accumulating evidence demonstrating consider-
able heterogeneity within disorders designated as paraneoplastic pemphi-
gus in addition to overlap with other immunobullous diseases. Patient sera
frequently contain additional IgA antibodies against Dsg3 and a patient
with IgA antibodies to desmocollins analogous to IgA pemphigus has
recently been reported.66,81 Immunophenotypic variability among paraneo-
plastic pemphigus patients has thus been established. The documentation
of patients displaying p. vulgaris-like or p. foliaceus-like features has led
some authors to suggest that immunobullous disorders arising in association
with malignancy would be best viewed as representing a spectrum rather
than a distinct entity.62 Included within this spectrum are other nonpem-
phigus immunobullous disorders resembling erythema multiforme, graft-
versus-host disease, and lichen planus. The description of antibodies reactive
with desmoplakin I and II in some patients with erythema multiforme raises
the possibility that these autoantibodies play a pathogenic role in a subset
of patients.82 However, further study will be necessary to determine the
significance of this finding.
Analogous to other forms of pemphigus, recent studies have suggested a
genetic predisposition. HLA typing has identified HLA-Cw*14 as the pre-
Fig. 5.34 disposing allele in a Chinese population while DRB1*03 was identified in a
Paraneoplastic pemphigus: IgG is evident in an intercellular distribution. French study.83,84
The histological findings in paraneoplastic pemphigus are highly variable
trachea and bronchi may be affected.57–59 The latter is sometimes accompa- but are characterized by an admixture of suprabasal acantholysis, often resem-
nied by an invariably fatal bronchiolitis obliterans-like disorder.46,58,59 Colonic bling p. vulgaris, with cleft or vesicle formation (sometimes involving adnexal
involvement is unusual.60 Frequently, patients also have severe pseudomem- epithelium), and interface changes with basal cell liquefactive degeneration,
branous conjunctivitis with symblephara, and eventual blindness may occur.5 dyskeratotic keratinocytes, and lymphocytic exocytosis (Figs 5.35–5.37).69,85
The vulva, vagina, and penis are sometimes affected.4 Rarely, the disease is Spongiosis is often present.3 A perivascular and lichenoid chronic inflamma-
accompanied by other autoimmune disorders including myasthenia gravis tory cell infiltrate is typically seen in the superficial dermis.77 In some cases,
and alopecia areata.46,56 the histological features may closely simulate lichen planus. Eosinophils,
Cutaneous lesions are typically polymorphic and often present as a pruritic however, are rare. Pigmentary incontinence is frequently evident.85
papulosquamous dermatosis with subsequent blistering. The trunk, proximal Acantholysis-like change has also been described affecting the bronchial
extremities, palms, and soles are characteristically affected.61 Nail involve- lining epithelium and brochiolitis obliterans-like features may be seen.57,59
ment may occur. Although the eruption typically resembles p. vulgaris, it may
also mimic p. foliaceus, IgA pemphigus, bullous pemphigoid, linear IgA dis- Differential diagnosis
ease, lichen planus pemphigoides, erythema multiforme, and toxic epidermal The biopsy findings of admixed acantholysis and interface change appear to
necrolysis.39,62–67 P. vegetans-like lesions have been described.49 Paraneoplastic be relatively non-specific. This contention is demonstrated by skin lesions
pemphigus is associated with a very high mortality.5 in patients with typical autoimmune pemphigus without evidence of neo-
plasia that have histological features considered typical of paraneoplastic
Pathogenesis and histological features pemphigus.79
In paraneoplastic pemphigus, circulating antibodies bind to desmosomal and The differential diagnosis includes mainly interface dermatitides (e.g.,
hemidesmosomal plakin family members including 250-kD (desmoplakin I), drug eruption, lichen planus, erythema multiforme, graft-versus-host disease)
230-kD (bullous pemphigoid antigen), 210-kD (a doublet originally thought rather than other variants of pemphigus. A very high index of suspicion on
to be desmoplakin II but later determined to represent envoplakin) and a the part of the pathologist and clinician alike and confirmatory immunofluo-
190-kD antigen (periplakin).68–71 The presence of antibodies to envoplakin rescence studies are prerequisites to achieving a correct diagnosis.
Pemphigus 165
Fig. 5.35 Fig. 5.37

Paraneoplastic pemphigus: this medium-power view shows suprabasal acantholysis Paraneoplastic pemphigus: note the basal cell hydropic degeneration and cytoid
and interface change. Note the hyperkeratosis and hypergranulosis. Courtesy of bodies. There is an intense lymphohistiocytic infiltrate. A single eosinophil is
N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, evident. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical
Virginia, USA. Center, Richmond, Virginia, USA.
• Patients with SPD-like IgA pemphigus present with superficial flaccid

pustular lesions, often arising on an erythematous base and typically
affecting the trunk and proximal limbs, although the intertriginous sites
are predilected.11 Very uncommonly, there is exclusive involvement of
the oral mucosa and perianal skin.23 Occasionally, there is generalized
skin involvement. Lesions are crusted and progress with peripheral
extension to form ringlike and rosette patterns.15 The features may be
indistinguishable from classical non-IgA-associated SPD.
• Patients with the IEN IgA dermatosis variant present with generalized
pustules and crusts and erythematous macules with peripheral vesicles
forming the so-called sunflower-like configuration (Figs 5.38, 5.39).7
A dermatitis herpetiformis-like presentation with grouped edematous
papules may also be encountered.11,12,15
Pruritus is common and is sometimes severe.8
Fig. 5.36
Paraneoplastic pemphigus: higher-power view of acantholysis with suprabasal
cleft formation. Courtesy of N. Brinster, MD, Virginia Commonwealth University
Medical Center, Richmond, Virginia, USA.
IgA pemphigus
Clinical features
IgA pemphigus is a rare dapsone-responsive variant of pemphigus that, as its
name suggests, is characterized by intercellular IgA deposition and presents
clinically with pustular rather than bullous or vesicular lesions.1–6 This disease
has been described under a number of different names, such as intraepidermal
neutrophilic IgA dermatosis, IgA pemphigus foliaceus, IgA herpetiform pem-
phigus, intraepidermal IgA pustulosis, intercellular IgA dermatosis, and inter-
cellular IgA vesiculopustular dermatosis.7–16 Most patients are middle aged Fig. 5.38
IgA pemphigus:
or elderly but children may also be affected.8,17–21 The sex incidence is equal.
erythematous lesions
There is no racial or geographic predilection.8,11 Drug-induced variants have
and an intact vesicle are
occasionally been documented.22 present. From the slide
IgA pemphigus is divided into two major subtypes: subcorneal pustular collection of the late
dermatosis (SPD) variant (IgA pemphigus foliaceus) and intraepidermal neu- N.P. Smith, MD, The
trophilic IgA dermatosis (IEN) variant (IgA pemphigus vulgaris).7 Other less Institute of Dermatology,
readily classifiable variants may also be encountered. London, UK.
Fig. 5.39 Fig. 5.40

IgA pemphigus: high-power view showing pus-filled intact blisters and an erosion. IgA pemphigus: this biopsy is from the edge of an established blister. Note the
From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, heavy inflammatory cell infiltrate and focal acantholysis.
London, UK.
The lesions in occasional patients resemble classic p. vulgaris or p.

f oliaceus. In one childhood case, a p. vegetans-like presentation associated with
α1-antitrypsin deficiency was documented.18 Mucous membrane involvement
in either variant is exceptional.17 Nikolsky's sign has been reportedly nega-
tive at least in a subset of patients.2,12,13 IgA pemphigus tends to be a chronic
relapsing but relatively benign disorder.11,12,15
A significant number of patients (approximately 20%) may have an
associated monoclonal gammopathy, usually of the IgA class.11,24–26 Two
documented cases have been benign and the others have represented B-cell
lymphoma or multiple myeloma.11

SPD IgA pemphigus is characterized by intercellular IgA deposition in the
upper epidermis, and circulating IgA antibodies which preferentially bind to
the upper epidermis are typically present.4 In contrast, in the IEN variant, IgA
is deposited preferentially in the lower epidermis, and circulating antibodies
also generally bind to the lower epidermis. In some patients, however, the IgA
antibody binds to the entire thickness of the epithelium. A linear subcorneal
distribution has also been documented.9 Complement is not usually present
Fig. 5.41
and IgG and IgM are absent.7 The antibodies are of the IgA1 subclass and
IgA pemphigus: the blister cavity contains neutrophils and eosinophils.
are usually of low titer.4,17 They have been identified in approximately 50%
of patients.12
By immunoelectron microscopy performed on a limited number of cases,
the immunoglobulin has been identified within the intercellular space, on Acantholytic cells are usually (but not always) present. Typically, they are
the keratinocyte cell membrane, in some cases showing desmosomal accen- sparse and, as such, this diagnostic clue may be very easily overlooked.11–13
tuation.27–29 In the SPD type, labeling has been predominantly detected Prominent dyskeratotic cells have been described in a single case of IgG/IgA
in extracellular spaces between keratinocytes at desmosomes while label- pemphigus.42 Significant numbers of eosinophils may also be seen in occa-
ing is mainly in intercellular spaces in nondesmosomal areas in the IEN sional IEN cases.20,43 Neutrophil dermal papillary microabscesses have also
variant.30 been described, sometimes accompanied by neutrophil spongiosis.12,20 A
The two subtypes result from autoantibody production to different perivascular infiltrate of neutrophils, lymphocytes, and histiocytes surrounds
desmosomal proteins.31 Patients with the SPD variant show reactivity with the superficial vascular plexus and eosinophils may also sometimes be pres-
desmocollin 1.32–35 In contrast, anti-Dsg1 or anti-Dsg3 IgA antibodies are ent. In addition to the major variants characterized by pustules, some patients
present in the IEN variant.19,36–38 One patient with the SPD variant showed with IgA pemphigus show histological features typical of classic p. vulgaris,
both anti-Dsc1 as well as anti-Dsg1 IgA.39 In some patients, however, nei- p. foliaceus or even, exceptionally, p. vegetans.4,18
ther desmocollins nor desmogleins appear to be involved, suggesting that IgA
pemphigus is a heterogeneous group of conditions.13,18,35,38 Differential diagnosis
Histologically, in the SPD variant, vesicles are typically found in a sub- The differential diagnosis includes subcorneal pustular dermatosis, typical
corneal location associated with a neutrophil infiltrate. It is thought that the p. foliaceus, and infections such as bullous impetigo. Although clinically sub-
presence of IgA is responsible for the striking neutrophil response of this dis- corneal pustular dermatosis tends to be more restricted to the flexural sites,
order since IgA is associated with neutrophil chemotaxis and neutrophils bear absolute distinction from the subcorneal variant of IgA pemphigus depends
IgA receptors.40,41 upon immunofluorescent studies. Gram stain and a periodic acid-Schiff (PAS)
In the IEN variant, the pustules can be distributed throughout all layers of should always be included in the histological workup to exclude an infective
the epidermis and may also involve the hair follicles (Figs 5.40, Figs 5.41).18 process.
Acantholytic dermatoses with dyskeratosis 167
Drug-induced pemphigus
There are at least 25 drugs that have been shown to be associated with the
development of pemphigus.1 Penicillamine and captopril are the most com-
mon offenders; however, enalapril, propranolol, bisoprolol, glibenclamide,
cilazapril, penicillins, cephalosporins, rifampicin, pyrazolon derivatives, and
lisinopril, among others, have also been implicated.1–8 Some drugs such as
penicillamine may elicit either p. foliaceus or p. vulgaris, but the former is
much more common.
Symptoms disappear in most patients following withdrawal of causative
drugs that contain a sulfhydryl group (thiol drugs). Non-thiol drugs are much
less likely to be associated with remission following withdrawal.2
Histologically, drug-induced pemphigus resembles sporadic counterparts
with positive direct immunofluorescence in most, but not all, patients.9 As
expected, given the different variants of pemphigus that drugs may induce,
antibodies against both Dsg1 and Dsg3 have been documented.10 It has been
suggested that a monoclonal antibody against desmogleins 1 and 3 may be
useful in the diagnosis and prognosis of drug-induced pemphigus.11 Staining
with this antibody is usually patchy in idiopathic pemphigus and diffuse in
drug-induced pemphigus. Furthermore, cases of drug-induced pemphigus Fig. 5.42
with diffuse pattern tend to have a poorer prognosis. Hailey-Hailey disease: erythematous and scaly lesions are present in the groin
and on the labia majora. From the slide collection of the late N.P. Smith, MD, The
Contact pemphigus
as the genitalia, umbilicus, inframammary regions and scalp, may also be
Clinical features affected. Rarely the disease may be generalized.4,5 Nikolsky's sign is some-
There is a growing body of literature documenting contact with topical sub- times positive.3 Vesicles and bullae, arising on normal or erythematous skin,
stances preceding the onset of pemphigus. The pathogenesis is not under- are soon replaced by erosions, crusting and scaly plaques sometimes resem-
stood, but in some cases the exposure is thought somehow to trigger or bling impetigo (Figs 5.43, 5.44).2,6 Healing is accompanied by hyperpig-
induce pemphigus. The term ‘contact pemphigus’ has been proposed as a mentation, but scarring is not a feature.3 Lesions are frequently itchy and
designation for this phenomenon, which has been described in the vulgaris, malodorous. Sometimes pain is a considerable problem, particularly if fissur-
vegetans, foliaceus and erythematosus variants.1,2 Substances that have been ing is present.3 Symptoms often improve with advancing age.1 Superinfection
implicated include nickel, pesticides, chromium sulfate, tincture of benzoin, by Candida albicans, herpes virus, and Staphylococcus aureus are frequent
phenol, diclofenac, dihydrodiphenyltrichlorethane, ketoprofen, feprazone, complications.7,8 Segmental involvement has rarely been reported as a result
and imiquimod.1–14 Clearly, further study is necessary to elucidate the rela- of type 1 or type 2 mosaicism according to the classification by Happle, and it
tionship between exposure to topical agents and contact pemphigus. has now become clear that at least some of the cases of relapsing linear acan-
tholytic dermatosis represent type 2 segmental Hailey-Hailey disease.9–13
Pathogenesis and histological features The development of the lesions is related to mechanical trauma, stress,
Whether this phenomenon relates to systemic absorption, contact allergy or and ultraviolet radiation and exacerbation of the disease has been reported
a direct ‘toxic’ effect on epidermal antigens is as yet unknown. It is interest- due to scabies, contact irritation, and patch testing.14–18 An exceptional case
ing to note that in the majority of documented cases, the patient has been of a patient developing the disease while on efalizumab for psoriasis has been
exposed to the offending agent for a considerable period of time before the reported.19 Symptoms often improve or even disappear during winter, but
onset of the blistering eruption.6 tend to worsen in summer.1,20 Mucosal involvement is unusual. Anogenital
Biopsy of contact pemphigus shows histological features similar to those disease, however, occasionally presents as multiple 3–5-mm diameter warty
of p. vulgaris, although one patient developed features more reminiscent of
pemphigus vegetans. Immunofluorescent studies show intercellular IgG and
sometimes C3.
The main differential diagnosis is with classic pemphigus. Only clinical infor-
mation will allow distinction of contact pemphigus from other members of
the pemphigus family of disorders.
Acantholytic dermatoses with dyskeratosis

Hailey-Hailey disease
Clinical features
Hailey-Hailey disease (benign familial pemphigus) is a rare, episodic, acan-
tholytic disorder with an autosomal dominant mode of inheritance.1,2 In only
about two-thirds of patients, however, is a family history obtained. There is
an equal sex incidence.2,3
Lesions usually present in the second to fourth decades and appear par- Fig. 5.43
ticularly at sites of minor trauma or friction, especially flexural, around the Hailey-Hailey disease: lesions are most often seen in the flexures as a consequence
neck, and in the axillae and groin (Fig. 5.42). However, other sites, such of friction. By courtesy of the Institute of Dermatology, London, UK.
differentiation demonstrate premature expression and reduced levels of invo-

lucrin due to increased mRNA degradation, and it has been proposed that
intact ATP2C1 is necessary for basal cell layer keratinocytes to maintain their
undifferentiated state.56,57 A number of interesting observations have been
made recently in both Hailey-Hailey and Darier's disease that provide further
insight into how the alteration in the calcium gradient affects ATP receptors
and keratin expression.58 In both diseases there is a lower level of calcium in
the basal cell layer of the epidermis compared to normal skin, the ATP recep-
tor P2Y2 is not identified at the cellular membrane in affected cells whereas
P2X27 which is usually not present on the cellular membrane is expressed in
these cells probably mediating apoptosis. Furthermore, both keratins 14 and
10 are expressed in diseased cells whereas these keratins are mutually exclu-
sive in normal keratinocytes.
While early lesions show suprabasilar lacunae, established Hailey-Hailey
disease is characterized by massive acantholysis associated with suprabasal
vesicle or bulla formation.3 Typically, however, the acantholysis is incom-
plete, the cell retaining some connections and giving an appearance often
likened to a ‘dilapidated brick wall’ (Figs 5.45–5.47). The adnexal epithelium
is usually spared. Occasionally, dyskeratotic cells resembling the corps ronds
Fig. 5.44 and grains of Darier's disease are seen.
Hailey-Hailey disease: close-up view of keratotic warty lesions. By courtesy of the
papules.21 This occurs most often in females, particularly blacks, and some-
times may be a presenting feature. In such instances there is overlap with
papular acantholytic dyskeratosis of the vulva.22
Asymptomatic white longitudinal bands may be present on the fingernails
in up to 70% of affected patients.1,23 The other nail changes of Darier's dis-
ease are absent.
Significant associated conditions have not been documented with the pos-
sible exception of a bipolar disorder and a patient with affective disorder (see
Darier's disease).24,25 An association with supernumerary nipples has been
documented in one Tunisian family.26
Exceptionally, squamous carcinoma has been documented as a compli-
cation in patients with Hailey-Hailey disease.27 It is likely, however, that
those arising on the vulva have a human papillomavirus-associated basis.28,29
Condylomatous change and evidence of HPV infection has recently been
detected in genital lesions of the disease.30,31
While it has rarely been reported that Darier's disease may coexist with
Hailey-Hailey disease, the available evidence supports the contention that
these two conditions represent completely different entities.32
Fig. 5.45
Pathogenesis and histological features Hailey-Hailey disease: early lesion showing the characteristic ‘dilapidated brick wall’
appearance.
Hailey-Hailey disease is primarily an abnormality of cell adhesion.
Development of this disease has recently been shown to be caused by mul-
tiple mutations in ATP2C1 on chromosome 3q21–24, a gene that encodes the
calcium pump SPCA1.33,34 SPCA1 is a Ca2+/Mn2+ ATPase present within the
membrane of the Golgi apparatus and responsible for the transport of Mn2+
as well as Ca2+ ions into the Golgi.35,36 Over 100 mutations have been identi-
fied spanning the entire ATP2C1 gene including missense, frameshift, splice
site as well as nonsense mutations.37–46 However, no clear genotype–pheno-
type correlation has emerged as yet. Studies have shown that calcium regula-
tion in cultured keratinocytes is impaired.33 In addition, there is evidence that
integrity of intercellular junctions may be dependent on intracellular calcium
stores.47–50 The precise mechanism by which the abnormality in the calcium
pump causes acantholysis is not known. However, the addition of calcium to
monolayers of squamous cells in culture elicits stratification.48 In contrast,
cells grown in low calcium medium fail to stratify.50 It should be noted that
Darier's disease, another disorder showing acantholysis, is also associated
with a mutation in another calcium pump – ATP2A2. That both of these dis-
orders of acantholysis are associated with mutations in a calcium pump is
strong evidence for an important role in maintaining cell–cell cohesion.
Immunohistochemical studies have confirmed that the major desmosomal
proteins and glycoproteins are synthesized in Hailey-Hailey disease and dis-
tributed along the plasma membranes in uninvolved epidermis.51 In lesional Fig. 5.46
skin there is marked cytoplasmic labeling for the desmoplakins (DpI, DpII), Hailey-Hailey disease: in this example, there is marked hyperkeratosis, parakeratosis,
desmogleins (Dsg2, Dsg3) and the desmocollins.51–55 Studies on keratinocyte and acanthosis. Villi project into the blister cavity.
The disease has been shown to be a type-2 mosaicism according to Happle,

resulting in homozygosity for the mutated gene and pronounced disease in a
segmental distribution superimposed on more classical disease in a heterozy-
gous individual.4–7
The features are indistinguishable from Hailey-Hailey disease.
Darier's disease
Clinical features
Darier's disease (keratosis follicularis, morbus Darier), which is character-
ized by abnormal keratinocyte adhesion, is a rare hereditary disorder, usually
transmitted in an autosomal dominant pattern. In a large series, however,
47% of patients had no clear family history of Darier's disease.1 Presumably
these cases represent new mutations or evidence of incomplete penetrance.
Its documented incidence is variable. In Oxfordshire (UK), the incidence is
1:55 000, in the north of England it is 1:36 000, in the west of Scotland it is
1:30 000, whereas in Denmark it is 1:100 000.2–5 The sex incidence is equal,
although males appear to be more severely affected than females. The disease
Fig. 5.47 usually presents in the first or second decade (with a peak around puberty)
Hailey-Hailey disease: and often follows exposure to ultraviolet light.1 Exceptionally, patients may
in contrast to Darier's not present until their sixth or seventh decade.6 Darier's disease is a long-term
disease, dyskeratosis is
illness. Remissions do not occur, although some patients show improvement
usually minimal or even
absent.
with increasing age.6
The lesions are frequently itchy and, less commonly, painful.1,6 They
are characterized by greasy, crusted, keratotic yellow-brown papules and
Ultrastructural studies have primarily disclosed abnormalities of the des- plaques found particularly on the ‘seborrheic’ areas of the body – the scalp,
mosome-tonofilament units, characterized by diminished numbers of desmo- forehead, ears, nasolabial folds, upper chest, back, and supraclavicular fos-
somes and clumped tonofilaments.59–62 The latter have a linear distribution in sae (Figs 5.48–5.52).1,5 There is mild involvement of the flexures in the
the basal keratinocytes, but develop a whorled configuration in the suprabasal majority of patients although sometimes this distribution predominates.1,6
layers.60,62 The cell membranes show microvillus formation.59 An electron Lesions may be induced or exacerbated by stress, heat, sweating, and mac-
microscopic study of artificially induced early lesions suggests the desmo- eration.1,7 In some areas the lesions have a warty appearance, while in the
somal splitting precedes the tonofilament clumping.61 Dyskeratotic cells are flexures they are often vegetative, malodorous (a particularly distressing
characterized by condensed tonofilaments surrounding pyknotic nuclei. problem), and often secondarily infected (Figs 5.53, 5.54).6 Bullous lesions
generally following sun exposure can occur, albeit rarely.8–10 Leukodermic
Differential diagnosis macules in black patients have also been described.11–14 Additional features
including cutaneous horns and hemorrhagic palmar lesions have also been
The histological features of Hailey-Hailey disease must be distinguished from
documented.15–18
those of Darier's disease, p. vulgaris, and Grover's disease. Pemphigus is dis-
Patients with Darier's disease are susceptible to bacterial (particularly
tinguished from Hailey-Hailey disease by the presence of relatively intact epi-
Staphylococcus aureus), dermatophyte, and viral infections.1,19,20 There are
thelium in the adjacent epidermis (versus disintegrating ‘dilapidated brick
rare case reports of eczema vaccinatum and eczema herpeticum complicating
wall’) and involvement of adnexal structures. In difficult cases, positive
immunofluorescence staining supports a diagnosis of pemphigus. Darier's
disease tends to show prominent suprabasal cleft formation with involve-
ment of adnexae and is associated with numerous corps ronds and grains.
These points of distinction are summarized in Table 5.2.
Immunofluorescence studies for immunoglobulin and complement are
invariably negative, aiding in the distinction from immunobullous disorders.
Distinction from acantholytic dermatosis of the genital area can, however,
be extremely difficult. In fact, the relationship between these disorders is not
well understood. The combination of clinical features of a lesion or lesions
localized to the vulvogenital area and a negative family history favors acan-
tholytic dermatosis of the genital area.
Relapsing linear acantholytic dermatosis

Clinical features
Relapsing linear acantholytic dermatosis (Hailey-Hailey-like epidermal
nevus) is an exceptionally rare nevus-like condition characterized by ery-
thematous plaques with vesicles and erosions arranged in a linear distribu-
tion along Blaschko's lines.1–3 It typically undergoes spontaneous resolution
followed by recurrence and has a chronic course. Insufficient cases have been Fig. 5.48
documented to precisely determine its relationship to Hailey-Hailey disease. Darier's disease: in this patient keratotic brown papules are present on the back of
Recent data, however, demonstrate that at least some of the patients harbor the neck. From the slide collection of the late N.P. Smith, MD, The Institute
mutations in the gene responsible for Hailey-Hailey disease, the ATP2C1. of Dermatology, London, UK.
Fig. 5.49 Fig. 5.51

Darier's disease: close-up view of keratotic papules. From the slide collection of the Darier's disease: lesions
late N.P. Smith, MD, The Institute of Dermatology, London, UK. may be induced by heat,
sweating, and maceration.
From the slide collection
of the late N.P. Smith,
MD, The Institute of
Fig. 5.50
Darier's disease: this patient shows a striking symmetrical distribution. From the
slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Darier's disease and a patient who developed localized anogenital cowpox

has also been reported.21–23 Life-threatening Kaposi's varicelliform eruption is Fig. 5.52
a rare but important complication.24–26 No consistent abnormality of immune Darier's disease: close-up view. From the slide collection of the late N.P. Smith, MD,
function has been found to explain this.27,28 Recently, however, persistence of The Institute of Dermatology, London, UK.
intracellular S. aureus small-colony variants in a patient with Darier's disease
has been shown to be of importance in chronic cutaneous infection and resis-
tance to antibiotic therapy.29 Whether this mechanism is involved in other in a small nick on the free margin, are typical findings (Figs 5.56,
patients awaits confirmation. 5.57).1 Painful splitting and subungual hyperkeratoses are additional
Other cutaneous manifestations of Darier's disease include unilateral, lin- manifestations.1 The toenails are affected less often (and less severely) than
ear or zosteriform variants, which some regard as acantholytic, dyskeratotic the fingernails.1 Subtle hand and nail manifestations may sometimes be a
epidermal nevi rather than true Darier's disease (see below).30,31 It is more presenting feature.6
likely that these variants, at least in part, result from genetic mosaicism.32 The mucous membranes of the mouth, pharynx, larynx, esophagus, and
The hands are affected in 96% of patients.1 Pits and punctate keratoses female genitalia can also be affected.38–41 Oral lesions are present in up to
with focal disruptions of the skin ridges of the palms and soles are charac- 50% of patients and consist of small white papules on the hard palate.42,43
teristic features (Fig. 5.55).1,6,33 Acrokeratosis verruciformis-like lesions are Large nodular and verrucous plaques are also sometimes present and occa-
common on the backs of the hands.1 Indeed, acrokeratosis verruciformis of sionally there are gingival, buccal mucosal, and tongue lesions.15 Involvement
Hopf, a localized disorder of keratinization of distal extremities, is closely of the salivary ducts is said to be uncommon and results in salivary gland
related to Darier's disease and appears to be caused by mutations in the same swelling with obstruction and sialadenitis.44,45 Recently, however, one
gene.34,35 series reported an incidence of 30% involvement of the parotid gland.42
Nail changes are a particularly important diagnostic feature.1,2,6,36,37 Anal involvement may present as pruritus ani or less often as vegetating
Longitudinal white or red streaks (often both), some of which terminate malodorous plaques.46
Fig. 5.53 Fig. 5.55

Darier's disease: skin Darier's disease: palmar pits are a helpful diagnostic clue. By courtesy of J. Wilkinson,
involvement as severe MD, Wycombe General Hospital, High Wycombe, UK.
as this is fortunately
extremely rare. By
courtesy of M. Greaves,
MD, the Institute of
Fig. 5.56
Darier's disease:
parallel white and red
longitudinal streaks are
pathognomonic features.
Fig. 5.54 By courtesy of the
Darier's disease: severe involvement can be very disfiguring and a source of Institute of Dermatology,
considerable disability and embarrassment. By courtesy of M. Greaves, MD, the London, UK.
Ocular lesions, particularly affecting the cornea, are seen in up to 76%

of patients.47 Peripheral corneal opacities and central epithelial irregularity Pathogenesis and histological features
are the usual findings. Pannus formation may rarely be present. Lesions are Positional cloning studies of different families have all shown the gene of
typically asymptomatic. Darier's disease to be located at 12q23-q24.56,57 Mutations in ATP2A2, a
Associated systemic abnormalities are unusual, but include epilepsy, gene that encodes for SERCA2 (type 2 sarcoendoplasmic reticulum CA2+-
pulmonary lesions, bone cysts, low intelligence, and small stature.1 Various ATPase), cause the disease and have been identified in the majority of patients
neuropsychiatric problems including depression and bipolar disorder have screened.57 So far, over 100 different mutations have been reported. They are
been linked with Darier's disease.6,48 There is some evidence to suggest that predominantly missense mutations, but frameshift and splice site mutations
there is familial cosegregation of bipolar disorder with Darier's disease, at as well as mutations resulting in a premature stop codon have also been iden-
least in a proportion of cases.48,49 tified.58–67 However, no clear genotype–phenotype correlation has emerged.
Rare and likely incidental associations include visceral malignancy, horse- The disease is likely a result of haploinsufficiency since only one correct copy
shoe kidney, hemodialysis, gynecomastia, cutis verticis gyrate, and Fanconi of the ATP2A2 gene is expressed.68 The mutant copy may furthermore lead
anemia.50–55 to enhanced proteasome-mediated degradation and/or protein dimerization
Spontaneous remissions in Darier's disease are rare, and in the majority of resulting in complete loss of SERCA2 activity.68,69 The precise mechanism
patients the disease persists throughout life. of how mutations in the ATP2A2 gene lead to disease is unknown although
Fig. 5.58
Fig. 5.57 Darier's disease: very early lesion showing multiple characteristic corps ronds.
Darier's disease: notches
on the free margin of the pyknotic nucleus surrounded by a clear halo enclosed within a basophilic
nail are common findings. or eosinophilic ‘shell’ (Fig. 5.58). Variable amounts of highly irregular
By courtesy of the keratohyalin granules may also be evident.
Institute of Dermatology, • Grains are located within the horny layer and consist of somewhat
London, UK. flattened oval cells with elongated cigar-shaped nuclei and abundant
keratohyalin granules.
In the fully established lesion there is hyperkeratosis and often parakera-
there is emerging evidence to suggest that the integrity of intercellular junc-
tosis, sometimes arranged in a clearly defined tier (Figs 5.59–5.61). The epi-
tions is dependent on the intracellular calcium stores.70 SERCA is a ubiqui-
dermis may appear acanthotic or atrophic and typically shows acantholysis
tously expressed calcium-ATPase and its function is the transport of cytosolic
with suprabasal cleft formation in which the underlying dermal papillae, cov-
calcium ions into the endoplasmic reticulum.68 There are three different genes
ered by a single layer of epithelium, project into the cavity (villus formation).
encoding these proteins, resulting in a total of nine different isoforms. Of the
The roof contains variable numbers of grains and the adjacent epithelium has
different isoforms only SERCA2b appears to be expressed in keratinocytes.71
variable numbers of corps ronds. Occasionally, epithelial proliferation can be
Loss of SERCA2 function can therefore not be compensated for, explaining
marked, resulting in pseudoepitheliomatous hyperplasia. Bullous lesions are
the severe skin manifestations in the absence of further systemic involvement
illustrated in Figures 5.62 and 5.63.
in most patients with Darier's disease.68 Ultimately, intact intracellular cal-
There may be a perivascular chronic inflammatory cell infiltrate in the
cium ion homeostasis has been identified as a major factor in the complex
superficial dermis, although this is not a common finding.
process of desmosome assembly and is necessary for intracellular interactions
The histological features of the oral, pharyngeal, laryngeal, and esopha-
between desmosomal cadherins and intracellular plaque proteins such as pla-
geal lesions are similar to those described in the skin although dyskeratosis
koglobin.68,72 Apoptosis in Darier's disease resulting in dyskeratotic cells is
is said to be less conspicuous.42 Salivary gland lesions show ductal dilata-
likely directly related to the imbalance in calcium homeostasis, and immuno-
tion and squamous metaplasia of the lining epithelium with acantholysis and
histochemical studies have revealed reduced expression of antiapoptotic pro-
dyskeratosis.44,45
teins of the bcl-2 gene family in lesional epidermis.73–75
No single specific ultrastructural abnormality has been identified in
Darier's disease. Changes described have included complete loss of desmo-
somes in foci of acantholysis with formation of cell membrane microvilli,
cytoplasmic vacuolization, cell membrane defects, abnormal tonofilament
aggregation, clumping and distribution, premature and abnormal forma-
tion of keratohyalin granules and membrane coating (Odland) bodies, and
excessive lipid lamellae between the flattened keratinocytes of the stratum
corneum.76–80 Hemidesmosomes and the lamina densa usually appear morpho-
logically normal, although discontinuities of the latter have been described.
Ultrastructurally, corps ronds are characterized by large dense keratohyalin
masses, numerous membrane coating granules, and tonofilament clumps.76
They are distributed particularly around the nucleus, often surrounding a
perinuclear cytoplasmic halo containing distended vesicles. Grains of Darier
are composed of nuclear remnants with surrounding dyskeratotic debris.76
Acantholysis develops as a consequence of desmosomal breakdown and
dissociation of tonofilaments, although which comes first is uncertain.
The histological features of Darier's disease depend upon a variable
interplay between acantholysis and abnormal keratinization (dyskeratosis),
the acantholysis resulting in suprabasal cleft formation (and rarely vesicles
or even blisters), and the dyskeratosis manifesting as corps ronds and grains
of Darier. Fig. 5.59
• Corps ronds are large structures, usually most conspicuous in the Darier's disease: scanning view through a typical lesion. Note the keratotic tier and
granular layer, and consist of an irregular eccentric and sometimes suprabasal cleft formation.
Fig. 5.60 Fig. 5.63

Darier's disease: higher-power view showing the well-developed vesicle with Darier's disease: high-power view of Figure 5.62 showing multiple corps ronds.
suprabasal acantholysis and well-developed corps ronds and grains.
Corneal lesions are characterized by corneal epithelial edema, subepithe-

lial granular deposits, and basement membrane thickening. Acantholysis and
dyskeratosis are not seen.47
Although warty dyskeratoma, Hailey-Hailey disease, and pemphigus are
considered in the differential diagnosis of Darier's disease, their distinction is
not challenging when clinical information is considered. Warty dyskeratoma
is a single umbilicated lesion that typically forms more pronounced papillary
structures. Hailey-Hailey disease is characterized by full-thickness epidermal
acantholysis and does not show extensive dyskeratosis. Grover's disease may
be indistinguishable from Darier's disease in a given biopsy, but the lesions are
usually small, spanning only a few rete ridges. The presence of some combina-
tion of spongiosis, and changes mimicking more than one of the acantholytic
dermatoses, is characteristic of Grover's disease. In cases that show only Darier-
like changes, clinical information should allow for definitive diagnosis.
Linear Darier's disease

Fig. 5.61
Darier's disease: in this example both corps ronds and grain of Darier are evident. Clinical features
Linear Darier's disease (acantholytic dyskeratotic epidermal nevus, unilat-
eral Darier's disease, zosteriform Darier's disease, segmental Darier's disease)
is a rare acquired condition characterized by the development of grouped,
keratotic, sometimes pruritic, yellow-brown papules which affect the trunk,
trunk and limbs, limbs, scalp, vulva, and face in decreasing order of frequency
(Fig 5.64).1–9 Their linear distribution corresponds to the lines of Blaschko.
Lesions may be aggravated by sunlight, heat, and sweating. Although a wide
age range may be affected, the majority of patients are in the third or fourth
decade. There is an equal sex incidence. There is no family history of Darier's
disease. Usually, patients are free from other stigmata of Darier's disease but
there are very occasionally reports of patients with linear lesions associated
with ipsilateral nail changes and palmar pits typical of Darier's disease.10,11

The precise nature of this lesion remains conjectural. Although many authors
prefer to regard it as a variant of epidermal nevus with superimposed acantho-
lytic dyskeratosis, there is an alternative school of thought which believes that
many, if not all, such lesions represent localized or unilateral Darier's disease,
arguing that the condition develops as a consequence of genetic mosaicism.
Certainly, the late age of onset is unlike a typical epidermal nevus, which usu-
Fig. 5.62 ally presents in childhood. The distribution along the lines of Blaschko and
Darier's disease: bullous variant showing suprabasal acantholysis, epidermal the occasional reports of additional Darier-like features on the ipsilateral side
regeneration and a subcorneal blister. of the body offers support to a concept of localized Darier's disease. Recently,
Fig. 5.64 Fig. 5.65

Linear Darier's disease: the trunk is a commonly affected site. Note the small papules. Grover's disease:
Courtesy of the Institute of Dermatology, London, UK. innumerable
erythematous papules
ATP2A2 mutations have been identified in lesional tissue but not unaffected are present on the chest
skin patients with linear acantholytic epidermal nevi, confirming the relation- wall. By courtesy of the
ship of these lesions to Darier's disease.12,13 Institute of Dermatology,
London, UK.
Histologically, these lesions are indistinguishable from Darier's disease.
Very rarely, true epidermal nevus may show histological features of acan-
tholysis and dyskeratosis presenting against a background of a verrucous
plaque characterized by marked acanthosis and papillomatosis.14,15 Such
lesions, which are present at birth, would be best classified as epidermal
nevus showing acantholysis and dyskeratosis rather than being included in
the spectrum of acantholytic dyskeratotic epidermal nevus.
Transient acantholytic dermatosis

(Grover's disease)
Clinical features
Transient acantholytic dermatosis (persistent acantholytic dermatosis) is a
primary acquired, self-limiting, acantholytic disease of unknown etiology,
seen predominantly in the middle aged or elderly although there are rare
reports of the disorder in children.1–5 Males are affected more often than
females (3:1).2,3 The white races are predominantly affected.5 Cases involv-
ing blacks are exceptionally rare.6 The disease shows a predilection for the
winter months in nonhospitalized patients.7 Although the disease is usu- Fig. 5.66
Grover's disease: close-up view. By courtesy of the Institute of Dermatology,
ally transient, persistent and recurring variants have also been described
London, UK.
(persistent acantholytic dermatosis) in the literature.8–10 The development
of Kaposi's varicelliform eruption is a rare and unusual complication of
the disease and occult colonization by herpes simplex virus has also been and renal as well as bone marrow transplantation.25–29 It is likely, however,
documented.11,12 that the majority of these associations are coincidental. Transient acantho-
The skin lesions are usually rather polymorphic, consisting of 1–3-mm lytic dermatosis shows a positive correlation with asteatotic eczema, allergic
erythematous, red-brown or flesh-colored papules, vesicles, and eczema- contact dermatitis, and atopic dermatitis.3,30,31
tous plaques with a predilection for the chest, back, and thighs (Figs 5.65
and 5.66).2 The palms and soles are unaffected. Superimposed excoria- Pathogenesis and histological features
tions are associated with the intensely pruritic eruption. Pustular, bullous, The pathogenesis of Grover's disease is incompletely understood. There are,
nummular, follicular herpetiform, and zosteriform variants have all been however, a number of important known etiological factors including:
documented.2,13–16 The mucous membranes, palms, and soles are commonly • sun exposure,
spared although there are rare reports of oral, nasal, and laryngeal involve- • excessive heat and sweating,
ment.2,17,18 Postinflammatory pigmentary changes following resolution of • ionizing radiation,
the acute phase are common. Transient acantholytic dermatosis has been • adverse reaction to drugs.
described in association with leukemia and lymphoma in addition to numer- Transient acantholytic dermatosis has long been known to be associated
ous solid tumors including carcinoma of kidney, renal pelvis, bladder, and with sun exposure.2,3,32–35 The lesions are photodistributed and the patients
prostate.2,19–24 In one study, 25% of patients had some form of malignancy.21 commonly give a history of having recently spent time in the sun.36 There
Other rare associations include scabies, renal failure, peritoneal dialysis, is also a well-established relationship to excessive heat and sweating.35,37–39
Bedridden, febrile patients are particularly at risk and as a result it has

been proposed that the pathogenesis might be analogous to that of miliaria.
Occlusion of sweat ducts and increased sweating resulting in acantholysis
mediated by high concentrations of sweat urea has been proposed, although
this has yet to be proven.40 More recent immunohistochemistry studies have
not generally offered support for this hypothesis although bedridden, febrile
patients may occasionally show prominent involvement of the eccrine duct;
this has been termed sudoriferous acrosyringeal acantholytic disease.21,41,42
Associations with sunlamps, sun parlors, PUVA therapy, steam bath, hot tub,
hot water bottle, and polyester jogging suits have also been documented.1,2,21
Despite these well-recognized associations, there must be other important
predisposing factors, since overexposure to sunlight and excessive sweating
are extremely common yet this disease is rare.
Very occasional reports have described transient acantholytic dermato-
sis developing after radiotherapy for cancer, exceptionally with lesions con-
fined to the area of the port.2,22,43,44 Only a small number of drugs have
been associated (rarely) with the development of transient acantholytic der-
matosis.2 There are reports of lesions following treatment with sulfadox-
ine-pyrimethamine, 2-chlorodeoxyadenosine, D-penicillamine, recombinant
interleukin-4, cetuximab, and induction chemotherapy for allogeneic bone Fig. 5.68
Grover's disease: high-power view showing acantholysis.
marrow transplantation.45–50 The presence of eosinophils in the dermal
inflammatory cell infiltrate has raised the possibility of a hypersensitivity
reaction.21 Occasional cases arising in patients with HIV infection have been
recorded.21
Despite the histological similarity to Darier's and Hailey-Hailey diseases,
there is no evidence of a mutation in the ATP2A2 gene.51
There have been a variety of both direct and indirect immunofluores-
cence observations including lupus erythematosus-like, bullous pemphigoid-
like, and pemphigus-like findings.21,52 These are reviewed in reference 2. They
are the exception rather than the rule and are unlikely to be of any great
significance.
Immunohistochemistry observations have included a reduction or absence
of desmosomal staining with cytoplasmic redistribution of the proteins,
desmoplakins I and II, plakoglobin, and desmoglein.53–55 Redistribution and
dissolution of desmosomal attachment plaques have been demonstrated as
the first stage in the development of Grover's disease.55
Instead of featuring specific histopathological changes, transient acantholytic
dermatosis mimics three other diseases: Darier's disease, Hailey-Hailey disease,
and pemphigus (p. vulgaris and p. foliaceus) (Figs 5.67–5.70).21 The first is by
far the most commonly encountered. Thus, in the typical case, there is hyperker-
atosis, parakeratosis, acanthosis, and acantholysis accompanied by corps ronds
formation and grains of Darier. In the Hailey-Hailey pattern, the acantholy- Fig. 5.69
sis is much more pronounced such that the dilapidated brick wall appearance Grover's disease: this example is indistinguishable from pemphigus vulgaris.
is seen. Follicular involvement may be present. In the pemphigus-like variant,
Fig. 5.67 Fig. 5.70

Grover's disease: low-power view showing an intact intraepidermal vesicle. Grover's disease: early lesion showing intraepidermal vesiculation.
yskeratosis is typically absent. Multiple specimens from any one patient

d
may disclose differing histological variants, and superimposed spongiosis is
often present. Occasional bullae are encountered. A variable dermal mononu-
clear infiltrate is usual and significant numbers of eosinophils are seen in some
cases.21
Patients with sudoriferous acrosyringeal acantholytic disease show, in
addition to typical features of Grover's disease, acantholysis of the superficial
portion of the eccrine duct.
Clinically, transient acantholytic dermatosis is easily differentiated from
Darier's disease, Hailey-Hailey disease, and pemphigus. However, the biopsy
findings often mimic these diseases. A histological clue to the diagnosis is the
small size of the lesion. Usually only one or two small discrete lesions that
span a few rete ridges are noted. This is in contrast to other acantholytic
dermatoses, which tend to involve the entire biopsy. Biopsies from a patient
with Grover's disease often show varying features mimicking more than one
of the acantholytic dermatoses and occasionally a number of patterns are
seen in a single biopsy specimen. Sometimes, a biopsy will show non-spe-
Fig. 5.71
cific features of spongiotic dermatitis. The association of both spongiosis and Warty dyskeratoma: scaly nodule on the scalp, a commonly affected site. By courtesy
acantholysis may be a useful pointer to the diagnosis of Grover's disease (see of the Institute of Dermatology, London, UK.
also Table 5.2).
in the literature.2,3 Although the cutaneous lesions are believed to be of folli-
Acantholytic dermatosis of the cular derivation, histologically similar nodules have been described affecting
the oral and vulval mucosa.8–11 The former occur most often on keratinized
genitocrural area mucosa of the palate, alveolar ridge, and gingiva.9 Subungual warty dyskera-
toma-like lesions have also been documented.12
Clinical features
In acantholytic dermatosis of the genitocrural area (papular acantholytic Pathogenesis and histological features
dermatosis of the vulvocrural area) focal dyskeratosis and/or acantho- The etiology of warty dyskeratoma is unknown, although in the past authors
lysis may present as an isolated phenomenon on the vulvocrural region have suggested an effect of actinic radiation or possibly a viral infection.
of young or middle-aged females.1–10 Lesions sometimes extend on to the Neither of these has been substantiated. There is no relationship with Darier's
thigh and perineum.5 Patients present with variably pruritic, multiple, disease. Multiple lesions have been associated with chronic renal disease.5,6
0.1–0.4-mm isolated or groups of white papules, solitary keratotic nod- Warty dyskeratoma is most probably of follicular derivation. Thus, many
ules or, less often, with erythematous or white plaques measuring up to examples appear in continuity with a dilated hair follicle and, less frequently,
1.0 cm in diameter involving the labia majora or inguinal region. More a sebaceous gland may be evident.3,6 The recent observation of positive stain-
recently, cases with histologically similar findings have been described in ing with antibodies directed towards cortex and inner root sheath provides
males, presenting on the penis, scrotum, thigh, perianal region, and in the additional support. Mucosal and subungual variants must have a different
anal canal.11,12 derivation.
Family history is invariably negative for either Darier's or Hailey-Hailey Histologically, warty dyskeratoma is composed of a widely dilated cup-
disease and, by definition, there is no evidence of similar lesions elsewhere on shaped or cystic lesion containing keratinous debris and often associated
the body.4 Two cases have developed in the presence of syringomas.1 with a hair follicle (Fig. 5.72). Superficially, the keratinous debris contains
conspicuous corps ronds and grains of Darier. The adjacent and deeper
Pathogenesis and histological features epithelium shows marked acantholysis and suprabasal villi are a prominent
The pathogenesis is unknown although it is likely that the moist environment feature (Figs 5.73 and 5.74). The underlying dermis is often infiltrated by
of the body folds is of importance. Candida albicans infection has accompa- lymphocytes and histiocytes, and sometimes plasma cells are evident.
nied a number of cases although this may have been coincidental.4,6 With the
exception of one case showing intracellular IgG and C3 staining, immuno-
fluorescence (when performed) has been negative.3–5,8
The lesions show features of hyperkeratosis, parakeratosis, acantho-
sis, and acantholysis, sometimes with dyskeratosis, resembling Darier's or
Hailey-Hailey disease. Warty dyskeratoma-like features associated with fol-
licular involvement may also be encountered.2,4 Typically, minimal or no
inflammation is present.
Warty dyskeratoma
Clinical features
Warty dyskeratoma is a peculiar hyperkeratotic, umbilicated, persistent nodule
that usually presents on the sun-exposed skin of the head and neck of middle-
aged adults, although lesions on the trunk and extremities have occasionally
been documented (Fig. 5.71).1–4 Most cases are solitary, but occasional patients
with multiple tumors have been reported, particularly in Japanese patients.3,5–7
Lesions are commonly asymptomatic but occasionally discharge and bleeding Fig. 5.72
may be encountered.2 There are conflicting data regarding gender distribution Warty dyskeratoma: typical scanning view of a cystic nodule with acantholysis.
nodule should not be confused with any of the above disorders with the
possible exception of familial dyskeratotic comedones; however, villi are not
conspicuous in the latter. There is also considerable overlap with both focal
acantholytic dyskeratosis and acantholytic acanthoma; however, in neither of
these conditions is there a deeply penetrating crateriform lesion.
Familial dyskeratotic comedones

Clinical features
Although thought to be common, familial dyskeratotic comedones have been
extremely rarely documented in the literature. To date, fewer than 10 families
have been reported.1–8 The condition is characterized by an autosomal domi-
nant mode of inheritance. Lesions develop in childhood or adolescence and
are permanent.5 Patients present with 1–3-mm diameter papules containing
small hard keratotic plugs, which on removal leave crateriform lesions resem-
bling comedones (Fig. 5.75). Cutaneous horns may also sometimes be appar-
ent (Fig. 5.76).2 Lesions are often generalized but show a predilection for
the extremities, particularly the forearms and thighs. The face, scalp, palms,
soles, and mucous membranes are typically unaffected. Some patients com-
plain of pruritus or inflammation. There is no evidence of ectodermal dyspla-
sia and systemic lesions are absent.
Fig. 5.73
The lesions are characterized by a follicle-like crateriform cystic cavity con-
Warty dyskeratoma: note
the acantholysis and villi. taining laminated hyperkeratotic and parakeratotic debris and lined by
squamous epithelium showing dyskeratosis and sometimes acantholysis at
the base (Figs 5.77, 5.78).4 Grains of Darier are typically present but corps
ronds are sparse and poorly developed. Villi, as seen in Darier's disease, are
not a feature. Hair shafts and sebaceous glands are absent.
The consistent folliculocentric nature of the eruption and absence of nail and
oral mucosal changes help to distinguish familial dyskeratotic comedones
from Darier's disease. Corps ronds, a characteristic finding in Darier's dis-
ease, are usually not prominent in familial dyskeratotic comedones. Villus
formation and well-developed corps ronds within a solitary lesion distinguish
warty dyskeratoma.
Fig. 5.74
Warty dyskeratoma: corps
ronds are conspicuous.
Oral lesions can be morphologically indistinguishable although a num-

ber of cases more likely represent focal acantholytic dyskeratosis arising
in a background of a benign trauma-related keratosis. A single case report
has documented verruciform xanthoma-like features within a typical oral
lesion.13 Fig. 5.75
Familial dyskeratotic
Differential diagnosis comedones: numerous
comedones are present
Although there are histological similarities with familial dyskeratotic come- on the penis and foreskin.
dones, Darier's disease, Hailey-Hailey disease, and Grover's disease, deeply By courtesy of B.J.
penetrating crateriform lesions with villus formation are not associated with Leppard, MD, Royal South
these entities. In addition, the clinical findings of a solitary umbilicated Hants Hospital, UK.
Fig. 5.76
Familial dyskeratotic Fig. 5.78
comedones: a small Familial dyskeratotic
cutaneous horn is seen comedones: note the
arising on the scrotum. By superficial dyskeratosis.
courtesy of B.J. Leppard, By courtesy of B.J.
MD, Royal South Hants Leppard, MD, Royal South
Hospital, UK. Hants Hospital, UK
Perforating folliculitis presents in adults and shows a predilection for the

extremities. It is characterized by a crateriform lesion containing a distorted
and often curled-up hair shaft.
Acantholytic acanthoma
Clinical features
Acantholytic acanthoma is a common entity consisting of a solitary, usually
asymptomatic, keratotic papule or plaque, 0.5–1.5 cm in diameter, often
with overlying scale/crust. It usually presents on the trunk, arm or neck
and is clinically thought to be a seborrheic keratosis or actinic keratosis.1–5
A case with central umbilication reminiscent of molluscum contagiosum
has also been described.6 Very occasionally multiple lesions have been docu-
mented.7 Some patients report pruritus. Patients are usually elderly (median
Fig. 5.77 age 60 years) and there is a predilection for males (2:1).2,4 Lesions are not
Familial dyskeratotic seen about the head, palms, and soles and the mucous membranes appear
comedones: this section to be spared.2
comes from the edge of a
lesion. Note the dell with Pathogenesis and histological features
associated hyperkeratosis
The pathogenesis of this lesion is unknown. Although one case has been doc-
and parakeratosis. The
acanthosis is in part due
umented in association with immunosuppression, it is likely that this was
to the oblique angle of the coincidental.7
cut. By courtesy of B.J. Diagnosis is one of exclusion and depends upon the solitary nature of the
Leppard, MD, Royal South lesion. The histological features are those of hyperkeratosis, acanthosis, and
Hants Hospital, UK. papillomatosis accompanied by acantholysis affecting all or any layer of the
epidermis (Figs 5.79 and 5.80).1 Dyskeratosis may be evident. A perivascular
lymphohistiocytic chronic inflammatory cell infiltrate, sometimes with occa-
Diffuse familial comedones differ by the absence of dyskeratosis.9,10 sional eosinophils, may be present in the superficial dermis.
Familial dyskeratotic comedones may also be mistaken for Kyrle's and
Flegel's diseases: Differential diagnosis
• Kyrle's disease typically presents on the extensor aspect of the lower In acantholytic seborrheic keratosis the acantholysis is typically focal and
extremities and presents in adulthood. There is no familial incidence. the lesion elsewhere shows the typical features of horn cysts and squamous
Histologically, it is characterized by transepidermal elimination of eddies.8 Darier's disease, acantholytic dermatosis of the genitocrural area,
parakeratotic and inflammatory debris. There is no dyskeratosis. warty dyskeratoma and pemphigus, Hailey-Hailey disease, and Grover's
• Flegel's disease typically presents in older adults and is characterized by disease may show similar histological features but are easily distinguished
epidermal atrophy, interface change, and dyskeratosis. A keratin-filled clinically. Acantholytic actinic keratosis also shows dysplasia in addition to
crateriform lesion is absent. acantholysis.
Histological characteristics include regular epidermal acanthosis showing

acantholytic dyskeratosis with grains and corps ronds.1,2 Acantholytic
acanthosis is typically confluent, affecting varying levels of the epidermis.
Occasionally, it may be confined to the granular and corneal layers or it
may be nonconfluent and multifocal.1 Cup-shaped endophytic growth and
follicular involvement are not observed.
Acantholytic dyskeratotic acanthoma differs from acantholytic acanthoma by
the presence of marked dyskeratosis. Focal acantholytic dyskeratosis shows
identical histological features but is an incidental finding rather than a clini-
cally distinct lesion. Warty dyskeratoma is characterized by its cup-shaped
and endophytic growth. Pemphigus, Darier's disease, and Grover's disease
differ in their clinical presentation.
Focal acantholytic dyskeratosis

Clinical features
Fig. 5.79 By definition, this is an incidental histological feature without a clinical
Acantholytic acanthoma: low-power view showing hyperkeratosis, parakeratosis, correlate.
intraepidermal vesiculation, and multiple foci of acantholysis.
Focal acantholytic dyskeratosis is a descriptive histopathological term referring
to the finding of Darier-like features within the epidermis overlying or adja-
cent to an otherwise unrelated pathological lesion.1,2 The pathogenesis is not
known. The histological features comprise hyperkeratosis, parakeratosis with
suprabasal cleft formation, acantholysis, and dyskeratosis.3 These changes
may be seen in the overlying or adjacent epithelium in a variety of lesions,
such as basal cell carcinoma, melanocytic nevi, chondrodermatitis nodularis
helicis, malignant melanoma, dermatofibroma, and as part of an epidermal
nevus (Fig. 5.81). Focal acantholytic dyskeratosis has recently been described
in a patient with pityriasis rubra pilaris.4 It is important to recognize this as
an incidental finding to avoid misdiagnosis as Darier's disease.
Fig. 5.80
Acantholytic acanthoma: high-power view showing acantholysis and dyskeratosis.
Acantholytic dyskeratotic acanthoma

Clinical features
Acantholytic dyskeratotic acanthoma is a recently described entity with
clinical features similar to acantholytic acanthoma. There is a predilection for
the trunk of middle-aged to elderly adults with an equal gender distribution.1
They are solitary lesions characteristically measuring less than 1 cm with a
clinical impression of basal cell carcinoma, actinic keratosis or squamous cell
carcinoma in situ.1,2
Fig. 5.81
Focal acantholytic dyskeratosis: this example showing the changes of Darier's disease
Pathogenesis and histological features was an incidental finding adjacent to a completely unrelated lesion. There was no
The pathogenesis of acantholytic dyskeratotic acanthoma is unknown. clinical evidence of Darier's disease.
Chapter
Spongiotic, psoriasiform and
6 pustular dermatoses
See
for references and
additional material
ECZEMATOUS DERMATITIS 180 Actinic prurigo 194 Inflammatory linear verrucous epidermal
Eosinophilic spongiosis 194 nevus 214
Eczema – general considerations 180 Erythroderma 194
Sulzberger-Garbe syndrome 195
Bazex syndrome 215
Endogenous dermatitis 180
Atopic dermatitis 180 Vein graft site dermatitis 195
Papular acrodermatitis of childhood 195 PUSTULAR DERMATOSES 215
Seborrheic dermatitis 182
Discoid dermatitis (nummular eczema) 183 Pityriasis rosea 196 Pustular drug reactions 215
Hand eczema (dyshidrotic eczema, palmoplantar Juvenile plantar dermatosis 199
eczema, pompholyx) 183 Miliaria 199 Subcorneal pustular dermatosis 215
Autosensitization (Id) reaction 184 Fox-Fordyce disease 200 Toxic erythema of the neonate 217
Transient acantholytic dermatosis with prominent
Exogenous dermatitis 184 eccrine ductal involvement 200 Infantile acropustulosis 217
Contact dermatitis 184
Infective dermatitis 186 Transient neonatal pustular melanosis 218
PSORIASIFORM DERMATOSES 201
Asteatotic dermatitis 186 Eosinophilic pustular folliculitis of
Lichen simplex chronicus 188 Psoriasis 201 infancy 218
Nodular prurigo and prurigo nodule 190
Reiter's syndrome 211
Stasis dermatitis and acroangiodermatitis 192
Pityriasis alba 193 Pityriasis rubra pilaris 211
Eczematous dermatitis
This chapter discusses a number of disorders under the rubric eczematous der- For instance, in pompholyx (acute vesicular dermatitis of the hands and
matitis, also called eczema and spongiotic dermatitis. The term eczema refers to feet), the fluid is trapped beneath the thickened horny layer as small tense
a group of disorders that share similar clinical and histological features but may white blisters resembling rice grains. In other regions where the skin is loosely
have different etiologies. Some object to a diagnosis of eczema since it does not attached, as on the eyelids, scrotum, and backs of hands, tissue edema is often
reflect a specific disease but is a non-specific term that simply can be used for any marked.
clinical lesion that exhibits spongiosis, which clinically manifests as moist, often Eczematous dermatitis has two major etiological classifications:
‘bubbly’ papules or plaques superimposed on an erythematous base. The patho- • endogenous dermatitis, related to major constitutional or hereditary
genesis of some forms is poorly understood. The histopathologist usually can- factors,
not render a more specific diagnosis other than ‘spongiotic dermatitis consistent • exogenous dermatitis, involving environmental factors.
with eczematous dermatitis’ and precise classification within the differential
diagnosis of spongiotic dermatitis is often not possible. For these reasons, this
class of disorders is discussed as a group. Distinguishing clinical, pathogenetic, Endogenous dermatitis
and histological features are presented in the appropriate sections.
Atopic dermatitis
Eczema – general considerations Clinical features
Eczema encompasses a number of disorders with variable etiologies and Although atopic (infantile or flexural) dermatitis may begin at any age, it usu-
clinical manifestations and is one of the most common complaints of patients ally commences from about the sixth week onwards. It is characterized by a
visiting dermatology clinics. chronic, relapsing course.1 In the infantile phase lesions are present mainly
The earliest clinical lesions are erythema and aggregates of tiny pruritic ves- on the head, face, neck, napkin area, and extensor aspects of the limbs (Fig.
icles, which rupture readily, exuding clear fluid, and later become encrusted 6.3). As the patient grows older and enters childhood, the eruption shifts to
(Fig. 6.1). More chronic lesions become scaly and thickened (lichenification), the flexural aspects of the limbs. Chronic atopic cheilitis may also be evident.1
resulting in lichen simplex chronicus (Fig. 6.2). Lichenification occurs if the Pruritus is intense and constant scratching and rubbing leads to lichenifica-
skin is continually scratched or rubbed as, for example, in atopic dermatitis. tion and frequent bouts of secondary bacterial infection (Fig. 6.4).2,3 Atopic
Therefore, the clinical features of dermatitis depend upon the duration of the eczema is commonly associated with dry skin (xerosis). Vesiculation is uncom-
lesions, site(s) involved, and the amount of scratching. mon. There is an increased risk of dermatophyte and viral infections.1
Fig. 6.1 Fig. 6.3

Eczema: this is a plaque of discoid eczema. Small vesicles are present at the edge Atopic dermatitis: lesions on the face and trunk are particularly seen in infants and
of the lesion. By courtesy of the Institute of Dermatology, London, UK. young children. This child has bilateral involvement of the cheeks. By courtesy of
J. Dayrit, MD, Manila, The Philippines.
Fig. 6.4
Atopic dermatitis: these crusted, exudative and infected lesions with lichenification are
characteristic. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
patients with atopy; this does not appear to be due to a response to an envi-
ronmental antigen.7 Atopic dermatitis is a multifactorial disease. Its pathogen-
Fig. 6.2 esis is complex and, despite recent advances, only incompletely understood.
Lichenification: pronounced pebbly lichenification on the dorsum of the hand of a In addition to a genetic susceptibility, the main elements responsible for the
patient with atopic dermatitis. Bizarre forms, as seen here, are not uncommon in initiation and maintenance of the disease state include abnormal skin barrier
black children. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. function, abnormal activity of the innate and adaptive immune systems, as
well as environmental factors and infectious agents.7–15
Since patients with atopic dermatitis often have a personal or family his-
The disease improves during childhood and, in over 50% of cases, clears tory of asthma or allergies, a genetic predisposition to the disease has long
completely by the early teens. Approximately 75% of patients with atopic been suspected. Recent studies have demonstrated that loss-of-function
dermatitis have a family history of atopy and up to 50% have associated mutations in the FLG gene, encoding the cornified envelope protein pro-
asthma or hay fever.4,5 The condition typically worsens in the winter months. filaggrin, are present in a significant subset of patients with atopic derma-
It is associated with an increased incidence of contact dermatitis, particularly titis and represent the highest risk factor for development of the disease.16
affecting the hand.6 Other features that may be seen include ichthyosis Together with involucrin and loricrin, filaggrin is a major constituent of the
(50%), nipple eczema, conjunctivitis, keratoconus, bilateral anterior cata- cornified envelope during terminal keratinocyte differentiation responsible
racts, sweat-associated itching, wool intolerance, perifollicular accentuation, for intact epidermal barrier function. Disruption of the skin barrier function
food intolerance and white dermatographism.5 Infraorbital folds (Dennie- appears to be of particular significance in the initiation and early stages of
Morgan folds) are said to be characteristic of atopic dermatitis, particularly the disease. Nevertheless, 40% of patients with FLG mutations never develop
when double.1 atopic dermatitis and FLG mutations have been identified in only 14–56%
of patients, indicating that other factors may also play an important role in
Pathogenesis the pathogenesis of the disease. In addition to the cornified envelope, epider-
Atopy is defined as a genetically determined disorder encompassing dermati- mal barrier function is maintained also by other factors such as proteases
tis, asthma, and hay fever. It is associated with excess immunoglobulin E (IgE) and protease inhibitors as well as direct keratinocyte–keratinocyte interac-
antibody formation in response to common environmental antigens. A subset tion. Increased expression of kallikrein-related peptidases has been observed
of patients with ‘intrinsic atopic dermatitis’ represents perhaps 10–30% of in the stratum corneum in atopic dermatitis and in one study a 4-bp insertion
182 Spongiotic, psoriasiform and pustular dermatoses
into the 3′ untranslated region of KLF7 leading to increased levels of this with atopic dermatitis is colonized with Staphylococcus aureus. In contrast,
protease was identified in patients with atopic dermatitis.13,17,18 However, this S. aureus is found on the skin of only a minority of control subjects.33 Disease
finding has not been substantiated in further studies.13 Linkage has also been severity has been shown to correlate with the presence of toxigenic S. aureus.34
demonstrated to the gene SPINK5, encoding the serine protease inhibitor It is thought that staphylococcal superantigens SEA and SEB (staphylococcal
LEKTI. LEKTI, expressed at the granular cell layer, is an important inhibi- enterotoxins A and B, respectively) activate T cells.34–37 In a study of children
tor of the kallikrein-related peptidases KLK5 and KLK7 and is responsible with atopic dermatitis, there was a correlation of disease severity and pres-
for controlling desquamation. Linkage to SPINK5 is, however, significantly ence of SEA and SEB antibodies.35 Recently, application of SEB was shown to
weaker than to profilaggrin.13 A further mechanism involved in skin barrier be associated with T-cell activation in both normal and atopic patients.38 In
function is the presence of intercellular junctions, and recent data have dem- summary, there is mounting evidence that staphylococcal superantigens play
onstrated reduced expression of the tight junction protein claudin-1 in atopic a role in the symptomatology of atopic dermatitis. Whether superantigens
dermatitis.15 play a key role in the development of disease or simply exacerbate symptoms
Many lines of evidence also implicate an abnormal immune response as in atopic patients requires further study.
pivotal in the pathogenesis of atopy. It is interesting to note that atopy is cured
by bone marrow transplantation in patients with Wiskott-Aldrich syndrome,
an immunological disorder characterized by susceptibility to infection and
Seborrheic dermatitis
thrombocytopenia, in addition to eczematous dermatitis.19 Wiskott-Aldrich
syndrome shows an X-linked recessive pattern of inheritance and is charac- Clinical features
terized by depletion of nodal and circulating T lymphocytes. Contrariwise, Seborrheic dermatitis is a common dermatosis which affects up to 1–3% of
patients without a prior history of atopy may develop atopic disease follow- the population.39–41 There is a male predominance. It presents in infants, with
ing transplantation of bone marrow from an atopic individual.20 a second peak affecting adults.42 There is often a family history of the disease.
Patients with atopic dermatitis have an abnormal immune reaction to a It particularly affects those areas where sebaceous glands are most numerous,
variety of environmental antigens leading to production of IgE antibodies i.e., the scalp, forehead, eyebrows, eyelids, ears, cheeks, presternal and inter-
and a T-cell response.9,21–23 There is evidence that certain subpopulations of scapular areas (Figs 6.5, 6.6).43 Occasionally, the flexural regions are affected
T cells selectively circulate to and perform immune surveillance for the skin (intertrigo). Often the lesions of seborrheic dermatitis are sharply margin-
and lymph nodes that drain cutaneous sites.9,23 This subset of lymphocytes ated, dull red or yellowish, and covered by a greasy scale.43 They are therefore
is characterized by a unique immunophenotype and is defined by expression easily confused with psoriasis.
of cutaneous lymphocyte antigen (CLA). In patients with atopic dermatitis, Dandruff and cradle cap are also sometimes included within the spectrum
antigens such as dust mites and bacteria activate CLA T cells, resulting in the of seborrheic dermatitis.
production of cytokines, which stimulate eosinophils to produce IgE, which, Seborrheic dermatitis is one of the most common dermatoses seen in
in turn, promotes mast cells and basophils to release cytokines and chemot- patients with acquired immunodeficiency syndrome (AIDS). Seborrheic der-
actic factors in what has been termed the intermediate-phase response.8 The matitis has also been associated with stress and neurological disorders includ-
so-called late-phase reaction is characterized by migration of eosinophils, ing Parkinson's disease, syringomyelia, and trigeminal nerve injury.44
lymphocytes, histiocytes, and neutrophils from the circulation into the der-
mis and epidermis. Pathogenesis
Factors released by the various cells present in the dermis certainly play
The precise pathogenesis of this condition is unknown. Surprisingly, and in
a role in the generation of the clinical appearance and induction of pruritus,
spite of the distribution (and the name) of the disease, sebaceous gland activ-
leading to scratching and rubbing. In the early phase, mechanical trauma and
ity and sebum composition appear to be normal.44
skin barrier disruption lead to release of proinflammatory cytokines (IL-1α,
Seborrheic dermatitis is associated with heavy colonization of the skin by
IL-1β, TNF-α, GM-CSF) which activate cellular signaling and induce expres-
the lipophilic yeast Malassezia furfur (Pityrosporum ovale) while more recent
sion of vascular endothelial cell adhesion molecules after receptor binding
data have identified a predominance of Malassezia restricta and Malassezia
to endothelial cells.15,24,25 These steps subsequently initiate transvascular
globosa.41,45–50 Although many workers in the field believe this to be of etio-
migration of inflammatory cells.8,26 Chemokines released by inflammatory
logical importance, an almost equal number are unconvinced. The body of
cells attract a more directed cellular immune response. In particular, CCL27,
evidence favoring a significant relationship relates to the successful treatment
CCL22, and CCL17 are increased in patients with atopic dermatitis and levels
correlate with disease activity.14,25 Disease onset is related to TH2 cytokines
IL-4, IL-13, and IL-31 while disease maintenance (chronic phase) is associate
dwith TH1 cytokines. Other T cells, such as Treg and TH17, are also present
in cutaneous lesions but their precise role is uncertain.14 The demonstration
that squamous cells in patients with atopic dermatitis show increased produc-
tion of GM-CSF, a cytokine thought to play a role in Langerhans/dendritic
cell function, further suggests that a keratinocyte defect may be involved in
the pathogenesis of atopy.27
Another area of interest has been the role of superantigens in the patho-
genesis of atopy as well as other immunologically mediated cutaneous and
noncutaneous disorders.28–33 Although superantigens have been implicated in
the pathogenesis of psoriasis and Kawasaki's disease, in addition to atopic
dermatitis, their precise role in these and other diseases is not well understood
and is controversial.29,30 Further research is necessary to clarify the role of
superantigens in immunologically mediated diseases.
Superantigens are microbiological (viral, bacterial, fungal) toxins that
stimulate CD4+ T cells. They bind to T-cell receptors and to the class II major
histocompatibility complex (MHC), thus stimulating lymphocyte prolifer-
ation, activation and release of cytokines, as well as T-cell-mediated tissue
damage. They may also stimulate B cell activation. Superantigens are power-
ful mediators of the immune system by virtue of their ability to stimulate a Fig. 6.5
large population of T cells in a non-specific manner. Staphylococcal superan- Seborrheic dermatitis: there is diffuse erythema and scaling of the scalp. By
tigens have, in particular, been an area of research.32 The skin of most patients courtesy of B. Al Mahmoud, MD, Doha, Qatar.
Fig. 6.6 Fig. 6.8

Seborrheic dermatitis: note the marked scaling. By courtesy of the Institute of Discoid eczema: the lesion is sharply defined and there is a pronounced scale.
Dermatology, London, UK. By courtesy of the Institute of Dermatology, London, UK.
of seborrheic dermatitis with antifungal therapy.39,40,51 Whether this implies a

causal relationship or merely an exacerbating factor is, however, uncertain.
Discoid dermatitis (nummular eczema)

Clinical features
The presence of single or multiple pruritic, coin-shaped, erythematous
plaques with vesiculation, particularly involving the lower legs, forearms,
and backs of hands (Figs 6.7–6.9) characterize this chronic form of derma-
titis.52 The absence of a raised border clinically distinguishes it from ring-
worm.52 There are two peak ages of onset: it affects young women (15–30
years of age) and middle-aged adults of both sexes. The disease tends to
chronicity.
Fig. 6.9
Discoid eczema: there is
extensive involvement
of the leg. A sharply
demarcated erythematous
and scaly circular lesion
is present just below the
knee. By courtesy of R.A.
Marsden, St George's
Pathogenesis
The pathogenesis is poorly understood. A participatory role for organisms in
the pathogenesis has been suggested but not been widely accepted.53 Discoid
dermatitis may follow irritants such as soap, acids or alkalis (Fig. 6.10).52
Sometimes it may be a manifestation of atopy and, occasionally, it develops
as a consequence of nickel, chromate or cobalt allergy.54,55 Generalized dis-
ease has also been documented in the setting of interferon alpha-2b plus riba-
virin treatment for hepatitis C infection.56
Fig. 6.7
Discoid eczema:
circumscribed,
Hand eczema (dyshidrotic eczema,
erythematous lesions palmoplantar eczema, pompholyx)
on the forearm, a
characteristic site. By
Clinical features
of Dermatology, London, Hand eczema is characterized by a recurrent pruritic vesicular eruption of
UK. the palms, soles or digits. Because of the increased thickness of the keratin
Fig. 6.10 Fig. 6.12

Discoid eczema: lesions localized to the fingers most often represent a contact Hand eczema: more chronic example showing marked scaling. From the collection
irritant reaction. By courtesy of R.A. Marsden, St George's Hospital, London, UK. of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Autosensitization (Id) reaction

Clinical features
On occasion, patients will develop generalized spongiotic dermatitis in
response to a dermatosis or infection at a distant site. The eczematous derma-
titis resolves if the underlying infection or specific dermatosis is successfully
treated. This phenomenon has also been designated an autoeczematization
or Id reaction. The lesions that characterize the Id reaction may be a local-
ized pompholyx-like eczematous dermatitis of the hands and feet or scattered
papules on the trunk and limbs.65–69 Disorders that may be associated with
the Id reaction include fungal infection (e.g., dermatophyte infection), scabies
infestation, molluscum contagiosum, tick bite, pediculosis capitis, and bacte-
rial and mycobacterial infections.65–69 A generalized nummular dermatitis has
been reported in association with localized dental infection.70
Pathogenesis
The pathogenesis of the Id reaction is poorly understood but some data sug-
gest that an abnormal T-cell-mediated immune response directed against skin
antigens is responsible for this curious disorder.71
Fig. 6.11
Hand eczema: tense yellow vesicles are present. By courtesy of B. Al Mahmoud, MD, Exogenous dermatitis
Doha, Qatar.
Contact dermatitis
layer at these sites, the vesicles appear as small pale papules before rupturing This form of dermatitis is due to external agents and is divided into two vari-
(Figs 6.11, 6.12). Occasionally, frank bullae can form. With the passage of ants: allergic contact and irritant contact.
time, the affected parts may show scaling and cracking. The nails sometimes
become dystrophic, with discoloration and transverse ridging.57 In the major- Allergic contact dermatitis
ity of cases the cause is unknown, although heat or psychological stress may Allergic contact dermatitis is an idiosyncratic cell-mediated immunologi-
precipitate an attack.57 In some patients there is a personal or family history cal reaction to an environmental allergen, which may be present in very
of atopy or coexisting tinea pedis. Rubber, latex, chromium, cobalt or nickel low concentration. Common examples seen in clinical practice include
sensitivity may be the trigger.58–62 The condition can be exacerbated by heat sensitivity to nickel (found in items such as jewelry, buttons, watches,
and, rarely, it is photoinduced.63 and suspenders), constituents of synthetic rubber (e.g., thiuram in rubber
Pompholyx is often associated with hyperhidrosis.58 Females are affected gloves), primula, poison ivy, topical medicaments (e.g., neomycin, anti-
slightly more often than males and patients are predominantly in the second histamines, local anesthetics), and chromates found in cement and leather
to fifth decades.59 A familial autosomal dominant form has been reported (Figs 6.13–6.15).72–82
where the candidate gene has been mapped to chromosome 18q22.1- Dinitrochlorobenzene (DNCB) is a potent contact sensitizer and this is
18q22.3.64 used as a test of cell-mediated immunity.83,84
A growing understanding of allergic contact dermatitis has emerged over
Pathogenesis the last decade with the preponderance of evidence pointing to a T-cell-
The pathogenesis is obscure. It has been noted that serum IgE levels are often mediated hypersensitivity reaction.3,85–88 It is thought that antigens causing
raised.58 allergic contact dermatitis are often unstable (haptens) and need to bind to
Exogenous dermatitis 185
Fig. 6.13 Fig. 6.15

Contact dermatitis: this early erythematous predominantly macular eruption Contact dermatitis: a
developed as a reaction to fabric softener. By courtesy of J. Dayrit, MD, Manila, severe reaction to poison
The Philippines. ivy. From the collection
UK.
Occasionally, exposure to strong haptens may result in the development

of allergic contact dermatitis in previously unsensitized individuals (primary
allergic contact dermatitis).89
Ingested or inhaled allergens in a person who has been previously sen-
sitized by cutaneous absorption may result in a clinical picture similar to
allergic contact dermatitis (e.g., ingested nickel, chromium or cobalt may
result in the appearances of hand eczema).93 Much less commonly, systemic
allergic contact dermatitis may be histologically associated with an erythema
multiforme-like eruption, vasculitis or urticarial morphology.93 This is thought
to result from systemic exposure of a hapten via hematogenous transport to
the skin.94 It may occur with or without prior sensitization, and a large num-
ber of drugs have been implicated in the pathogenesis.94
Fig. 6.14
Contact dermatitis: bilateral involvement in a patient using a watch on the right Irritant contact dermatitis
wrist and a leather bracelet on the left wrist. From the collection of the late N.P.
Irritant contact dermatitis, which is much more common than allergic con-
Smith, MD, the Institute of Dermatology, London, UK.
tact dermatitis, follows exposure to physical or chemical substances capable
of direct damage to the skin. Mechanisms of damage are variable and include
epidermal host proteins.3,85 These hapten–protein interactions are formed via keratin denaturation, removal of surface lipids and water-holding substances,
covalent binding of electrophilic residues of the chemical with amino acids, damage to cell membranes, and/or direct cytotoxic effects.95 Acute irritant
especially cysteine.89–91 In contrast, metal ions, such as nickel, are thought dermatitis usually results from a relatively short single exposure to a potent
to form noncovalent protein–metal chelate complexes.89 In the sensitization/ irritant, such as strong acid or alkali, whereas chronic cumulative insult or
initiation phase of the disease, hapten-specific T cells are generated in lymph ‘wear and tear’ dermatitis is due to more prolonged contact with one or more
nodes after the initial contact of the skin with a potent hapten.91 Langerhans weaker irritants, for example, soap and water, detergents or industrial oil and
cells in skin and dendritic cells in lymph nodes process antigen and stimulate plants (Fig. 6.16).96–100
appropriate naive CLA T cells. CLA-positive T cells are a subset of T cells Most forms of occupational dermatitis of the hands, including ‘house-
that express a skin-selective homing receptor and perform immune surveil- wives’ and ‘wedding ring’ dermatitis are of the irritant contact type. A diag-
lance for the skin and lymph nodes that drain cutaneous sites.92 CLA-positive nosis of contact dermatitis is made from the history and distribution of
T cells proliferate when stimulated by the appropriate antigen or antigen– lesions and, in the case of allergic dermatitis, is confirmed by patch testing
protein complex. The number of CLA-positive memory T cells increases with to the suspected allergen. Although both forms of contact dermatitis tend to
repeated exposures to its antigen.3,85 When the patient is exposed to the anti- be confined to exposed areas, the reaction may eventually spread to involve
gen, the elicitation phase, the CLA-positive T cells are activated and release nonexposed sites and can persist even when the causative agent is removed
cytokines which lead to the immune reaction responsible for the clinical and from the environment.
histological features associated with allergic contact dermatitis.87 CD8+ T cells Similar to atopic dermatitis, loss-of-function mutation in the FLG gene,
appear to be the main effector cell in the elicitation phase.89 Keratinocytes encoding filaggrin, may confer an increased susceptibility to chronic irritant
are also thought to play a role through the release of cytokines after hapten contact dermatitis evoking an underlying skin barrier defect in the pathogen-
exposure and binding.88 esis of the disease.101
Fig. 6.16 Fig. 6.18

Contact dermatitis: there is a superimposed pustular element due to an infection Asteatotic dermatitis: these typical appearances are the result of scaling and
in this patient with a contact reaction to a domestic antiseptic. By courtesy of B. Al fissuring. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.
Mahmoud, MD, Doha, Qatar.
Infective dermatitis ity, all of which tend to dry the skin.111 The affected regions are inflamed and
criss-crossed by scaly lines and superficial fissures (Fig. 6.18). Asteatotic der-
Infective dermatitis is a severe chronic and recurrent eczematous dermati- matitis may be associated with internal malignancy, including lymphoprolif-
tis showing pronounced exudation and crusting and presenting in children erative disorders and solid tumors.112–115
with human T-cell lymphotropic virus type 1 (HTLV-1) infection.102–105 Adult
onset is exceptional.106,107 The disease has a predilection for the scalp, flex- Pathogenesis and histological features
ures, the ears and feet, and sometimes around wounds and ulcers (Fig. 6.17),
The histopathological features of spongiotic dermatitis include both dermal
and is frequently associated with Staphylococcus aureus and beta-hemolytic
and epidermal changes. Their relative proportions vary to some extent with
Streptococcus infection of the skin and nasal vestibule. It occurs in regions
the subtype, but perhaps more importantly, with the stage of evolution of the
where HTLV-1 is endemic. It has frequently been reported in Jamaica, while
disease. It is essential not to consider the changes of spongiotic dermatitis as
presentation in Japan appears relatively rare.108 Development of the disease
static: different features are seen at different stages.116–118 Attempting to dis-
may be associated with a defective immune system and may be a risk factor
tinguish the various clinical subtypes based on histological features alone is
for the development of other HTLV-1-related diseases such as adult T-cell leu-
generally futile. Instead, once the disorder has been recognized as spongiotic
kemia and tropical spastic paraparesis.109,110
in nature, clinical examination is a much more satisfactory method of deter-
mining the particular variant.
Asteatotic dermatitis The histological hallmark of spongiotic dermatitis is the presence of inter-
Commonly seen in the elderly, particularly in winter and in those with minor cellular edema or spongiosis (L., Gr. spongia, sponge). Slight degrees of intra-
degrees of ichthyosis, asteatotic dermatitis (eczema craquelé) may be precipi- cellular edema may also be evident but may easily be overlooked. In the early
tated by excessive washing, exposure to detergents, cold winds or low humid- stages of development, spongiosis results in widening of the intercellular
spaces, rendering the intercellular bridges conspicuous (Fig. 6.19). Further
accumulation of fluid leads to the eventual development of an intraepidermal
vesicle. A common finding in association with the intercellular edema is lym-
phocytic infiltration of the epidermis (exocytosis). In severe contact irritant
dermatitis, the epidermis may be infiltrated by large numbers of neutrophil
polymorphs in association with necrotic keratinocytes.119 In addition, such
reactions may be accompanied by dermoepidermal separation resulting in a
vesicle or blister. The lesions very often become traumatized and may show
marked crusting.
Spongiotic dermatitides not uncommonly become infected with bacterial
or fungal organisms. Superimposed infection may dramatically alter the his-
tological picture by causing marked acute inflammation with subepidermal,
intraepidermal, and subcorneal pustules. Such changes may dominate the his-
tological picture and obscure the underlying spongiotic dermatitis. Use of
stains for organisms – Gram, periodic acid-Schiff (PAS) – or cultures are nec-
essary to evaluate for infection.
Concomitant with these changes are varying degrees of epithelial prolif-
eration, ranging from mild acanthosis in early acute dermatitis to marked
psoriasiform epidermal hyperplasia in chronic variants. Parakeratosis is
frequently seen overlying spongiotic foci, while hyperkeratosis is a usual
Fig. 6.17 accompaniment of chronic spongiotic dermatitis that has been scratched or
Infective dermatitis: lesions affecting the foot web spaces are often due to rubbed (lichenification).
staphylococci or streptococci and are associated with excess sweating. By The dermis is often congested and edema is usually marked in active
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. lesions. The vessels of the superficial vascular plexus are surrounded by a
Fig. 6.19
Dermatitis: the earliest visible manifestation of intercellular edema is widening of
the intercellular spaces with accentuation of the intercellular bridges.
Fig. 6.21
Acute dermatitis:
the vesicle contains
mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and lymphocytes and
occasional eosinophils or neutrophils. The degree and composition of der- occasional eosinophils.
mal inflammation is highly variable. Eosinophils may be numerous in allergic
contact dermatitis.119
Traditionally, spongiotic dermatitis is subclassified histologically into
acute, subacute, and chronic variants:
• In acute lesions, vesiculation and blister formation may be seen (Figs
6.20–6.22).
• Acanthosis and spongiosis, often with vesiculation, also characterize
subacute spongiotic dermatitis (Fig. 6.23).
• In chronic spongiotic dermatitis, although spongiosis is evident, it may be
subtle, and vesicles are uncommon. Epithelial acanthosis is marked and
often shows a psoriasiform pattern (Fig. 6.24).
Systemic contact dermatitis may be associated with the features of vascu-
litis or erythema multiforme.120 As with other forms of spongiotic dermatitis
the histological appearances can be divided into acute, subacute, and chronic
forms. Spongiosis is more conspicuous in the acute phase although it is never
marked. In contrast, the epidermal hyperplasia becomes more conspicuous
and psoriasiform towards the chronic end of the spectrum.
Fig. 6.22
Acute dermatitis: in contact reactions, Langerhans cell-rich vesicles are often
present, as shown in this picture. These should not be mistaken for the Pautrier
microabscesses of mycosis fungoides.
The features of seborrheic dermatitis are often non-specific and subtle. It

is characterized by hyperkeratosis and parakeratosis, the latter particularly
related to hair follicles and typically associated with neutrophil exocytosis
(Figs 6.25, 6.26). Yeasts may sometimes be found in the stratum corneum
particularly if PAS stained sections are examined. Epidermal acanthosis with
thickened rete ridges is present and often marked in chronic lesions. It is,
however, somewhat irregular in contrast to the uniform hyperplasia charac-
teristic of psoriasis. Variable spongiosis with lymphocyte exocytosis is com-
mon. The dermis may be edematous and mild vascular dilatation is usually
seen. A mixed inflammatory cell infiltrate consisting of lymphocytes, histio-
Fig. 6.20 cytes, and small numbers of eosinophils surrounds the superficial vascular
Acute dermatitis: fluid-filled vesicle due to intense spongiosis. plexus.
Fig. 6.23
Subacute dermatitis showing patchy parakeratosis, crusting, marked acanthosis Fig. 6.25
with considerable elongation (and fusion) of the epidermal ridges, and focal Seborrheic dermatitis:
spongiotic vesiculation. The dermis contains an intense lymphocytic infiltrate. in this field, there is
perifollicular psoriasiform
hyperplasia. Parakeratosis
is present on either side
of the follicular ostium.
Fig. 6.24
Chronic dermatitis (lichenification): there is hyperkeratosis with hypergranulosis
and psoriasiform hyperplasia. The papillary dermis is fibrosed and there is a patchy
chronic inflammatory cell infiltrate.
Although spongiosis is a characteristic feature of spongiotic dermatitis, it Fig. 6.26
is also encountered in many other inflammatory dermatoses (Table 6.1), Seborrheic dermatitis:
particularly superficial dermatophytoses. A diagnosis of spongiotic der- there is parakeratosis, and
matitis should never be made until a stain for fungus (e.g., PAS reaction) occasional neutrophils are
has been performed to exclude this possibility. This is especially impor- present.
tant since the common treatment of spongiotic dermatitides – topical
corticosteroids – would exacerbate a fungal infection (tinea incognito)
(Figs 6.27–6.29).
condition (Fig. 6.30).1 Lichenification is an identical process in which an
underlying intensely pruritic dermatosis such as atopic eczema is present.2
Lichen simplex chronicus Dermatophyte infections, stasis dermatitis, and chronic allergic contact
dermatitis may also predispose to lichenification. Picker's nodules and nodu-
Clinical features lar prurigo are related conditions (see below).3
The term lichen simplex chronicus (circumscribed neurodermatitis) refers to Patients present with profound pruritus and localized scaly plaques with
the development of localized areas of thickened scaly skin complicating pro- accentuated skin markings described as resembling tree bark. There is a pre-
longed and severe scratching in a patient with no underlying dermatological dilection for females, and young to middle-aged adults are predominantly
Table 6.1
Conditions featuring spongiosis
• Pityriasis rosea
• Superficial fungal infections
• Herpes gestationis (early lesions)
• Polymorphic eruption of pregnancy
• Erythema multiforme
• Miliaria rubra
• Erythema annulare centrifugum
• Guttate parapsoriasis
• Acral papular eruption of childhood
• Eczema
• Lichen striatus
• Insect-bite reaction
• Prurigo nodularis
Fig. 6.29
Spongiotic superficial dermatophyte infection: numerous fungal hyphae are seen in
this PAS-stained section.
Fig. 6.27
Spongiotic superficial dermatophyte infection: there is marked subcorneal
vesiculation.
Fig. 6.30
Lichen simplex chronicus:
thick, scaly erythematous
plaques are present on
the shins, a commonly
affected site. By courtesy
London, UK.
Histological features and pathogenesis

Although the etiology and pathogenesis of lichen simplex chronicus remains
elusive, psychological factors may play an important role.4,5 Recent data fur-
ther suggest that an underlying neuropathy may be of importance in at least
a subset of patients.6
Fig. 6.28 Histologically, lichen simplex chronicus is characterized by marked hyperk-
Spongiotic superficial dermatophyte infection: higher-power view. eratosis, sometimes with small foci of parakeratosis, and a usually prominent
granular cell layer (Fig. 6.31).7 The epidermal ridges are elongated and irregu-
affected. Accessible skin is particularly affected and the nape and sides of the larly thickened. Mild spongiosis is variably present depending upon the cause.
neck, the thighs, the lower legs and ankles, vulva, and scrotum are sites gen- A perivascular and sometimes interstitial inflammatory cell infiltrate consisting
erally involved.2 of lymphocytes, histiocytes, and small numbers of eosinophils is present in the
Pebbly lichenification refers to a distinct variant in which lichenoid superficial dermis. Enlarged, angulated myofibroblasts are sometimes evident
papules follow intense scratching in patients with inflammatory dermatoses and, as in many other chronic skin conditions, scattered small, multinucleated
such as atopic eczema.2 cells, so-called Montgomery giant cells, are identified. Papillary dermal fibrosis is
Fig. 6.33
Fig. 6.31 Nodular prurigo: typical
Lichen simplex chronicus: there is hyperkeratosis, patchy parakeratosis, and globular nodules; the
elongation of the rete ridges. intervening skin appears
normal. From the
collection of the late N.P.
Smith, MD, the Institute
UK.
Fig. 6.32
Lichen simplex chronicus:
there is hypergranulosis.
Note the vertically
orientated collagen fibers,
a characteristic feature. Fig. 6.34
Nodular prurigo: there are scattered, excoriated discrete nodules on the buttocks
and thighs. Note the postinflammatory hyperpigmentation. By courtesy of R.A.
a characteristic feature and in some cases nerve hyperplasia is seen (Fig. 6.32).3 Marsden, MD, St George's Hospital, London, UK.
In our experience, however, the latter feature is distinctively uncommon.
Nodular prurigo (prurigo nodularis) and Individual lesions are often described as globular with a warty and excori-
ated surface and may measure up to 2 cm in diameter (Fig. 6.33).2 They are
prurigo nodule (picker's nodule) often grouped, symmetrical, and occur predominantly on extensor aspects
of the (distal) limbs (Figs 6.34, 6.35).1 The trunk may also be affected.2
Clinical features Occasional disseminated cases have been described.2 The palms and soles are
Nodular prurigo is characterized by the development of chronic, intensely typically uninvolved.2 The intervening skin usually appears normal. Similar-
pruritic, lichenified, and excoriated nodules.1,2 It occurs over a wide age looking lesions are sometimes seen in patients with eczema (see below).
range, from 5 to 75 years, with a mean of 40 years. Rarely, children are The majority of patients with nodular prurigo are perfectly well and inves-
affected.3 Disease duration ranges from 6 months to 33 years, with a mean tigations are unhelpful; however, occasionally nodular prurigo is found in
of 9 years. Nodular prurigo occurs equally in men and women. It shows patients with gluten enteropathy.4 Psychosocial disorders have been reported
significant overlap with lichen simplex chronicus, although this is not uni- in a high proportion of patients.5 In some cases the eruption occurs after an
formly accepted.1,2 insect bite, but subsequent lesions develop spontaneously.5
Fig. 6.35
Nodular prurigo: in this Fig. 6.36
patient there is very Nodular prurigo: there is hyperkeratosis, hypergranulosis, and
severe involvement of pseudoepitheliomatous hyperplasia. The dermis is scarred and there is a
the shins and dorsal perivascular and interstitial chronic inflammatory cell infiltrate.
surface of the feet. By
UK.
The pruritus is episodic and may be precipitated or aggravated by heat and

anxiety.5 Significant laboratory abnormalities may include anemia, eosino-
philia, and raised serum IgE levels.5
Nodular prurigo (eczema) is defined as lesions of nodular prurigo arising
on a background of overt eczema.5 While this distinction is of academic inter-
est it has no clinical or prognostic importance.
A prurigo nodule is a solitary variant that develops as a consequence of
localized scratching and picking.
On occasion, nodular prurigo is accompanied by the features of bullous
pemphigoid (pemphigoid nodularis).6

Classical nodular prurigo, which is focal and characterized by hyperplasia,
has recently been related particularly to follicular epithelium.2,7 In the epider-
mis this manifests as orthohyperkeratosis, hypergranulosis and acanthosis, Fig. 6.37
sometimes to the degree of pseudoepitheliomatous hyperplasia (Figs 6.36, Nodular prurigo: higher-power view.
6.37).8 Superficial mild spongiosis and focal parakeratosis is occasionally
present and the features may resemble chronic eczema.5 Subepidermal fibrin
deposition is sometimes a feature.9
In the dermis there is vascular hyperplasia, with dilated vessels in both the
papillary and reticular dermis. New vessel formation is apparent and there
is a surrounding perivascular mild inflammatory cell infiltrate, consisting
mainly of lymphocytes and some histiocytes, plasma cells, occasional eosino-
phils and scattered, superficial, small multinucleated cells (Montgomery giant
cells) (Fig. 6.38).8 Mast cells are present in normal numbers.1 The infiltrate
has been described as having an inverted triangular configuration extending
from the superficial dermis.2 This has not been the present author's experi-
ence. Occasionally, the dermal features include lymphoid follicles with germi-
nal center formation, thereby resembling a persistent insect bite reaction.5 An
additional finding is the presence of fibrosis of the papillary dermis.8
With light microscopy the nerves may appear normal, increased in number
or occasionally hyperplastic (Fig. 6.39).1,5 Special neural stains or S-100 pro-
tein immunocytochemistry may accentuate mild proliferative changes. Nerve
changes, however, do not appear to be essential for the diagnosis.1 Studies
have shown no evidence of true neuroma formation and it is thought by some
authors that the neural changes are secondary to chronic trauma and scratch-
ing of the intensely pruritic nodules.1,5,7 This intense pruritus may have been Fig. 6.38
partly responsible for the large amount of attention given to neural changes in Nodular prurigo: note the conspicuous eosinophils.
Acroangiodermatitis (pseudo-Kaposi's sarcoma, congenital dysplastic

angiopathy, arteriovenous malformation with angiodermatitis) refers to the
clinical manifestation of purple macules, nodules, and sometimes verrucous
plaques typically developing on the dorsal aspects of the feet and toes in
patients with severe and longstanding venous insufficiency.7 Varicose veins
are often present. The condition is of particular importance in that it may
be clinically mistaken for Kaposi's sarcoma.8 Identical lesions have been
described complicating Klippel-Trénaunay, Stewart-Bluefarb, and Prader-
Willi syndromes, surgical arteriovenous fistulae as seen for example in hemo-
dialysis patients, complicating poorly fitting suction socket prostheses on
amputation stumps and on paralysed limbs.9–22

The pathogenesis of stasis dermatitis and acroangiodermatitis is unknown
although it may be related to the tissue anoxia that typically results from
increased venous pressure or circulatory disturbance.13
Stasis dermatitis shows, in addition to the epithelial changes of spongiotic
dermatitis, marked hemosiderin deposition in the dermis accompanied by fibro-
sis and a characteristic lobular pattern of superficial and/or deep dermal neo-
Fig. 6.39
Nodular prurigo: in our experience, nerve hyperplasia is an uncommon observation.
vascularization (Figs 6.41–6.45). Inflammatory cells – including lymphocytes,
histiocytes, and variable numbers of plasma cells – are often numerous, and
erythrocyte extravasation is usually prominent.
nodular prurigo in the past. Very rarely, however, hyperplastic nerve trunks are
associated with Schwann cell proliferation, giving rise to small neuromata.10
Electron microscopy has shown vacuolation of Schwann cell cytoplasm,
together with loss of definition of internal structure of the mitochondria.5,10,11
Stasis dermatitis and acroangiodermatitis

Clinical features
Stasis (varicose) dermatitis usually involves the medial aspect of the lower leg
or ankle, but may be more widespread, and develops as a complication of
impaired venous return from the lower limbs.1 Superficial varicose veins are a
frequent predisposing factor. The lesion appears as an itchy, scaly, often swol-
len and hyperpigmented area. Such changes are often seen around chronic
stasis ulcers (Fig. 6.40). Malignant tumors (both squamous and basal cell car-
cinomas) may occasionally develop at the edge of these ulcers.2–5 Furthermore,
in the early stages of the disease, the lesion may present singly and can be clini-
cally mistaken for a cutaneous malignancy, i.e., squamous cell carcinoma.6
Fig. 6.41
Stasis dermatitis: there is hyperkeratosis, focal parakeratosis and marked epidermal
hyperplasia. The dermis is chronically inflamed and scarred.
Fig. 6.40
Stasis dermatitis: there is
vesiculation, exudation,
and crusting on the lower
leg around a stasis ulcer,
which was precipitated
by allergy to the antibiotic
dressing. By courtesy
St George's Hospital, Fig. 6.42
London, UK. Stasis dermatitis: note the increased vascularity.
Fig. 6.43 Fig. 6.46

Stasis dermatitis: there is marked mural fibrin deposition. The features often overlap Acroangiodermatitis showing lobular capillary proliferation, red cell extravasation,
with atrophie blanche. and a chronic inflammatory cell infiltrate.
In acroangiodermatitis, the vascular proliferation is often so exuberant that

it may mimic a vascular neoplasm, most often Kaposi's sarcoma (Fig. 6.46).23
Acroangiodermatitis differs from Kaposi's sarcoma by the absence of a spin-
dle cell population or irregular lymphatic-like vascular channels dissecting
the dermal collagen. In addition, the promontory sign (tumor vessels partially
surrounding normal vessels and the adnexae) is absent. In acroangiodermati-
tis, the hallmark is the presence of lobular capillary proliferation.
In cases where the diagnosis is in doubt, CD34 immunocytochemistry is of
value. The spindle cells in Kaposi's sarcoma express this antigen whereas those
in acroangiodermatitis do not.24 Smooth muscle actin emphasizes the pericytes in
acroangiodermatitis and a reticulin stain can be used to highlight the lobularity.
Pityriasis alba
Clinical features
Fig. 6.44
Pityriasis alba is a very common form of chronic dermatitis usually affecting
Stasis dermatitis: in this view, there is marked new blood vessel formation and
abundant hemosiderin is present. preadolescent children of either sex.1 In the United States, the prevalence is
1.9% in a healthy population.2 The lesions are seen on the face in particu-
lar, but the shoulders, upper extremities, and legs may also be involved (Figs
6.47–6.49).1,3 Early lesions present as slightly scaly, mildly pruritic, round to
oval pink plaques measuring from 0.5 to 5.0 cm or more in diameter, which
later appear as scaly hypopigmented lesions.1 The races are equally affected
although lesions are more prominent in dark-skinned persons.1,4 The condi-
tion usually resolves spontaneously after months or years.

The etiology is unknown although some authors believe it may be a form
of atopic dermatitis since many patients also have features of classic
atopic dermatitis or a family history of atopy.5 However, some patients
with pityriasis alba lack typical features of atopy. An association with
xerosis has also been postulated and the condition has also been linked to
copper deficiency.6,7
The histological features of the early stage include follicular dilatation and
plugging with infundibular spongiosis, parafollicular parakeratosis, and seba-
ceous gland atrophy accompanied by a superficial perivascular lymphocytic
infiltrate and edema.8 In the later stages, the changes are those of chronic
non-specific dermatitis including hyperkeratosis, parakeratosis sometimes
Fig. 6.45 accompanied by mild acanthosis, and slight spongiosis.8–10 There is variable
Stasis dermatitis: the hemosiderin can be highlighted with a Prussian blue reaction hypo- and hyperpigmentation of the basal keratinocytes with reduced or nor-
for iron. mal numbers of melanocytes and pigmentary incontinence.8,11
Fig. 6.47
Fig. 6.49
Pityriasis alba: there are
Pityriasis alba: lesions in white-skinned patients are much more subtle. By courtesy
multiple hypopigmented,
of the Institute of Dermatology, London, UK.
scaly patches on the
arms. Lesions are more
obvious in the colored eruption. Lesions may form nodules and plaques and there may be evidence of
races. By courtesy of C. lichenification and excoriation due to repeated scratching and postinflamma-
Furlonge, MD, Port of tory scarring.1–3 Sun-exposed areas of the face, neck, upper chest, forearms, and
Spain, Trinidad. hands are predominantly involved. The lips and conjunctiva are also frequently
affected.1,3 Associated cheilitis particularly affecting the lower lip is characterized
by edema, fissuring, ulceration, and chronic dry scaling and may be the sole mani-
festation.6 Conjunctival involvement results in photophobia, hyperemia, and for-
mation of a pseudopterygium.1,3 The disease course of actinic prurigo is chronic
with significant adverse impact on the quality of life.7 Remission may be observed
in the winter months in patients living in geographic areas with significant varia-
tion of sunlight throughout the year.1,3 In a subset of patients with childhood onset,
symptoms will improve in adulthood with occasional spontaneous remission.3

Using phototesting, the majority of patients show increased sensitivity to a
broad spectrum of UVA as well as UVB radiation.1,2 The disease has strong
associations with HLA haplotypes, in particular DRB1*0407 (60–70% of
patients) and DRB1*0401 (20% of patients).3
The histological features are often nondiagnostic and areas of excoriation
are frequently biopsied. In late lesions changes include regular epidermal acan-
thosis with overlying hyperparakeratosis and some degree of hypergranulosis.
There is an associated marked superficial to mid-dermal perivascular chronic
inflammatory cell infiltrate composed predominantly of lymphocytes. In the pap-
illary dermis focal fibrosis may be seen and there is often pigment incontinence.
Lymphoid follicles can be present especially in areas of ulceration, particu-
Fig. 6.48 larly in lesions on the lip. Eosinophils are frequently noted. Biopsies from the
Pityriasis alba: there is lip show similar epidermal features in addition to spongiosis and basal cell
striking leukoderma on vacuolar change. Dermal edema and prominent telangiectatic vessels are fur-
the cheek and chin, which ther characteristic features. An associated lymphoplasmacytic infiltrate may
are commonly affected be bandlike or show lymphoid follicles with germinal centers. The latter is
sites. By courtesy of R.A. mainly seen in conjunctional biopsies.
Marsden, MD, St George's
Eosinophilic spongiosis
Eosinophilic spongiosis is the histopathological term used to describe spon-
Actinic prurigo giosis in which eosinophils are the predominant cell type.1–5 Eosinophilic
spongiosis is a non-specific finding with which a considerable number of der-
matoses may be associated. Table 6.2 lists dermatoses in which eosinophilic
Clinical features
spongiosis is commonly encountered. Detailed discussion of each of these dis-
Actinic prurigo is a rare familial photodermatitis with a female predilection orders is found in the appropriate chapters.
and disease onset in childhood (4–5 years of age) although disease manifesta-
tion has also been documented in adulthood.1–4 The disease is most commonly
observed in Native Americans as well as Latin Americans. Caucasians, Asians,
Erythroderma
and Australians are less frequently affected.1,2,4,5 The clinical presentation is varied. Spongiotic dermatitis is one of the causes of erythroderma. Sometimes incor-
Patients typically present with intense pruritus and an erythematous papular rectly called exfoliative dermatitis, erythroderma is applicable only when the
Table 6.2 Table 6.3

Diseases featuring eosinophilic spongiosis Causes of erythroderma
• Incontinentia pigmenti • Dermatitis

• Pemphigus • Lymphoma (mycosis fungoides, T-cell leukemia, Hodgkin's lymphoma)
• Bullous pemphigoid • Drugs (gold, penicillin, etc.)
• Linear IgA disease • Psoriasis
• Pemphigoid (herpes) gestationis and polymorphic eruption of • Pityriasis rubra pilaris
pregnancy • Ichthyosiform erythroderma
• Insect-bite reactions • Scabies
• Atopic eczema • Lichen planus
• Contact dermatitis
• Grover's disease
• Drug reactions
to lichenoid lesions and vice versa is also thought to be a typical feature. The
lesions are chronic, lasting from months to years, but eventually resolving.

The existence of Sulzberger-Garbe syndrome as a distinctive entity is contro-
versial. Some authors consider patients classified under this designation as
having nummular dermatitis.3
Biopsy of exudative lesions shows a non-specific spongiotic dermatitis.
Biopsy of lichenoid lesions is characterized by a bandlike lymphocytic infil-
trate. Variable numbers of eosinophils may be present.
Vein graft site dermatitis

Occasionally, patients undergoing coronary artery bypass develop an eczema-
tous dermatitis in the region of the scar from the saphenous vein donor site.1,
2 The pathogenesis is unclear. Since patients often have objective evidence of
neuropathy, some authors believe that the neuralgia may play a pathogenic
role.1 It is also possible that stasis changes play a role in this disorder.
Biopsy shows non-specific spongiotic dermatitis.
Papular acrodermatitis of childhood

Clinical features
Papular acrodermatitis of childhood (Gianotti-Crosti syndrome, infantile
papular acrodermatitis) is a rare disease representing a cutaneous response to
a number of viral infections. It is characterized by the acute onset of mono-
morphic, symmetrical flat-topped papules or papulovesicles, 1–10 mm across,
which range in color from pink to red or brown and are located primarily
on the face (particularly the cheeks), buttocks, and extensor surfaces of the
Fig. 6.50 forearms and legs, with the trunk typically being spared (Figs 6.51–6.53).1–4
Erythroderma: the entire skin surface is erythematous and slightly scaly. The Lesions are usually blanchable although petechial and hemorrhagic variants
appearances are relatively non-specific and give no indication of the cause. By
can be rarely encountered.4 A positive Koebner phenomenon is sometimes
courtesy of the Institute of Dermatology, London, UK.
elicited.4 The lesions are occasionally pruritic and are self-limiting, lasting
up to 3 weeks. Mucous membranes are not affected. Infants and children are
entire skin surface is inflamed, erythematous, and scaly (Fig. 6.50).1–5 The clini- predominantly affected although there are occasional reports of the condition
cal features are remarkably consistent irrespective of the underlying disease and developing in adults.4–9
therefore often pose a diagnostic challenge. Pruritus is variable, being particu- Systemic signs include hepatosplenomegaly and axillary and inguinal
larly severe in the Sézary syndrome and in mycosis fungoides. Lymphadenopathy lymphadenopathy. Sometimes a fever is evident. There may be an anicteric
is usually present (dermatopathic lymphadenopathy). Prolonged erythroderma, acute hepatitis and occasionally patients progress to chronic liver disease.
particularly in the elderly, may be complicated by cardiac failure, peripheral
circulatory collapse, hypothermia, and infection. Patients with erythroderma Pathogenesis and histological features
are frequently biopsied since the clinical examination findings are often non- In the original and early reports, Gianotti-Crosti syndrome was documented
specific. Diagnosis without clinical information is often not possible.1 Table following infection with hepatitis B virus.10–12 More recently cases have been
6.3 lists the various causes of erythroderma. The specific diseases that cause reported in association with hepatitis A virus, coxsackievirus, influenza virus,
erythroderma are discussed in detail in the appropriate chapters. Epstein-Barr virus, cytomegalovirus, parainfluenza virus, human herpesvi-
rus-6 (HHV-6), poxvirus, parvovirus, and rotavirus.13–25 In addition, the dis-
ease had been associated with HIV infection.26 Gianotti-Crosti syndrome has
Sulzberger-Garbe syndrome also been reported following Mycoplasma infection, Lyme borreliosis, and
immunization.27–35 The pathogenesis is unknown although viral antigenemia
Clinical features and immune complex-mediated mechanisms have been proposed.36
Sulzberger-Garbe syndrome (distinctive exudative discoid and lichenoid Biopsies of skin lesions show entirely non-specific histological features.
chronic dermatosis) was originally described as a widespread pruritic eruption The epidermis often appears normal or it may be mildly acanthotic with
associated with discoid lesions in middle-aged Jewish males.1–3 Involvement parakeratosis. Lymphocytic exocytosis is usually present.3 The upper dermis
of the penis was said to be characteristic. Transformation from eczematous contains a lymphohistiocytic infiltrate in a perivascular distribution and there
Fig. 6.53
Gianotti-Crosti syndrome: the papules are very uniform. A viral etiology is often
identified. By courtesy of C. Gelmetti, MD, Milan University, Italy.
In cases with hepatitis, the appearances are those of an acute viral hepa-
titis, which usually resolves over a period of up to 6 months. Rarely, chronic
disease ensues.
Fig. 6.51 Pityriasis rosea

Gianotti-Crosti syndrome: the eruption is present on the face and arms, there is
sparing of the trunk. By courtesy of C. Gelmetti, MD, Milan University, Italy.
Clinical features
Pityriasis rosea (‘rose-colored scale’) presents as an acute inflammatory der-
matosis characterized by self-limiting oval papulosquamous lesions on the
trunk and extremities.1–3 The disease appears to be more common in females,
and 75% of cases occur between the ages of 10 and 35 years.4 It is character-
ized by seasonal variation, being most common in the months of December to
February.5 Although pityriasis rosea typically presents as a solitary episode,
recurrent disease may occur in up to 2% of patients.6,7
In the majority of cases the disease first manifests itself with the appear-
ance of a ‘herald patch’, a single red scaly lesion that increases in size over
48 hours up to 2–10 cm in diameter (Fig. 6.54).8 A significant proportion of
patients report symptoms, including pyrexia, headache, malaise, arthralgia,
chills, vomiting, diarrhea, and lymphadenopathy, up to 2–3 weeks before the
onset of the eruption.9
After the appearance of the herald patch there is a ‘secondary incu-
bation period’ of 7–14 days before the generalized eruption of pink to
salmon-colored elliptical scaly lesions (Fig. 6.55).10 The latter are approxi-
mately 1 cm in length and their longest axes occur along the Blaschko skin
tension lines, producing the characteristic ‘fir’ or ‘Christmas tree’ effect.
There is usually an erythematous center, the periphery of the macule being
Fig. 6.52 slightly brown and scaly. In dark-skinned patients the macules tend to be
Gianotti-Crosti syndrome: darker than the surrounding skin (Fig. 6.56). The lesions spread from the
note the widespread chest to the abdomen, thighs, arms, and back, generally within 2 weeks,
erythematous papules persist for 2—4 weeks, and fade over a further 2 weeks. Pityriasis rosea
on the cheeks of this may be pruritic.
young girl. By courtesy of Oral lesions have been described in up to 16% of patients.4 They may take
C. Gelmetti, MD, Milan
the form of a single large erythematous plaque, bullae, multiple hemorrhagic
University, Italy.
puncta, round erythematous macules and plaques or erythematous annular
lesions.4,11–14
is also swelling of endothelial cells sometimes accompanied by marked papil- Several morphological variants may occur: a papular variant is seen in
lary dermal edema.31 Scattered eosinophils may be present.36 Occasionally, a young children, pregnant women and those of Afro-Caribbean descent; a
more lichenoid pattern of inflammation is encountered. There is no evidence vesicular or bullous variant may occur in infants and children; and an urti-
of vasculitis. carial form has also been noted.5,14,15 Occasionally, pityriasis rosea has a pur-
Direct immunofluorescence is negative.3 puric, hemorrhagic component.5,14,16 Localized and unilateral forms, and
By immunohistochemistry, the infiltrate consists of an admixture of CD4+ an ‘inverse’ form presenting on the face and extremities, have also been
helper T cells and CD8+ cytotoxic T cells.19,36,37 documented.17
A B
Fig. 6.54
Pityriasis rosea: (A) the ‘herald patch’ which marks the onset of this dermatosis, is marked by an arrow; (B) close-up view. By courtesy of R.A. Marsden, MD, St George's
Pathogenesis and histological features of old trauma and scars, suggesting an isomorphic (Koebner's) response.17
The exact etiology of pityriasis rosea is unknown; however, most of the evi- Atypical pityriasis rosea has also been described in bone marrow transplant
dence points to an infectious, probably viral, cause. It sometimes complicates recipients and following treatment with interferon-alpha (IFN-α) as well as
an upper respiratory tract infection.18 The herald patch may develop at the Hodgkin's disease, and a pityriasis rosea-like eruption has been documented
site of an insect bite, particularly fleas, but patches have also occurred in areas due to drugs such as imatinib mesylate, ACE inhibitors, and hydrochlorothi-
A B
Fig. 6.55
Pityriasis rosea: (A) the secondary rash presents as small pink slightly scaly macules; (B) close-up view. From the collection of the late N.P. Smith, MD, the Institute of
Fig. 6.56 Fig. 6.58

Pityriasis rosea: in pigmented skin, there is often postinflammatory Pityriasis rosea: small foci of parakeratotic scale are a characteristic finding. The
hyperpigmentation and the erythematous nature of the eruption is not apparent. By epidermis shows mild spongiosis.
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
azide.19–23 Case clustering in establishments with communal living supports an large numbers of Langerhans cells.41 Human leukocyte antigen DR (HLA-DR,
infectious etiology. Recently, HHV-7, as well as HHV-6 and HHV-8, has been Ia-like antigen) has been demonstrated on the surface of keratinocytes, and
identified in peripheral blood mononuclear cells in addition to plasma and this has been interpreted as showing that they are taking an active role in cel-
skin of patients with pityriasis rosea, and herpes virus-like particles have been lular immunity.42–44 HLA-DR antigen may also be expressed on the surface of
identified in cutaneous lesions of pityriasis rosea by electron microscopy.24–33 the T-helper cells.43
Other workers, however, have failed to confirm this observation.28,34,35 Rarely,
a pityriasis rosea-like eruption may be a manifestation of HIV/AIDS.36 Differential diagnosis
The histopathological features are those of a non-specific subacute or Guttate psoriasis shows considerable overlap with pityriasis rosea. The presence
chronic dermatitis and comprise focal hyperkeratosis and angulated paraker- of neutrophils within the parakeratotic mounds favors a diagnosis of psoriasis.
atosis with slight acanthosis (Figs 6.57–6.60).37 The granular cell layer may A wide range of drugs has been associated with a pityriasis rosea-like erup-
be absent beneath the foci of parakeratosis. Intraepidermal cytoid bodies are tion including barbiturates, ketotifen, clonidine, captopril, isotretinoin, gold,
present in as many as 50% of cases.38,39 Focal acantholytic dyskeratosis has bismuth, arsenic, organic mercurials, methoxypromazine, D-penicillamine,
occasionally been documented.40 A lymphohistiocytic infiltrate surrounds the tripelennamine hydrochloride, metronidazole, and salvarsan.15,17 In such cases,
vessels of the superficial vascular plexus and there is slight spongiosis. Rarely, the distinction depends upon clinicopathological correlation. The presence of
spongiotic vesiculation may be evident.5 Occasionally, scattered eosinophils large numbers of eosinophils is a clue to a hypersensitivity reaction.
are present. Red cell extravasation is a not infrequent feature and occasional Acute and subacute eczematous dermatitis may also be confused with
erythrocytes may be seen within the epidermis. pityriasis rosea. The presence of lens-shaped parakeratosis and limited spon-
Immunocytochemical staining has demonstrated that the dermal infiltrate giosis favors pityriasis rosea. Again, clinical findings should help make this
consists mainly of T cells, including helper and suppressor cells, together with distinction.
Fig. 6.59
Pityriasis rosea: there
is spongiosis and a
perivascular lymphocytic
infiltrate. The angulated
Fig. 6.57 tier of parakeratosis
Pityriasis rosea: low-power view showing multiple foci of scale with psoriasiform (teapot lid sign) is
hyperplasia. characteristic.
Fig. 6.60 Fig. 6.62

Pityriasis rosea: in this field, there is red cell extravasation. Juvenile plantar
dermatosis: close-up
view showing scaling
Pityriasis lichenoides chronica is characterized by interface change and and fissuring. By
vacuolar degeneration of the basal layer of the epidermis, features not seen courtesy of the Institute
in pityriasis rosea. of Dermatology, London,
A PAS stain is mandatory in all cases to exclude a dermatophyte infection. UK.
Juvenile plantar dermatosis years before resolving.1,3 However, many patients develop features of classic
eczema of the hands later in life.2
Clinical features
Scaly palms and soles with loss of a normal epidermal rete pattern charac- Pathogenesis and histological features
terize juvenile plantar dermatosis. The affected area often has a shiny red The pathogenesis of this disorder is not understood; however, it has been sug-
appearance with fissures (Figs 6.61, 6.62).1–4 As its name suggests, the dis- gested that synthetic footwear may play a role in its development.3
ease is seen in prepubertal children with a mean age of 9.6 years.1 The most Biopsy shows epidermal acanthosis and subacute to chronic spongiosis.1
common sites affected are the volar aspect of the great toe and the ball of Variable parakeratosis and hypogranulosis may be seen. A lymphocytic infil-
the foot.1 The hand is only rarely affected. Patients often have a personal or trate centered on the eccrine duct is said to be characteristic.1
family history of atopy.2,4 The disorder usually lasts for 6 months to several
The histological changes are probably non-specific but the presence of chronic
inflammation centered on the sweat duct should suggest juvenile plantar derma-
tosis in the appropriate clinical setting and allow distinction from other spongi-
otic dermatitides, which typically spare the acrosyringium. One group could not
identify PAS-positive material occluding sweat ducts in multiple histological sec-
tions of juvenile plantar dermatosis (compare with miliaria).1 A PAS stain with
diastase digestion should also be performed to evaluate for fungal infection.
Miliaria
Clinical features
This common disorder, although most often seen in children, may affect any
age group but congenital presentation is rare.1 It develops as a consequence
of obstruction to the outflow tract of the intraepidermal component of the
eccrine sweat duct and is associated with excessive sweating and exposure to
high humidity. Traditionally, the condition is subdivided into three subtypes:
miliaria crystallina, miliaria rubra, and miliaria profunda.2,3
• In miliaria crystallina the level of obstruction is within the stratum
corneum, and results in the formation of small, clear vesicles, located
Fig. 6.61 particularly on the trunk (Fig. 6.63). There are accompanying symptoms
Juvenile plantar
of a high fever and pronounced sweating.
dermatosis: multiple
erythematous lesions
• Miliaria rubra (prickly heat) is particularly common in hot, humid
are present on the climates and is due to obstruction within the prickle cell layer, resulting
soles of the feet. By in erythematous papules and vesicles, usually located about the
courtesy of the Institute trunk and intertriginous regions (Fig. 6.64). This form of miliaria is
of Dermatology, London, particularly common in infants. The term miliaria pustulosa has been
UK. applied to the above subtypes when pustules develop. Miliaria rubra
both variants the lesions can be seen to be centered upon an intraepider-

mal eccrine sweat duct. Miliaria pustulosa is characterized by features of
miliaria in addition to an intraepidermal or subcorneal pustule. Miliaria
profunda is characterized by spongiosis of the dermal portion of the eccrine
duct, often associated with dermal chronic inflammation adjacent to the
affected duct.
Fox-Fordyce disease
Clinical features
Fox-Fordyce disease (apocrine miliaria, chronic itching papular eruption of
the axillae and pubic region) presents as a chronic papular eruption, associ-
ated with pruritus, and located in areas containing apocrine sweat glands
(i.e., the axillae, the pubic area, the vulval labia, the perineum, and areola)
(Fig. 6.65).1–3 The papules are discrete, firm, and flesh-colored or pigmented.
Associated hair loss is often present.
The disease is uncommon and over 90% of reported cases have occurred
in women, usually aged 13–35 years. Rarely, prepubescent and postmeno-
Fig. 6.63 pausal patients have been described.4,5
Miliaria crystallina: tiny vesicles resembling water droplets are scattered over the
abdomen of this young male. By courtesy of R.A. Marsden, MD, St George's
Patients with Fox-Fordyce disease have apocrine anhidrosis. Although eccrine
sweating is normal, apocrine sweating does not occur due to the keratotic
plugging of the apocrine duct orifice. The continued secretion of sweat, how-
ever, causes the duct to rupture and an apocrine sweat retention cyst forms
in the epithelium. The exact cause of the follicular plugging is unknown,
but a hormonal link has been postulated. Occasional instances of coexistent
hidradenitis suppurativa have been recorded.6
Follicular infundibular plugging is present in association with acanthosis,
parakeratosis, spongiosis, and an underlying non-specific chronic inflamma-
tory cell infiltrate. Dilation of the apocrine glands may be present and the
presence of perifollicular foamy histiocytes is a frequent and diagnostically
helpful feature.7–9 Further reported findings include vacuolar change, dysker-
atosis, and parakeratotic lamellae affecting the follicular infundibulum.10 The
keratinous obstruction prevents the outflow of apocrine secretion and leads
to the diagnostic feature of an intrafollicular sweat retention vesicle; serial
sections may be needed to demonstrate this lesion.11,12
Transient acantholytic dermatosis with

prominent eccrine ductal involvement
Grover's disease (transient acantholytic dermatoses) is discussed more com-
Fig. 6.64 prehensively elsewhere; however, since it is commonly associated with spongi-
Miliaria rubra: the characteristic appearance is of large numbers of minute papules osis (often in the absence of acantholysis), it deserves mention in this chapter.
and vesicles. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK. Recent studies of Grover's disease have shown a strong correlation with high
temperature and sweating and it has been suggested that its pathogenesis may
be analogous to that of miliaria.1–3 Supporting this concept is the development
and its pustular variant have also been found in association with of Grover's disease in bed-ridden and febrile patients. The lesions are usually
pseudohypoaldesteronism, type I.4,5,6 present on the back. These patients often have prominent involvement of
• In miliaria profunda, also typically seen in tropical climates, the the eccrine duct and the lesions have been termed sudoriferous acrosyringeal
obstruction is at level of the sweat duct. Small papules are seen on the acantholytic disease (sudoriferous Grover's disease).4 Biopsies taken from
trunk and occasionally the extremities. patients with sudoriferous acrosyringeal acantholytic disease often show, in
addition to typical features of Grover's disease, acantholysis of the superfi-
cial portion of the eccrine duct. When acantholysis is present and a clinical
Pathogenesis and histological features history is provided, the diagnosis is usually straightforward. However, not
The pathogenesis of miliaria is poorly understood. It has been suggested that uncommonly, biopsies taken from patients with Grover's disease show spon-
bacteria play a role in the development of the disease. There is evidence that giosis only (often eosinophilic spongiosis). In these patients, a diagnosis of
extracellular polysaccharide substance (EPS), a PAS-positive material pro- Grover's disease may still be made in the appropriate clinical setting.
duced by some strains of Staphylococcus epidermidis, obstructs the sweat duct It is important to note that myriad cutaneous disorders may show some
and causes the disease.7 Normal controls who had S. epidermidis swabbed on degree of spongiosis. For example, such disparate conditions as mycosis fun-
to the volar aspect of their forearms followed by occlusion and heat devel- goides and psoriasis are not uncommonly associated with a degree of spon-
oped miliaria. These results have not been replicated with other bacteria.7 giosis. In this chapter, we have focused our discussion on entities for which
Biopsy revealed EPS in lesions from several patients. spongiosis is a dominant and fairly consistent histological finding. Other enti-
A subcorneal vesicle containing a few neutrophils characterizes miliaria ties that may occasionally be associated with some degree of spongiosis are
crystallina, while rubra involves an intraepidermal spongiotic vesicle. In discussed in the appropriate chapters.
Psoriasis 201
Fig. 6.65
Fox-Fordyce disease: (A) there are numerous white
papules. The axilla is a characteristic site; (B) close-up
A B view. By courtesy of the Institute of Dermatology,
London, UK.
Psoriasiform dermatoses
The psoriasiform reaction pattern is defined by the presence of epidermal (Fig. 6.69). The scalp, the extensor surfaces (mainly the knees and elbows),
hyperplasia with fairly uniform and marked enlargement of the rete ridges. the lower back, and around the umbilicus are particularly affected. The clini-
Although confluent parakeratosis with neutrophil exocytosis is characteris- cal features, however, show regional variation: scalp involvement often shows
tic of psoriasis (the prototype of this group of conditions), this feature is not very marked plaque formation, whereas on the penis scaling is commonly
included within the definition, which would otherwise become too restrictive. minimal and the features may be mistaken for Bowen's disease (Figs 6.70–
Diseases in addition to psoriasis which may manifest a psoriasiform pattern 6.72). Linear lesions (linear psoriasis) follow previous trauma (koebneriza-
include Reiter's syndrome, pityriasis rubra pilaris, lichen simplex chronicus, tion) (Fig. 6.73).
psoriasiform drug reactions, subacute and chronic spongiotic dermatitis, Psoriasis may manifest in a variety of other ways.
parapsoriasis, and pityriasis rosea (herald patch). Other conditions in which • Guttate (eruptive) psoriasis presents as small (0.5–1.5 cm in diameter)
psoriasiform hyperplasia may sometimes be a feature include dermatophyte papules over the upper trunk and proximal extremities, typically in
infections and candidiasis, secondary syphilis, scabies infestation, inflamma- younger patients (Figs 6.74–6.76).
tory linear verrucous epidermal nevus, necrolytic migratory erythema, acro-
dermatitis enteropathica, and pellagra. Neoplastic conditions such as Bowen's
disease and mycosis fungoides, which often show marked epidermal hyper-
plasia, are not included in this definition.
Psoriasis
Clinical features
Psoriasis is a chronic relapsing and remitting disease of the skin that may
affect any site.1 It is one of the commonest of all skin diseases, with a reported
incidence of 1–2% in Caucasians.2,3 It is rare among blacks, Japanese, and
native North and South American populations.4 Males and females are
affected equally. Although psoriasis may occur at any age, it most frequently
presents in the teens and in early adult life (type I psoriasis).5 A second peak
in which the disease is often milder appears around the sixth decade (type II
psoriasis).5
The classic cutaneous lesion of psoriasis vulgaris (plaque psoriasis),
developing in about 85–90% of patients with psoriasis, is raised, sharply
demarcated, with a silvery scaly surface (Figs 6.66–6.68).6,7 The underly-
ing skin has a glossy, erythematous appearance. If the parakeratotic scales Fig. 6.66
are removed with the fingernail, small droplets of blood may appear on the Psoriasis: typical plaque disease showing bilateral and fairly symmetrical
surface (Auspitz's sign); this is diagnostic. Plaques, when multiple, are often distribution. In this example, the silvery scale is well demonstrated. From the
symmetrical and annular lesions due to central clearing are a common finding collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 6.67 Fig. 6.69

Plaque psoriasis: note the symmetry of these lesions. By courtesy of R.A. Annular psoriasis: central clearing of plaques results in annular lesions. By courtesy
Marsden, MD, St George's Hospital, London, UK. of R.A. Marsden, MD, St George's Hospital, London, UK.
• Psoriasis inversa is characterized by the development of plaques in the

flexures (Fig. 6.77).
• Generalized pustular psoriasis (von Zumbusch) is an acute variant,
characterized by fever of several days' duration, together with the
sudden appearance of sterile pustules, 2–3 mm across, over the trunk
and extremities (Fig. 6.78).8 The surrounding skin is erythematous
and confluence may result in a generalized erythroderma (Fig. 6.79).
Usually, recurrent episodes of fever occur, followed by fresh outbreaks
of pustules (Fig. 6.80). Systemic signs include weight loss, weakness,
and hypocalcemia, with a raised white cell count and high erythrocyte
sedimentation rate (ESR). Although the precipitating factor is often
unknown, pustular psoriasis may follow a streptococcal or viral
infection. Withdrawal of systemic steroid therapy is also a known
predisposing cause.9 Treatment with systemic steroids or intensive
topical regimens has also been incriminated.10 Other risk factors for
developing a pustular episode include drugs, pregnancy, hypocalcemia,
Fig. 6.70
Plaque psoriasis: the scalp is a commonly affected site. By courtesy of the Institute
of Dermatology, London, UK.
Fig. 6.71
Plaque psoriasis: in this
extreme case, the initial
Fig. 6.68 diagnosis was Norwegian
Plaque psoriasis: close-up scabies. Surprisingly,
view showing the thick alopecia is an uncommon
scale. From the collection complication. By courtesy
of the late N.P. Smith, of R.A. Marsden, MD,
MD, the Institute of St George's Hospital,
Dermatology, London, UK. London, UK.
Psoriasis 203
Fig. 6.74
Guttate psoriasis: this infant shows a characteristic distribution over the trunk.
By courtesy of M. Liang, MD, Children's Hospital, Boston, USA.
Fig. 6.72
Psoriasis: penile lesion showing a sharply demarcated, erythematous, eroded,
slightly scaly plaque. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
Fig. 6.75
Guttate psoriasis: this close-up view shows the erythema and scaling.
Fig. 6.73
Plaque psoriasis: linear involvement is a manifestation of koebnerization following
trauma. By courtesy of the Institute of Dermatology, London, UK.
and sunlight or phototherapy.11 Uncommon variants of pustular

psoriasis include an annular form, exanthematous pustular psoriasis,
juvenile and infantile pustular psoriasis.12,13 The annular variant is
a somewhat less serious variant in which, due to central clearing,
lesions develop an annular or gyrate morphology.11 Often, the systemic
manifestations are less florid. The exanthematous variant, which tends
to develop de novo, may sometimes follow an infection or represent
a pustular drug reaction.11 Impetigo herpetiformis most probably
represents pustular psoriasis of pregnancy although some authors
classify it as a separate entity.14
• In psoriatic erythroderma, there is an intense generalized erythema
affecting the entire skin surface, associated with desquamation (Fig.
6.81). Ectropion may be present and scalp involvement is sometimes
followed by hair loss. Erythroderma may be precipitated in patients
with psoriasis vulgaris by infection with Staphylococcus aureus, abrupt Fig. 6.76
curtailment of steroid or methotrexate therapy, and sunburn.11 Systemic Guttate psoriasis: as with plaque disease, guttate psoriasis is associated with a
symptoms including fever, chills, shortness of breath, fatigue, and Koebner phenomenon. By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.79
Fig. 6.77 Pustular psoriasis: early
Flexural (inverse)
stage showing intense
psoriasis: this is a rare
erythema. By courtesy
variant in which the
of the Institute of
lesions develop on
flexural skin.
Fig. 6.78 Fig. 6.80

Pustular psoriasis (von Zumbusch): note the extreme generalized erythema and Pustular psoriasis: close-up view showing typical pustules arising on a background
pustulation. This variant is rare and may sometimes prove fatal. By courtesy of R.A. of intense erythema. By courtesy of the Institute of Dermatology, London, UK.
Marsden, St George's Hospital, London, UK.
myalgia are commonly present.11 Biochemical abnormalities include The nail is frequently affected in psoriasis; lesions may include pitting,
hypoalbuminemia, anemia, and dehydration.15 High-output cardiac discoloration, onycholysis, subungual hyperkeratosis, nail grooving, splinter
failure is an important complication. hemorrhages and complete loss in pustular psoriasis.18
• Localized (mixed) pustular psoriasis represents the development of Patients with psoriasis have a higher incidence of certain comorbidities
pustules on pre-existent plaques.9 This variant most often develops in including, depression, obesity, type 2 diabetes mellitus, hyperlipidemia,
acute flares of psoriasis or following treatment.11 It sometimes represents hypertension, metabolic syndrome, cardiovascular disease, Crohn's disease,
a harbinger of a more generalized process. and multiple sclerosis, as well as cutaneous and visceral malignancies.6,19
• Palmoplantar pustular psoriasis of Barber (pustulosis palmaris et
plantaris) refers to a chronic recurrent pustular dermatosis localized to Psoriatic arthritis
the palms and soles (Figs 6.82, 6.83). It shows a strong predilection Psoriatic arthritis has a prevalence of 0.02–7% but more recent data suggest
for females (9:1) in the fourth to fifth decade of life and the disease is that it could be as high as 30%.20 It may take a number of different forms
associated with a history of smoking.6,16,17 In about 25% of patients there (Fig. 6.86):21
is coexistent chronic plaque psoriasis.6 • The most common is an asymmetrical involvement of a few joints of the
• Acrodermatitis continua (acropustulosis) of Hallopeau is a rare sterile fingers or toes; this accounts for over 70% of cases.
pustular eruption of the fingers or toes, involving the nails and slowly • In 15% of cases a symmetrical polyarthritis, clinically indistinguishable
extending proximally (Figs 6.84, 6.85). from rheumatoid arthritis, but seronegative, is seen.
Psoriasis 205
Fig. 6.83
Palmoplantar pustular psoriasis: close-up view of palmar pustules.
Fig. 6.81
Psoriatic erythroderma: there is generalized erythema. Patients are at risk of
dehydration, hypoalbuminemia, and anemia. By courtesy of R.A. Marsden,
St George's Hospital, London, UK.
Fig. 6.84
Acropustulosis continua: there is pustulation with erythema and scaling, the nail
has been shed, and there is damage to the nail plate. By courtesy of R.A. Marsden,
Fig. 6.82
Palmoplantar pustular
psoriasis: there is intense
erythema, scaling, and
numerous pustules. By Fig. 6.85
courtesy of the Institute of Acropustulosis continua: a particularly severe example. By courtesy of S. Dalziel,
Dermatology, London, UK. MD, University Hospital, Nottingham, UK.
Fig. 6.86
Psoriatic arthropathy: joint involvement is a rare manifestation. Lesions of the
interphalangeal joints, while said to be characteristic, are an uncommon finding.
In this patient there is gross deformity. By courtesy of R.A. Marsden, St George's
Fig. 6.88
Psoriatic arthropathy: sacroiliitis. Note the virtual obliteration of the sacroiliac joints.
By courtesy of R.A. Marsden, St George's Hospital, London, UK.
The inherited predisposition to develop psoriasis has long been known.

A positive family history is common. Documented prevalence rates in first-
degree relatives have ranged from 7.8% to 17.6%.24,25 Monozygotic twins
have a concordance of 64–70% while that of dizygotic twins is in the order of
Fig. 6.87 14–23%.26 Linkage analysis has identified at least nine separate loci (PSORS1–
Psoriatic arthropathy: 9).6,7,27–30 PSORS1 shows the strongest genetic susceptibility, being implicated
classic type. Note the in 35–50% of familial psoriasis. 6,7,31,32 The locus is present on chromosome
destruction of the distal 6p within the major histocompatibility complex and more recent data have
interphalangeal joint demonstrated HLA-Cw6 as the susceptibility allele on PSORS1.31,32
of the first finger. By
Genetically, psoriasis is a heterogeneous disease at the level of PSORS1
and two distinct types have been identified:5
UK. • Type I disease which affects young adults and includes guttate psoriasis is
characterized by a familial segregation involving HLA-Cw6.5,33
• Type II disease includes psoriasis vulgaris presenting at an older age
• In approximately 5% of cases the distal interphalangeal joints are (over 50 years) as well as palmoplantar pustulosis and shows no familial
involved, the classical picture of psoriatic arthropathy (Fig. 6.87). segregation and no association with the PSORS1 locus.4,33,34 Patients with
• A further 5% have a destructive and severely deforming arthritis, pustular psoriasis have a higher incidence of HLA-B27, as do those with
arthritis mutilans. psoriasis and peripheral arthritis, and this is most marked if spondylitis
• The remaining cases have ankylosing spondylitis, with or without is present.35 Further genes related to increased genetic susceptibility for
peripheral joint involvement (Fig. 6.88). psoriasis include the interleukin-23 receptor gene on chromosome 1p,
Psoriatic arthritis is associated with a high incidence of mitral valve pro- the interleukin-12B gene on chromosome 5q, zinc finger protein 313 on
lapse with resultant incompetence.22 The peak age of onset is 36–45 years chromosome 20q, the CDKAL1 gene on chromosome 6p, the PTPN22
of age, although the destructive form may occur earlier. A high incidence of gene on chromosome 18p, the IL-4–IL-13 cytokine gene cluster on
immunoglobulin gene polymorphism has been identified in patients with pso- chromosome 5q, the LCE3B/3C gene on 1q, and the PSORS2 locus on
riatic arthritis, suggesting an inherited predisposition.23 chromosome 17q.7
Psoriatic arthritis in children, although uncommon, is of importance The IL-23 receptor is of interest as it is also associated with ankolysing
because frequently the arthritis precedes the onset of the skin lesions. A care- spondylitis and psoriatic arthritis while the CDKAL1 gene has also been
ful examination for nail changes and questioning about a family history may associated with Crohn's disease and type-2 diabetes mellitus.7
be of value in establishing the diagnosis. Certain factors are known to induce psoriasis in a person who is geneti-
cally predisposed. There is a tendency for lesions to develop at sites of previ-
Pathogenesis and histological features ous skin trauma (e.g., mechanical friction, sunburn or childhood illnesses such
Although the etiology of psoriasis remains incompletely understood, consid- as varicella); this is termed the isomorphic or Koebner's phenomenon.36–38
erable advances have been made in the past two decades to unravel the com- Infections are well known as predisposing factors in the onset of psoriasis.
plex mechanisms involved in the pathogenesis of this common dermatosis. In children in particular, upper respiratory tract infections frequently trig-
For many years psoriasis was considered to represent a primary epidermal ger psoriasis, while infections with Streptococcus pyogenes are implicated in
hyperproliferative disorder. More recent studies, however, have shown that the development of acute guttate psoriasis, together with an exacerbation of
a T-lymphocyte-driven immune process is central to the development of the other forms of psoriasis.39–42 Specific streptococcal serotypes, however, do not
psoriatic plaque and, in fact, may represent the earliest stage in its evolution. appear to be implicated.
Other important factors include genetic influences, the environment, and the Other factors known to exacerbate psoriasis include stress, bereavement,
contribution of keratinocyte-derived mediators of the inflammatory process. HIV/AIDS, withdrawal of corticosteroids after prolonged use, and treatment
Psoriasis 207
with a number of drugs including lithium, antimalarials, and beta-blocking promotes keratinocyte proliferation and induces angiogenesis.73,74 IL-8 is pre-
agents.6,43 dominantly derived from superficial keratinocytes and the associated neu-
The development of the psoriatic plaque results from a complex interplay trophils within the psoriatic plaque. MGS/GRO-α is an additional powerful
between keratinocyte hyperproliferation with loss of differentiation, changes neutrophil chemoattractant.69
in the superficial dermal vasculature, and a T-lymphocyte-mediated inflam- The pathogenesis of psoriasis therefore involves interaction between
matory component.44 The relative roles of keratinocyte hyperplasia, vascular injured keratinocytes and activated lymphocytes through the release of vari-
changes, and immunological reactions have been the subject of much discus- ous cytokines developing in a background of genetic predisposition.71 The
sion in the recent literature.45 Most recently, the focus has been particularly precise relationship between the T-cell-driven immune reaction and epider-
directed towards the importance of the innate as well as adaptive immune mal hyperplasia, however, remains unclear. Similarly, the initiator(s) of this
systems.7 process are uncertain. Although autoantigens and bacterial superantigens are
In the skin there is an increased epidermal proliferation rate: the transit currently favored, the possibility of a direct consequence of lymphocyte–kera-
time of keratinocytes through the epidermis in normal skin is 56 days; in pso- tinocyte interaction has not yet been disproved.74
riatic skin it is shortened to 7 days.46,47 The epidermal cell cycle is probably In biopsies of the early lesions, the histological features consist primarily
shortened, and there is a large increase in the number of proliferating genera- of dermal changes.75–79 The evolution of the psoriatic plaque consists initially
tive cells in the basal layers, where up to three layers of proliferating cells may of the development of tortuous, dilated, and frequently congested capillaries
be seen compared with only one in normal resting epidermis. in the superficial papillary dermis accompanied by edema and a perivascu-
Vascular proliferation predominantly affecting the postcapillary venules lar mononuclear cell infiltrate (Fig. 6.89).75 This vascular change is common
of the dermal papillae appears to be one of the earliest manifestations of to all forms of psoriasis and may even be seen in biopsies from clinically
psoriasis.48 This is mediated by upregulation of αVβ3 integrin and vascular resolved lesions following treatment.78 Lymphocytes then migrate into the
endothelial growth factor (VEGF).49–51 lower epidermis, which becomes spongiotic. Subsequently, the upper epider-
The current weight of evidence suggests that a T-cell-mediated immune mis shows focal vacuolation and eventual loss of the granular cell layer with
reaction is central to the pathogenesis of psoriasis.44,52 Clinical studies sup- the resultant formation of parakeratotic mounds. Migration of neutrophils
porting this hypothesis include the response to antilymphocyte therapies from capillaries in the dermal papillae through gaps in the epidermal base-
such as ciclosporin.53 More recently, remission in patients with severe pso- ment membrane and hence to the stratum corneum completes the process.
riasis has resulted from treatment with an activated T-lymphocyte selective Psoriasiform hyperplasia of the affected epidermis then follows.
toxin DAB389 IL-2 that interacts with the receptor-binding domain of IL-2.54 Classical plaque psoriatic lesions show marked and characteristic acan-
Successful responses to therapy with monoclonal anti-CD3 and anti-CD4 thosis of the epidermal ridges, which are evenly elongated and club-shaped at
antibodies adds further support.55,56 Additional evidence has come from bone their bases, alternating with long edematous papillae, which are club-shaped
marrow transplantation studies. Unaffected patients develop psoriasis follow- at their tips (Figs 6.90–6.93). Fusion of adjacent ridges is commonly pres-
ing a transplant from an affected donor whereas patients are cured of their ent in established lesions. The suprapapillary plate is typically thinned and
disease following transplantation from an unaffected donor.57 In vitro stud- the epidermal surface is covered by confluent parakeratosis associated with
ies in which intradermal injection of T-helper lymphocytes from an affected diminution or loss of the granular cell layer. The lower suprabasal layers of
patient into severe combined immunodeficient mice results in the development the epidermis can frequently be seen to be actively dividing. Large tortuous
of typical psoriasis further supports a T-lymphocyte-driven pathogenesis.58 capillaries are present in the papillary dermis and there is a slight perivascular
The innate immune system appears to play an important part in the early lymphocytic infiltrate in the subpapillary dermis. Palmar and plantar lesions
stages of the disease and increased numbers of activated plasmacytoid den- may sometimes cause diagnostic difficulty as spongiosis can be marked, and
dritic cells are present in early psoriatic lesions.59 Production of interferon occasionally vesiculation is evident.78
alpha by plasmacytoid dendritic cells and TNF-α and INF-γ by natural killer The diagnostic features of active lesions include the ‘Munro microab-
cells leads to activation of myeloid dendritic cells and subsequent prolifera- scess’ and ‘spongiform pustule of Kogoj’. Munro microabscesses represent
tion of T cells through IL-12 and IL-23 release.7,60 an accumulation of polymorphs within the parakeratotic stratum corneum.
Although CD4 T-helper (Th) lymphocytes are probably of importance in Spongiform pustules are seen beneath the keratin layer and consist of small
the earliest stages of plaque development, the major population is charac- accumulations of neutrophils and occasional lymphocytes intermingled with
terized by CD8 expression. The immunophenotype of the T cells includes the epidermal cells in foci of spongiosis.
CD45RO+, HLADR+, CD25+ and CLA+, indicating activated skin-specific
memory cells.61 The lymphocyte cytokine profile, which includes IL-2, IL-17,
interferon gamma (IFN-γ), and absence of IL-4, IL-10, and tumor necrosis
factor alpha (TNF-α), reflects a predominantly Th1-mediated inflammatory
reaction as well as IL-17-A producing type 17 helper T (Th17) cells.7,62–64
Th17 cells are of particular importance for epithelial immunosurveillance
and produce IL-22, a molecule involved in keratinocyte differentiation and
proliferation.65,66 IFN-γ is central to the development of the plaque. In vitro
studies have shown that the keratinocyte proliferation is IFN-γ dependent.67
Also, IFN-γ injection in normal human skin results in epidermal prolifera-
tion.68 In addition to the lymphocyte-derived cytokines discussed above, the
keratinocytes themselves are a rich source of inflammatory mediators, which
are likely to be of importance in initiating the inflammatory reaction and
the development and maintenance of the psoriasiform plaque.69 In particular,
keratinocytes secrete IL-1α, IL-1β, and TNF-α. These cytokines play a major
role in angiogenesis, in recruitment of circulating lymphocytes, and induc-
ing expression of a number of endothelial cell adhesion molecules includ-
ing E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell
adhesion molecule-1 (VCAM-1).69–71 These last are of particular importance
in facilitating the extravasation of lymphocytes through the endothelium.52
Keratinocytes are also a valuable source of chemokines including IL-8, mela-
noma growth stimulatory activity alpha (MGS/GRO-α), gamma inducible Fig. 6.89
protein 10 (IP-10), and molecule chemoattractant protein 1 (MCP-1).69 IL-8 Evolving psoriasis: in the early stages, there is capillary dilatation, with spongiosis,
is of importance in both neutrophil and T-lymphocyte chemotaxis.72 It also as shown in this field. A small parakeratotic mound is also demonstrated.
Fig. 6.90 Fig. 6.93

Plaque psoriasis: scanning view showing extensive parakeratosis, regular Plaque psoriasis: tortuous and dilated capillaries.
acanthosis, club-shaped epidermal ridges, and ridge fusion.
In guttate psoriasis, the histological features overlap with those of evolv-

ing disease.78 Parakeratosis associated with loss or diminution of the granular
cell layer is limited to small foci contrasting with a background of orthokera-
tosis (Figs 6.94, 6.95). Neutrophils are seen surmounting the parakeratotic
tiers. Acanthosis is much less marked than in fully established plaque disease.
Neutrophils and lymphocytes are commonly present in the superficial papil-
lary dermis and mild spongiosis is often a feature, particularly if biopsies of
early lesions are examined.80
In generalized pustular psoriasis and its three variants the histological pic-
ture is slightly different in that the spongiform pustule occurs as a macropus-
tule and is the characteristic lesion (Figs 6.96, 6.97).79 As the spongiform
pustule increases in size, the epidermal cells die, with resulting central cavita-
tion. At the edges, a shell of thinned epidermal cells remains. Eventually there
is migration of neutrophils into the horny layer and the picture resembles that
of a large Munro abscess. Although the epidermal and dermal features may
be similar to those of psoriasis vulgaris, particularly if the pustule has devel-
oped against a background of plaque-type disease, more often the features
are much less well developed (Fig. 6.98). Frequently, therefore, there is no or
only minimal epidermal hyperplasia although tortuous and dilated capillaries
Fig. 6.91 accompanied by a lymphocytic or mixed lymphocytic and neutrophil infiltrate
Plaque psoriasis: closer view showing parakeratosis with neutrophil aggregates are usually seen.11
(Munro microabscess). There is marked dilatation and tortuosity of the capillaries
within the dermal papillae. Spongiosis is also present.
Fig. 6.94
Fig. 6.92 Guttate psoriasis: the multiple discrete, parakeratotic mounds are characteristic.
Plaque psoriasis: Munro microabscess, spongiform degeneration, and parakeratosis. Hyperplasia is not as well developed as in plaque disease.
Psoriasis 209
Fig. 6.95 Fig. 6.98

Guttate psoriasis: close-up view. Pustular psoriasis: in this patient, the lesions developed dramatically in the absence of
significant plaque disease. There is only mild hyperplasia of the underlying epidermis.
In palmar/plantar pustular lesions, the initial changes are those of spon-

giosis with lymphocytic exocytosis in the lower epidermis.80 As the lesion
progresses, neutrophils infiltrate the epidermis and a macropustule develops.
In psoriatic erythroderma the histological features are variable but in the
majority of cases a positive diagnosis can be established.81 Most commonly,
the features are those of evolving psoriasis similar to guttate psoriasis, i.e.,
slight epidermal hyperplasia, focal diminution or loss of the granular cell
layer, and mild spongiosis (Fig. 6.99). Parakeratosis is often limited to slight
change overlying the hyperplastic epithelium and neutrophils are variably
present (Fig. 6.100). A lymphohistiocytic infiltrate is present in an edema-
tous papillary dermis and dilated, tortuous, spiraling vessels are regularly
evident. Extravasated red blood cells are a constant finding. Less commonly,
the features are those of psoriasis vulgaris and sometimes the changes overlap
regressing psoriasis.
In resolving lesions, foci of hyperkeratosis overlying hypergranulosis are
scattered through the parakeratotic scale and the epidermal hyperplasia is less
marked (Fig. 6.101).
Current treatment for severe widespread plaque psoriasis may include
Fig. 6.96 the use of PUVA therapy. Over the recent years it has been shown that this
Pustular psoriasis: a macropustule is present. Typical psoriasiform hyperplasia with is associated with an increased risk (albeit low) of cutaneous squamous
parakeratosis is seen in the adjacent epidermis. cell carcinoma and dysplastic keratoses.82–85 Patients at most risk include
Fig. 6.99
Fig. 6.97 Psoriatic erythroderma: there is only very focal parakeratosis with scattered
Pustular psoriasis: close-up view. neutrophils. The epidermal hyperplasia is only slight.
Fig. 6.100 Fig. 6.102

Psoriatic erythroderma: close-up view of parakeratosis and neutrophil karyorrhectic Bullous pemphigoid and pustular psoriasis: on the left is a subcorneal pustule while
debris. on the right is a subepidermal blister.
Fig. 6.101 Fig. 6.103

Resolving psoriasis: newly formed basket-weave orthokeratin is seen underlying Bullous pemphigoid and pustular psoriasis: higher-power view of the blister.
focal residual parakeratosis.
those who have had more than 200 PUVA treatments and/or a cumula-
tive dose in excess of 1000 J/cm2. There is some evidence to suggest that
these tumors behave in a low-grade fashion, with little risk of metastatic
spread.85
Psoriasis may rarely coexist with a number of autoimmune bullous
dermatoses including bullous pemphigoid, pemphigus vulgaris, linear IgA
disease, and epidermolysis bullosa acquisita.86–92 Although not in all cases,
there is often a relationship to treatment, particularly with PUVA ther-
apy. In some instances, the histology may show features of both conditions
(Figs 6.102–6.104).
The differential diagnosis of psoriatic lesions includes a number of
conditions:
• Pityriasis rubra pilaris differs from psoriasis by the presence of
alternating parakeratosis and hyperkeratosis in both vertical and
horizontal directions (spotty parakeratosis). Neutrophil infiltration of the
stratum corneum is not a feature of pityriasis rubra pilaris unless there is Fig. 6.104
secondary infection. Bullous pemphigoid and pustular psoriasis: higher-power view of the pustule.
Pityriasis rubra pilaris 211
• Lichen simplex chronicus typically shows scarring of the dermal papillae

due to persistent rubbing, and there is no thinning of the suprapapillary
plate. Hyperkeratosis and hypergranulosis are often marked and there is
minimal parakeratosis unless there is a background of spongiosis.
• Papulosquamous drug eruptions (e.g., due to lithium or propranolol)
may appear similar to psoriasis, but a moderate to high number of
eosinophils is usually present in the infiltrate.
• Seborrheic dermatitis typically shows psoriasiform hyperplasia and
corneal neutrophil infiltration may sometimes be a feature. It differs from
psoriasis by the presence of a more conspicuous spongiotic component,
which in psoriasis only occurs in early lesions and is usually not marked.
In those cases where the distinction is not possible, the term ‘sebo-
psoriasis’ is sometimes used.
• Pustular psoriasis and its variants are all similar; they must be
distinguished from other pustular eruptions, including conditions such
as pustular dermatophytoses, bacterial impetigo, and pustular drug
eruptions. Pustular psoriasis may be differentiated from subcorneal
pustular dermatosis by the absence of spongiform change or degeneration
in the latter condition. Gram and PAS stains and culture will exclude Fig. 6.105
infective conditions. Superficial pemphigus can be distinguished by Pityriasis rubra pilaris: there is characteristic hyperkeratosis and surrounding
the presence of acantholysis and the usual absence of psoriasiform erythema. At the edges individual follicular lesions are evident. By courtesy of M.M.
hyperplasia. In IgA pemphigus, acantholytic cells are usually, but not Black, MD, Institute of Dermatology, London, UK.
always, present and this diagnostic clue may be very easily overlooked,
but should allow distinction from psoriasis. In lesions of IgA pemphigus
that lack acantholytic cells, immunofluorescence studies may be
necessary to make the distinction from pustular psoriasis if the clinical
diagnosis is in doubt.
Reiter's syndrome
The skin lesions of Reiter's syndrome typically show psoriasiform hyperpla-
sia with parakeratosis. The epidermis is markedly acanthotic with elonga-
tion and hypertrophy of the epidermal ridges. The suprapapillary plates are
thinned and there is infiltration of the epidermis by neutrophils, associated
with the formation of spongiform pustules, microabscesses, and ultimately
macropustules indistinguishable from pustular psoriasis. A perivascular lym-
phohistiocytic infiltrate with neutrophils is seen in the upper dermis.
Pityriasis rubra pilaris

Pityriasis rubra pilaris:
Pityriasis rubra pilaris is an erythematous papulosquamous disorder character-
confluence of lesions
ized by follicular plugging (often best seen on the dorsal aspects of the hands leads to extensive
and feet), perifollicular erythema that becomes confluent, palmoplantar hyper- erythroderma.
keratosis, and pityriasis capitis.1–3 It is an uncommon disease, accounting for By courtesy of the
approximately one of every 5000 new dermatological referrals in the United Institute of Dermatology,
Kingdom.3 Males and females are affected equally and the age distribution London, UK.
tends to peak in the first and fifth decades.3 Although the majority of cases doc-
umented have affected Caucasian patients, occasional reports describing pityri-
asis rubra pilaris in black African patients have recently been published.4 The nails are also affected, showing distal yellow–brown discoloration,
Pityriasis rubra pilaris has been classified clinically into five types:3 subungual hyperkeratosis, nail thickening, and splinter hemorrhages.6
• Type I, classical adult pityriasis rubra pilaris, is seen in over 50% of Ectropion is often present,7 and there may be diffuse alopecia.8 Oral
patients. Initially, a single erythematous patch appears on the upper lesions are uncommon and include diffuse hyperkeratosis and macular
half of the body (typically the face and scalp) and gradually spreads as erythema with white streaks reminiscent of lichen planus.5 Prognosis for
large areas of sometimes pruritic or burning follicular hyperkeratosis patients in this group is good, with up to 80% resolving within 3 years.
with erythematous perifollicular halos (Fig. 6.105).4 The erythematous • Type II, atypical adult pityriasis rubra pilaris, occurs in approximately
areas coalesce and many patients develop generalized erythroderma 5% of patients and is manifested by atypical morphological features
(Fig. 6.106). Characteristically, occasional islands of unaffected skin and a lengthy duration, often up to 20 years. The scaling is more
are present (Fig. 6.107). Follicular papules on the dorsal aspects of ichthyosiform and there are often areas of eczematous change. The
the fingers and extensor surfaces of the wrists, arms, and thighs are prognosis in this group is poor, with only 20% resolving within 3 years.
said to be characteristic.5 Fine and powdery scaling occurs on the face • Type III, classical juvenile pityriasis rubra pilaris, resembles the classical
and scalp, with coarser scaling on the lower body (Fig. 6.108). The adult form except for its age distribution; it affects children up to 2 years
erythema has an orange–yellow tint, which is more noticeable on the of age, accounting for approximately 10% of patients (Fig. 6.110). More
palms and soles, together with marked hyperkeratosis (Fig. 6.109). often, however, the eruption commences on the lower half of the body.
Fig. 6.110
Fig. 6.107
classical juvenile type.
Pityriasis rubra pilaris: characteristic, scattered islands of unaffected skin are evident.
Note the very extensive
distribution of the lesions.
By courtesy of M.M.
The prognosis in this group is good, most patients clearing within 1 year
but a recurrence rate of up to 17% has been reported.9
• Type IV, circumscribed pityriasis rubra pilaris, affects 25% of patients
and presents in prepubertal children. Sharply defined areas of follicular
hyperkeratosis and erythema are seen on the knees and elbows, together
with occasional scaly erythematous patches on the rest of the body and
palmoplantar hyperkeratosis.10
• Type V, atypical juvenile pityriasis rubra pilaris, accounts for approximately
5% of patients; presentation occurs early in life and this type has a lengthy
duration. Characteristic follicular hyperkeratosis is present, together with a
mild erythema. Ichthyosiform features are sometimes seen.5 The skin of the
feet and hands may become thickened and scleroderma-like.
Familial variants, which account for 0–6.5% of cases, mostly present with atyp-
ical features as described in type V pityriasis rubra pilaris.5 In most families, inheri-
tance has been via an autosomal dominant mechanism with variable expression
and reduced penetrance although a recessive form has also been postulated.11
Fig. 6.108
Pityriasis rubra pilaris has been reported in association with HIV
Pityriasis rubra pilaris: in this patient, the scale is conspicuous.
infection.12,13 Nodulocystic acneiform or furuncle-like lesions and lichen
spinulosus may also be present. This is a particularly severe variant, which
responds poorly to therapy.13 Further associations include rheumatological
disease, in particular arthritis, dermatomyositis, and underlying malignancy
possibly representing a paraneoplastic phenomenon.14–25

The etiology of pityriasis rubra pilaris is largely unknown. It has been associ-
ated with abnormal vitamin A metabolism but there is little evidence in sup-
port for this other than a frequent response to vitamin A or retinoid therapy.5
Linkage to autoimmune disease, immune dysfunction, internal malignancy,
infections and, particularly in recent years, to human immunodeficiency
virus, have also been described.5,13,26,27 In the majority of cases, however, there
Fig. 6.109 is no preceding or associated condition. Pityriasis rubra pilaris is associated
Pityriasis rubra pilaris: with an increased rate of epidermopoiesis.28–32
palmar and plantar Fully developed follicular papules show characteristic features comprising
erythema with conical follicular plugging, with marked uniform acanthosis of the epidermis
hyperkeratosis are
and broad epidermal ridges and dermal papillae (Fig. 6.111).28,29,33 There is
frequent manifestations.
hyperkeratosis, with foci of parafollicular parakeratosis. In the dermis there
Sometimes, there is an
orange–yellow tint, as is a mild to moderate inflammatory cell infiltrate and sebaceous atrophy.
seen in this patient. By Although the histological features may be non-specific, biopsies from
courtesy of the Institute established, nonfollicular lesions comprise alternating orthokeratosis and
of Dermatology, London, parakeratosis in both vertical and horizontal directions, focal or confluent
UK. hypergranulosis, thick suprapapillary plates, broad epidermal ridges, narrow
Pityriasis rubra pilaris 213
Fig. 6.113
Fig. 6.111 Pityriasis rubra pilaris: alternating hyperkeratosis and parakeratosis.
follicular lesion showing
the conical keratin plug.
Parakeratosis is present
above the adjacent
epithelium.
dermal papillae, and a perivascular lymphocytic infiltrate in the superficial

dermis (Figs 6.112–6.114).34 Small numbers of plasma cells and eosinophils
are sometimes present.26 Superficial blood vessels may appear slightly dilated.
Occasionally there is also mild spongiosis with scattered intraepidermal lym-
phocytes.27 Neutrophil infiltration as seen in psoriasis is not usually a feature
of pityriasis rubra pilaris and its presence may indicate a bacterial or fungal
superinfection. Acantholysis with or without dyskeratosis involving follicular
and interfollicular epithelium has recently been emphasized, and exception-
ally a lichenoid infiltrate has been documented.26,35–38
In early lesions, the diagnosis is often problematical. Parakeratosis is usu-
ally poorly developed and lamellar orthohyperkeratosis predominates.34
Hypergranulosis is present and the rete ridges are broadened and slightly
elongated. The suprapapillary plates may be mildly thickened.
In erythrodermic lesions, the keratin layer may be thinned or lost and the
granular cell layer diminished.34
Palmar and plantar lesions show hyperkeratosis, focal parakeratosis, and
mild acanthosis (Fig. 6.115).
Fig. 6.114
close-up view.
Fig. 6.115
plantar lesion showing
hyperkeratosis, focal
Fig. 6.112 parakeratosis, and regular
Pityriasis rubra pilaris: there is hyperkeratosis with focal parakeratosis and acanthosis with a rounded
psoriasiform hyperplasia. lower border.
214 Spongiotic, psoriasiform and pustular dermatoses Inflammatory linear verrucous epidermal nevus
Pityriasis rubra pilaris may be confused both clinically and histologically
with psoriasis. Features in favor of pityriasis rubra pilaris include follicular
plugging with parakeratosis of the adjacent epithelium, focal parakeratosis,
broad rete ridges, thickened suprapapillary plates, increased granular cell
layer, and an absence of tortuous dilated capillaries immediately adjacent to
the epidermis. In psoriasis the acanthosis is typically more marked and often
strikingly regular, the rete ridges are thin and often fused, the suprapapillary
plate is thinned, parakeratosis is usually confluent, and characteristic collec-
tions of neutrophils are seen in the overlying parakeratotic stratum corneum
in association with spongiform degeneration of the underlying superficial
epidermis.
Inflammatory linear verrucous

epidermal nevus
Clinical features
Fig. 6.117
Inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon
Inflammatory linear verrucous epidermal nevus (ILVEN): in this view there is marked
condition which usually presents in infants or young children as an intensely psoriasiform epidermal hyperplasia with massive hyperkeratosis. Mild chronic
pruritic, persistent, scaly, unilateral, linear erythematous lesion following inflammation is seen in the superficial dermis.
the lines of Blaschko.1 Individual lesions are discrete, scaly papules, which
coalesce to form plaques.2 Superimposed lichenification and excoriations are
commonly present. Although lesions may be widely distributed, the leg, thigh,
and buttock are sites of predilection (Fig. 6.116).1,3 Females are more often
affected than males (4:1).2 The left side of the body is most often involved.2,4,5
Much less commonly, the disorder is bilateral and, exceptionally, the condi-
tion is generalized.6–8 Familial cases have been documented and adults may
sometimes be affected.7–11 Occasionally inflammatory linear verrucous epi-
dermal nevus coexists with psoriasis and rarely it presents as part of the epi-
dermal nevus syndrome.12,13 Exceptionally, the condition is associated with
arthritis.14
Histologically, the nevus is characterized by sharply demarcated, alternating
parakeratosis and orthohyperkeratosis (Figs 6.117–6.119).2,5,15 The epider-
mis shows papillomatosis with psoriasiform hyperplasia and absence of the
Fig. 6.118
Inflammatory linear verrucous epidermal nevus (ILVEN): alternating hyperkeratosis
and parakeratosis is characteristic.
Fig. 6.116
Inflammatory linear
verrucous epidermal
nevus (ILVEN): patients
present with scaly,
erythematous, itchy
papules and plaques
in a linear distribution,
showing a predilection
for the legs. From the
of Dermatology, London, Fig. 6.119
UK. Inflammatory linear verrucous epidermal nevus (ILVEN): close-up view.
Subcorneal pustular dermatosis 215
granular layer below the foci of parakeratosis contrasting with a thickened

granular cell layer underneath the orthohyperkeratosis. Occasionally, Munro
microabscesses are a feature. The rete ridges are elongated and thickened.
Focal slight spongiosis is present, accompanied by lymphocytic exocytosis.
A mild perivascular lymphocytic infiltrate is seen in the superficial dermis.
ILVEN must be distinguished from linear psoriasis.16 In ILVEN, parakera-
tosis alternates with orthohyperkeratosis in contrast with psoriasis where
the parakeratosis is confluent. Similarly, the thickened rete ridges of ILVEN
contrast with the thinned ones of psoriasis. By immunocytochemistry, in
ILVEN, involucrin expression is markedly diminished in the epithelium deep
to the parakeratosis, while it is increased in the epithelium underlying the
hyperkeratosis.17 In psoriasis, there is a general increase in involucrin expres-
sion throughout the entire lesion.
Rare cases of ILVEN showing histiocyte infiltration of the underlying
dermis reminiscent of verruciform xanthoma have been documented.18–21
Bazex syndrome (acrokeratosis Fig. 6.120

paraneoplastica) Bazex syndrome: note the
violaceous discoloration
Clinical features of the ear. By courtesy of
J.L. Bolognia, MD, Yale
Bazex syndrome denotes an acral psoriasiform dermatosis in association Medical School, CT, USA.
with internal malignancy.1–3 Elderly patients, usually males, present with
a symmetric erythematous or violaceous, scaly eruption affecting the ears,
nose, fingers, and toes (Fig. 6.120).1 The knees and elbows may some-
times be involved. Vesicles and bullae are less common manifestations.4
In patients with black or dark-brown skin, the lesions can present with
hyperpigmentation.2 Palmoplantar lesions are keratodermatous and nail
involvement ranges from paronychia, horizontal or vertical ridging, yellow
discoloration and thickening to onycholysis and subungual keratotic debris
(Fig. 6.121).1
Patients with Bazex syndrome invariably have an associated systemic malig-
nancy, most often affecting the oropharynx, larynx, esophagus, and lung, in
descending order of frequency.1 Cervical lymph node metastases are com-
monly present. Persistence of the cutaneous lesions is rare and they commonly
regress following successful treatment of the underlying malignancy.2,5
Histologically, there is considerable overlap with psoriasis and chronic spon-
giotic dermatitis, the epidermis showing hyperkeratosis, parakeratosis, and
acanthosis. In addition however, dyskeratosis and interface changes reminis-
cent of lichen planus are also commonly present.1 A perivascular or less com-
monly lichenoid chronic inflammatory cell infiltrate is present in the superficial Fig. 6.121
dermis. Bazex syndrome: keratoderma. By courtesy of J.L. Bolognia, MD, Yale Medical
Bullous lesions may be subepidermal or, less often, intraepidermal.1,6 School, CT, USA.
Pustular dermatoses
Pustular drug reactions ally been described.3,4 It may be associated with a benign or malignant IgA
paraproteinemia (up to 40% of cases) or multiple myeloma, and sometimes
This topic is discussed in the chapter on adverse reactions to drugs. pyoderma gangrenosum is also present.5–15 Other associations include rheu-
matoid arthritis, systemic lupus erythematosus, hyperthyroidism, Crohn's
disease, multiple sclerosis, IgG cryoglobulinemia, bullous pemphigoid, mor-
Subcorneal pustular dermatosis phea, diffuse scleroderma, Sjögren syndrome, marginal zone lymphoma,
chronic lymphocytic leukemia, squamous carcinoma of the bronchus, and
Clinical features metastatic gastrinoma, although it is doubtful whether these are of any great
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is a rare significance.15–26
chronic, relapsing, and apparently noninfective eruption of unknown eti- Clinically, patients present with waves of superficial flaccid pustules in
ology.1,2 It predominantly affects females (4:1) and is usually diagnosed circinate or serpiginous groups and sheets, particularly in the folds of the
during the middle years of life. Pediatric cases have, however, occasion- body, such as the axillae (Figs 6.122, 6.123) and groins, beneath the breasts,
Fig. 6.122
Subcorneal pustular
dermatosis: typical
example showing a
Fig. 6.123
succession of pustules
Subcorneal pustular dermatosis: close-up view of early lesions characterized by
spreading outwards from
numerous pustules arising on an erythematous background. By courtesy of R.A.
the axilla. At the periphery
the lesions are healing
with crust formation. By
London, UK.
and on the abdomen. Fluid levels are sometimes evident. Typically, the
mucous membranes, face, scalp, and peripheries are spared. Healing is rapid,
usually within a few days or weeks, and the condition responds to dapsone,
although not as dramatically as dermatitis herpetiformis. Postinflammatory
hyperpigmentation is common.
Canine subcorneal pustular dermatosis, particularly affecting Miniature
Schnauzers, has been reported.27

The etiology of subcorneal pustular dermatosis is unknown. Intercellular
IgA deposits have been identified in a significant number of cases by direct
immunofluorescence and many patients have a circulating IgA pemphigus
antibody. These cases have been documented in the literature as IgA pemphi- Fig. 6.124
gus.28–33 Subcorneal pustular dermatosis should be restricted to the immuno- Subcorneal pustular dermatosis: situated immediately below the stratum corneum
fluorescence-negative group. is a blister cavity containing edema fluid and numerous neutrophils. The epidermis
The characteristic lesion is a subcorneal pustule, which appears to sit on shows neutrophils in transit. Within the papillary dermis is a neutrophil and
the skin surface (Fig. 6.124). The contents of the pustules are predominantly lymphocytic infiltrate.
neutrophils, although an occasional eosinophil may be identified. The epi-
dermis beneath the pustule shows surprisingly little change except for poly-
morphs in transit and perhaps slight intercellular edema (Fig. 6.125).
Older lesions may contain acantholytic cells (Fig. 6.126). In the dermis,
superficial blood vessels are surrounded by a non-specific mixed inflamma-
tory cell infiltrate consisting of neutrophil polymorphs and mononuclear
cells.
The histological features of subcorneal pustular dermatosis cannot be reli-
ably distinguished from those of bullous impetigo, staphylococcal scalded
skin syndrome, pemphigus foliaceus, and IgA pemphigus. Impetigo is, how-
ever, a disease of young children and, although a Gram stain is often negative,
cultures should grow staphylococci or streptococci.
The staphylococcal scalded skin syndrome (Ritter's disease) is predomi-
nantly a disease of infants, but rarely it may present in adults. Clinically it
is different from subcorneal pustular dermatosis, being characterized by the
development of large flaccid blisters, which rupture, leaving extensive areas
of denuded skin.
Although acantholysis is typical of the pemphigus group of diseases, it Fig. 6.125
may occasionally be seen in impetigo, staphylococcal scalded skin syndrome, Subcorneal pustular dermatosis: close-up view.
Infantile acropustulosis 217
during delivery was initially thought to be of pathogenetic importance, more

recent data favor an immunological response to the initial colonization of the
skin by commensal microorganisms.11–16
Early erythematous lesions show a somewhat nondescript perivascular
inflammatory cell infiltrate with conspicuous eosinophils, which may be seen
penetrating the epidermis in close proximity to hair follicles. In an established
lesion, the pustules are follicular, lie subcorneally, and contain large numbers
of eosinophils and occasional neutrophils.17 The external root sheath of the
infundibulum may also be affected.
Toxic erythema of the neonate must be distinguished from incontinentia pig-
menti. The latter, however, is characterized by eosinophilic spongiosis, a fea-
ture not seen in toxic erythema. In miliaria rubra the vesicles are related to
sweat ducts rather than hair follicles and typically contain mononuclear cells
rather than eosinophils. Toxic erythema of the neonate must also be distin-
guished from infantile acropustulosis, transient neonatal pustular melanosis,
Fig. 6.126 and infantile eosinophilic pustular folliculitis (see below).
Subcorneal pustular
dermatosis: in addition
to neutrophils there are
scattered acantholytic Infantile acropustulosis
keratinocytes.
These features are Clinical features
indistinguishable from
those of pemphigus
This uncommon condition usually presents in the first year of life and is
foliaceus. sometimes evident at birth.1–4 There is a marked male predilection. Although
it is most often seen in black children, it has occasionally been reported in
Asians and whites.5–8
The disorder presents as crops of intensely itchy, erythematous papules
subcorneal pustular dermatosis, and pustular psoriasis. In difficult cases the 1–5 mm in diameter, vesicles, and pustules, which are found most often on the
demonstration of positive immunofluorescence will establish the diagnosis of palms and soles, but the volar surfaces of the wrists, the ankles, the face, and
pemphigus (however, see IgA pemphigus). scalp may occasionally be affected (Fig. 6.127).6 The mucous membranes
There has been considerable controversy in earlier literature concerning are spared.1 Lesions are often present for 1–2 weeks and tend to recur every
the relationship between subcorneal pustular dermatosis and pustular psoria- 2–4 weeks. With progression, the duration of the eruption diminishes and the
sis, with some authors claiming them to be one and the same condition and remission lasts for gradually increasing periods of time. Spontaneous resolu-
others equally determined that they are quite different. In our view, these are tion has usually occurred by 2–3 years of age.
two distinct diseases. Thus, in subcorneal pustular dermatosis, there is no
family history and there is no evidence of more typical psoriasiform lesions Pathogenesis and histological features
elsewhere. Subcorneal pustular dermatosis responds to dapsone in the vast
majority of cases and histologically spongiform change deep to the pustule The etiology and pathogenesis of this condition are unknown. However, infan-
(typical of psoriasis) is characteristically absent. Psoriasis is not associated tile acropustulosis may be associated with atopy and hypereosinophilia.6,9–11
with monoclonal gammopathy or multiple myeloma. Sometimes, a history of prior or concurrent scabies infection is present but
whether this is causal is uncertain.4
Toxic erythema of the neonate

Clinical features
Toxic erythema of the neonate (erythema toxicum neonatorum, erythema neo-
natorum) is a very common self-limiting disorder affecting from 48% to 72%
of all newborn infants.1–7 There is no racial predilection but males appear
more commonly affected.2,8 It presents as an asymptomatic erythematous mac-
ular rash usually in the first 3 days of life.1,9 Occasionally, it may be evident
at birth and, exceptionally, the onset is delayed until the second week after
birth.5,6,10 Sometimes there are papules and vesicles and, in some patients, pus-
tule formation is evident. The condition most often affects the forehead, face,
chest, trunk, and extremities.1 The palms and soles are typically uninvolved.
The eruption is asymptomatic and very typically transient, with lesions often
lasting only a number of hours or days.1 Full resolution is usually achieved by
1–5 days although recurrences may occur in up to 11% of neonates.2 Toxic
erythema of the neonate is frequently associated with a peripheral blood
eosinophilia.

The etiology of this condition is completely unknown.2 While an acute graft- Infantile acropustulosis: typical small pustules centered about the base of the
versus-host type of reaction resulting from transfer of maternal lymphocytes thumb. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Histology reveals a subcorneal pustule containing predominantly

eutrophils, although occasionally small numbers of mononuclears and
n Eosinophilic pustular folliculitis of infancy
eosinophils are evident. Eosinophil-rich pustules have also been described but
with hindsight most such cases probably represent eosinophilic pustular fol- Clinical features
liculitis.11 Slight acantholysis of the adjacent epidermis has been described.12 Eosinophilic pustular folliculitis (Ofuji's disease), which is largely a con-
The underlying dermis often contains a perivascular chronic inflammatory dition of adults and presents as recurrent episodes of itchy follicular pap-
cell infiltrate, sometimes with scattered neutrophils and eosinophils. Direct ules and pustules on the face, trunk, and extremities, may rarely develop
and indirect immunofluorescence tests are negative. in infants.1–6 There is a predilection for males.1 In the infantile form,
lesions, which may be present at birth or develop during the first 24
Differential diagnosis hours, are found particularly on the scalp, hands, and feet.1,7–10 The trunk
The diagnosis of infantile acropustulosis depends upon careful clinicopatho- and limbs can also be affected.2 Patients present with 1–3-mm white
logical correlation. Conditions that may enter the differential diagnosis to yellow crusted pustules arising on an erythematous base.1,2 A blood
include scabies, pompholyx, Candida and dermatophytosis, herpes simplex, eosinophilia is often present.7,11 The condition persists from 3 months to
juvenile dermatitis herpetiformis, toxic erythema of the neonate, bullous up to 5 years.2
impetigo, eosinophilic pustular folliculitis occurring in infancy, and transient
neonatal pustular melanosis.
The etiology is unknown, although in a small number of cases an associa-
Transient neonatal pustular melanosis tion with atopy has been documented.12 In contrast to the adult disease, HIV
infection is very rarely present.13
Clinical features The histological features are those of an eosinophil-rich ‘spongiotic’ pus-
Transient neonatal pustular melanosis is an uncommon condition which pres- tule related to the outer root sheath of the hair follicle from the stratum
ents with vesicles and pustules on the forehead, under the chin, on the nape of corneum to the level of insertion of the sebaceous duct.14–18 A heavy inflam-
the neck, chest, back, and buttocks.1–4 In contrast to eosinophilic pustular follic- matory cell infiltrate consisting of eosinophils, lymphocytes, and histiocytes
ulitis of infancy, the scalp is rarely involved. It affects 4–5% of black infants and is present in the adjacent dermis. The reported histological features are, how-
0.1–0.3% of white infants.2 There is no sex predilection.3 Lesions, which present ever, less distinctive and specific compared to classic, adult-type, eosinophilic
at birth or during the first day of life, heal rapidly to leave small brown macules pustular folliculitis.10,19
with a peripheral scale, and have usually disappeared by 3 months of age.3 Numerous other pustular dermatoses may be encountered including
superficial pemphigus, particularly IgA pemphigus, pustular drug reac-
Histological features tions, bullous impetigo and staphylococcal scalded skin syndrome, pustu-
Histologically, the features are identical to those of infantile acropustulosis: lar dermatophyte infections, pustular lesions in pyoderma gangrenosum,
i.e., a subcorneal neutrophil-rich pustule sometimes accompanied by small and necrolytic migratory erythema. These are discussed elsewhere in this
numbers of eosinophils.1 book.
Lichenoid and interface Chapter
See
for references and
additional material
dermatitis
Wei-Lien Wang and Alexander Lazar
7
Lichenoid dermatoses 219 Interface dermatoses 237 Rothmund-Thomson syndrome 246
Lichen planus 219 Erythema multiforme 238 Blooms' syndrome 247
Lichen nitidus 229 Toxic epidermal necrolysis and Stevens-Johnson Cockayne's syndrome 248
Lichenoid keratosis 231 syndrome 241 Dyskeratosis congenita 248
Lichen striatus 232 Paraneoplastic pemphigus 245 Graft-versus-host disease 249
Adult Blaschkitis 233 Poikiloderma 245 Pityriasis lichenoides 255
Keratosis lichenoides chronica 234 Poikiloderma of Civatte 245
Erythema dyschromicum perstans 236 Mitochondrial DNA syndrome-associated
Lichenoid and granulomatous dermatitis 236 poikiloderma 246
The term ‘lichenoid’ refers to inflammatory dermatoses which are character- gingivae are most often affected, in decreasing order of frequency.12 Patients
ized by a bandlike lymphohistiocytic infiltrate in the upper dermis, hugging frequently present with a white lacelike pattern, but papules, plaques and
and often obscuring the dermoepidermal interface. Lichen planus is the proto- erosions, ulcerated, atrophic, and bullous variants may also be found (Figs
typic lichenoid dermatitis (Box 7.1). Interface dermatitis refers to the presence 7.4–7.6).1,15 Lesions are usually asymptomatic, although erosions and bul-
of basal cell vacuolization (hydropic degeneration) and is often accompanied lae are sometimes tender and painful. Chronic ulcerated oral lichen planus
by single-cell keratinocyte apoptosis (Box 7.2). These two terms are by no is of particular importance because it has been related to an increased risk,
means mutually exclusive as most lichenoid infiltrates are accompanied by albeit low, of developing squamous cell carcinoma (Fig 7.7). The risk of
interface change. However, some dermatoses are characterized primarily by developing malignancy is debated, with current literature suggesting that
interface change without a lichenoid infiltrate such as lupus erythematosus 0–12.5% of affected patients will develop an oral malignancy.12,16–22 Oral
and erythema multiforme. involvement in lichen planus and its relationship to cutaneous squamous
cell carcinoma is discussed in greater depth elsewhere. Involvement of the
gums may present as desquamative gingivitis.1 Other mucous membranes
Lichenoid dermatoses that may be involved include those of the pharynx, larynx, esophagus,
nose, anus, and genitalia.23 Familial cases of lichen planus limited to oral
involvement are noted.24
Lichen planus Ocular involvement is rare and may include eyelid lesions, blephari-
tis, conjunctivitis, keratitis, punctate corneal opacities, iridocyclitis, and
Clinical features chorioretinitis.25,26
Lichen planus (Gr. leichen, tree moss) is a common, usually intensely pruritic, Esophageal involvement, although rare, is an important potential
symmetrical, papulosquamous dermatosis.1,2 Its prevalence in the general cause of morbidity, and is the most frequently involved gastrointestinal
population is approximately 1%, and it most often presents in the fourth to site.27 Concomitant oral lesions are invariably present. To date, middle-
sixth decades with a slight female predominance.3,4 It is uncommon in child- aged or elderly females are typically affected.28–31 Complications include
hood.5,6 Occasional familial cases have been reported.7,8 chronic dysphagia and stricture formation affecting the mid or upper
The disease is characterized by small, smooth, shiny, flat-topped polygonal esophagus.28,32–35 Patients with esophageal lichen planus may have a
papules measuring several millimeters to 1 cm in diameter and often having a risk of developing squamous cell carcinoma. The role of surveillance is
violaceous color (Fig. 7.1). Delicate white lines known as Wickham's striae uncertain.27,28,30,31,36,37
typically cross the slightly scaly surface (Fig. 7.2). The lesions are found Genital lesions in lichen planus are common (particularly in males),
most commonly on the flexor aspect of the wrists, the forearms, the exten- being present in up to 25% of patients, and sometimes adopting an annu-
sor aspect of the hands and ankles, the lumbar area and the glans penis (Fig lar configuration (Fig. 7.8).1 Similar annular lichen planus may be found
7.3). Lichen planus is associated with a positive Koebner's phenomenon. It is elsewhere on the body, including intertriginous areas.38 Occasionally, penile
a usually self-limiting although sometimes protracted disorder, patients clear- lesions are the sole expression of the disease.39 Vulval lesions may be found
ing of lesions within weeks to 1 or 2 years. in up to 51% of females with cutaneous involvement.40 Sometimes gingi-
Oral involvement, which is very common (affecting up to 60% of val and female genital lesions may coexist as a variant of erosive lichen
patients with cutaneous disease), shows a marked female preponderance planus, the so-called vulvovaginal-gingival syndrome.41–44 Patients present
and presents most often in the seventh decade. It may sometimes be the sole with dyspareunia and intense burning vulval pain. The vulva appears con-
manifestation (an estimated 15–35% of patients with oral lichen planus gested and there may be erosions, which are often surrounded by a white
never develop skin lesions).9–14 The buccal mucosa, vestibule, tongue, and reticulate border. Vaginal involvement similarly presents as dyspareunia
220 Lichenoid and interface dermatitis
Box 7.1
Causes of lichenoid dermatitis
• Lichen planus
• Lichenoid graft-versus-host disease
• Lichen nitidus
• Lichenoid keratosis
• Lichenoid drug reaction
• Fixed drug reaction
• Lichen planopilaris
• Lichen striatus
• Adult Blaschkitis
• Lichen aureus
• Lichenoid mycosis fungoides
• Ashy dermatoses
• Lichenoid and granulomatous dermatitis
Box 7.2 A
Causes of interface dermatitis
• Lichenoid dermatoses (see Box 1.)

• Stevens-Johnson syndrome/toxic epidermal necrolysis
• Connective tissue disorders: lupus erythematosus, dermatomyositis,
and mixed connective tissue disorders
• Graft-versus-host disease
• Poikiloderma including those related to rare inherited disorders
• Interface drug reactions
• Interface viral exanthem
• Pityriasis lichenoides
and often postcoital bleeding due to inflammatory, desquamative, and ero-

sive changes. More typical features of lichen planus may be encountered
elsewhere on the body. Squamous carcinoma is an important complication
of chronic vulval lichen planus.45 The development of penile cancer is rare.46
Genital involvement in lichen planus is discussed elsewhere. B
The nails are affected in about 10% of patients with lichen planus; mani-
festations include thinning of the nail plate, longitudinal ridging, striations, Fig. 7.2
pterygium formation, subungual hyperkeratosis and, very rarely, complete Lichen planus: (A) note the characteristic Wickham's striae at the edge of these
destruction of the nail (Figs 7.9).1 Although nail involvement in children is pigmented lesions; (B) Wickham's striae are evident on these lesions, which have
said to be rare, some authors regard twenty-nail dystrophy of childhood as a arisen on the back, an uncommonly affected site. (A) From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK. (B) Courtesy of J. Dayrit, MD,
variant of localized lichen planus, although not all accept this hypothesis.47–51
Manila, The Philippines.
Fig. 7.1 Fig. 7.3

Lichen planus: there are typical flat-topped polygonal papules on dorsum of the Lichen planus: there is extensive bilateral involvement of the flexor aspect of
hand. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, the forearms. From the collection of the late N.P. Smith, MD, the Institute of
London, UK. Dermatology, London, UK.
Lichenoid dermatoses 221
Fig. 7.4
Lichen planus: this lace-like pattern is characteristic. From the collection of the late
N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig 7.6
Lichen planus: the tongue
is commonly affected. By
courtesy of M. Blanes,
MD, Alicante, Spain
Fig. 7.5
Lichen planus: there
is extensive ulceration
of the buccal mucosa.
By courtesy of Fig. 7.7
R.A. Marsden, MD, Lichen planus: there is an ulcerated squamous carcinoma on the lower lip. By
St George's Hospital, courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
London, UK.
• Lichen planus actinicus (lichen planus subtropicus, summertime actinic

lichenoid eruption (SALE)), develops in patients with prolonged exposure
Most lesions of lichen planus heal within 6–18 months of onset. However, to sunlight and, therefore, usually manifests in spring or summer,62–66
oral and hypertrophic variants and lichen planopilaris tend to have a chronic with improvement or remission in the autumn or winter. It occurs
course. Postinflammatory hyperpigmentation, which may be very disfiguring, particularly in the Middle East (especially Egypt) and the Far East and
is not uncommon, particularly in colored races (Fig. 7.10). affects younger people, with a maximum incidence in the second and
A number of variants of lichen planus merit specific mention: third decades and a slight female predominance (Fig 7.14). Affected sites
• Lichen planopilaris (follicular lichen planus), presents as single or include the lateral aspects of the forehead, the dorsum of the hands, the
multiple plaques of scarring alopecia associated with a spectrum of forearms, face, and neck. The eruption can include a mixture of lichen
lesions including typical lichenoid papules involving the scalp to brown planus-like and lichen nitidus-like lesions, whereas in others, the lesions
or violaceous keratotic follicular papules affecting the trunk and appear as purely one or the other (see actinic lichen nitidus, below).
extremities (Figs 7.11–7.13).52–55 Nonscarring plaques with prominent Typically, the lichen planus lesions have an annular configuration with a
follicular papules may also be present. Linear lesions have rarely been bluish-brown, rather atrophic center and slightly raised border. They may
described.56–58 Some authors suggest that scalp lichen planus represents sometimes coalesce to form circinate plaques. Occasionally, a melasma-
pseudopélade of Brocq.59,60 Children can also be affected. 61 like appearance has been documented.66 There is usually little pruritus
• Atrophic lichen planus, the clinical features of which merely reflect and Koebner's phenomenon is commonly absent. The nails are often
resolution of the more typical active phase. unaffected.
Fig. 7.9
Lichen planus: there is longitudinal ridging and striation affecting the thumbnail,
with inflammatory changes in the nail folds. From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK.
B Fig. 7.10
Lichen planus: postinflammatory hyperpigmentation is a common manifestation.
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 7.8
Lichen planus: (A) typical papules are present on the shaft of the penis; (B) note the
erythematous erosions around the vulval introitus and labia minora. (A) From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK; • Ulcerative lichen planus, a chronic variant affecting the fingers, hands,
(B) By courtesy of S. Neill, MD, Institute of Dermatology, London, UK. soles, and toes, is often associated with permanent loss of the nails (Figs
7.18, 7.19). Squamous cell carcinoma may complicate this variant of
lichen planus.76
• Lichen planus pigmentosus, most commonly encountered in the tropics Other variants include lichen planus linearis, which occurs predominantly
in dark-skinned patients, is characterized by the development of variably in children, and the rare vesicular or bullous variants, which must be distin-
pruritic pigmented dark-brown macules predominantly affecting exposed guished from lichen planus pemphigoides. Bullous lichen planus implies the
skin and the flexures (Figs 7.15, 7.16). The most common affected sites development of vesicles or bullae on pre-existent lichenoid lesions as a con-
include the face and neck.67–72 There is no sex predilection. The disorder sequence of severe basal cell hydropic degeneration. It is more often a histo-
is characterized by periods of exacerbation and remission.4 Exceptionally, logical finding rather than a clinical observation. In contrast, lichen planus
involvement of the oral mucosa has been documented.5 pemphigoides is characterized by the development of large tense bullae aris-
• Hypertrophic lichen planus, which represents superimposed lichen ing on normal or erythematous skin in a patient with typical lichen planus
simplex chronicus, commonly affects the lower limbs, particularly the elsewhere. It represents the combined expression of lichen planus and bullous
shins, and manifests as highly pigmented warty plaques (Fig. 7.17).73 pemphigoid.77
Familial lichen planus shows an increased incidence of this variant.74 Childhood lichen planus shows a modest male predominance (2:1).5,6,61,78
The lesions are intensely itchy and very persistent. There may be an Although mucosal involvement is said to be rare, recent series report a fre-
attendant (albeit very slight) risk of neoplastic transformation although quency of 14–39%.6,61,78 Hypertrophic lesions may be seen in up to 26%
the evidence is weak and based largely on case reports.75 of cases.6
Fig. 7.13
Lichen planopilaris: follicular lichenoid papules are clearly seen in this patient. By
courtesy of the Institute of Dermatology, London, UK.
Fig. 7.11
Lichen planopilaris: there are characteristic hyperpigmented follicular papules, which
are confluent in some areas. The limbs are commonly affected. By courtesy of R.A.
Fig. 7.14
Lichen planus actinicus: there is marked facial hyperpigmentation representing
postinflammatory changes. From the collection of the late N.P. Smith, MD, the
Fig. 7.12
Lichen planopilaris: marked inflammatory changes with scarring and secondary hair
loss. These changes are difficult to distinguish from those of pseudopélade and
chronic discoid lupus erythematosus. From the collection of the late N.P. Smith,
MD, the Institute of Dermatology, London, UK.

The etiology of lichen planus is unknown. Theories of infectious (bacterial
and viral), autoimmune, metabolic, psychosomatic, and genetic causes have
all had their proponents. Currently, however, it is thought that lichen planus
represents an abnormal delayed hypersensitivity reaction to an as yet undeter-
mined epidermal neoantigen, possibly to a combination of an external anti- Fig. 7.15
gen coupled with an internal self-antigen.79,80 The association of lichen planus Lichen planus pigmentosus: there are coalescent pigmented papules. From the
with a number of viral infections including hepatitis B and C and human collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 7.19
Ulcerative lichen planus: the digits are often affected. This variant is associated with
a slightly increased risk of squamous cell carcinoma. By courtesy of R.A. Marsden,
Fig 7.16 MD, St George's Hospital, London, UK.
Lichen planus pigmentosus: the face is a commonly affected site. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
immunodeficiency virus (HIV), combined with the well-recognized relationship
to numerous drugs, adds support to this hypothesis.81–83
Lichen planus is associated with a variety of liver cell abnormalities including
aberrant liver function tests and serology.84,85 An increased incidence of chronic
active hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis has
also been recorded.86–91 Not all documented series, however, have confirmed
these observations, suggesting that the reported relationship may be dependent
upon the background level of hepatitis B virus infection.89 Lichen planus has
also followed hepatitis B vaccination.92–95 More recently, lichen planus (particu-
larly oral disease) has been linked to hepatitis C virus and chronic liver disease.
The incidence of hepatitis C virus in patients with lichen planus is, however,
very variable, ranging from effectively zero in some populations, including the
United Kingdom, India, and Slovenia, to as high as 100% in Japan.96–101
Evidence of other disorders including thyroid disease, dyslipidemia, and
impaired carbohydrate metabolism including overt diabetes mellitus has also
been documented in lichen planus, particularly the oral variant.102–110 A recent
study from Japan suggests a possible association of hepatitis C infection with
both diabetes and lichen planus.109
A significant association between lichen planus and human leukocyte anti-
gen (HLA)-DR1 and HLA-DQ1 has been noted by a number of authors.111–117
Fig. 7.17 This association pertains to patients with or without mucosal lesions but does
Hypertrophic lichen planus: raised, warty, violaceous plaques on the shin of an not extend to patients with the drug-induced variant. It is suggested that this
elderly man. These lesions had been present for 30 years. By courtesy of R.A. association relates to antigen presentation by HLA-DR1+ cells to T-helper
Marsden, MD, St George's Hospital, London, UK. cells with the resultant development of an autoimmune response.111
Although it is generally accepted that the pathogenesis of the basal cell
damage in lichen planus primarily involves the cellular immune response, the
precise mechanism(s) require further elucidation. It is unlikely that autoan-
tibody and immune complex-mediated damage have a significant role in the
lichenoid tissue reaction.79,80
The initial event in the evolution of the lichen planus papule is destruction
of the basal epidermal layer (keratinocytes and melanocytes).118,119 In the ear-
liest stage of development, increased numbers of Langerhans cells are present
within the epidermis and it is believed that these cells process modified epi-
dermal antigens for presentation to T lymphocytes.120 Keratinocytes express
HLA-DR and this is likely to be of pathogenetic importance. Subsequent
migration with resultant CD8+ T-cell activation results in basal keratinocyte
death due to the combined effects of interferon-gamma (IFN-γ), interleukin
(IL)-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and
tumor necrosis factor alpha (TNF-α).81–83,121 The expression of FasR/FasL by
the basal keratinocytes suggests that apoptosis is an important mode of cell
death in lichen planus.122 The dermal infiltrate consists predominantly of Ia+,
CD4+ lymphocytes.120,123 CD8+ lymphocytes are also present in close appo-
sition to the dermoepidermal junction adjacent to foci of basal keratinocyte
Fig. 7.18 necrosis and are said to predominate in early lesions.121,123–125 B lymphocytes
Ulcerative lichen planus: there is marked atrophy of the skin around this crusted are scarce and plasma cells are characteristically absent in cutaneous lesions,
ulcer. By courtesy of the Institute of Dermatology, London, UK. except in the hypertrophic variant.
Development of the typical papule appears to be due to a combination

of continued keratinocyte destruction and regenerative activity, with the lat-
ter depending upon the migration of epithelium from the edge of the lesion
and from adjacent eccrine ducts, rather than from increased mitotic activ-
ity. There is little uptake of tritiated thymidine at the site of basal cell dam-
age, but conspicuous uptake at the edges of the lesion and, as a reflection
of regeneration, keratin 17 expression is also up-regulated in the suprabasal
epithelium.126 The typical features of lichen planus therefore depend upon a
variable interplay between basal cell liquefactive degeneration and irregular
epidermal regeneration.
The earliest identifiable change in lichen planus is the presence of cytoid
bodies and associated pigmentary incontinence. Cytoid bodies (colloid or
Civatte bodies) are round or oval, homogeneous, eosinophilic bodies identifi-
able within the basal epithelium and the papillary dermis (Fig. 7.20). They
display diastase-resistant periodic acid-Schiff (PAS) positivity, and may be
identified within papules, perilesional skin, and even apparently uninvolved
skin. Although they may be seen in a variety of dermatoses (including lupus
erythematosus, graft-versus-host disease, and poikiloderma) and seemingly
normal skin, where their presence, if either in large numbers or in a cluster,
suggests lichen planus. Fig. 7.21
Lichen planus: this scanning view is characteristic and highlights the hyperkeratosis,
Ultrastructurally, cytoid bodies are composed of tightly arranged aggre-
hypergranulosis, and irregular acanthosis. Note the typical bandlike inflammatory
gates of filaments 6–8 nm in diameter; immunocytochemically they are com-
cell infiltrate and pigment incontinence.
posed of keratin.
Characteristic histological features of an established papule can usually
be recognized at scanning magnification (Fig. 7.21). They comprise hyper-
keratosis, typically wedge-shaped hypergranulosis (clinically presenting as
Wickham's striae) related to the intraepidermal components of sweat ducts
and hair follicles, and irregular acanthosis (Figs 7.22, 7.23). The acantho-
sis often has a saw-toothed appearance (Figs 7.24, 7.25). The presence of
prominent parakeratosis argues strongly against a diagnosis of lichen planus.
Lymphocytes and histiocytes may sometimes be seen in the epidermis and
very occasionally satellite cell necrosis is a feature. Liquefactive degeneration
of the basal layer of the epithelium is characteristic and often subepidermal
clefts are present (Max Joseph spaces). Pigmentary incontinence is common
(Fig. 7.26). A lymphohistiocytic bandlike infiltrate occupies the upper dermis
and obscures the dermoepidermal junction. Hyperkeratosis persists in resolv-
ing lichen planus, but the acanthosis regresses, leaving a flattened epidermis
(Fig. 7.27); there may be focal scarring and the dermal infiltrate is less con-
spicuous (Fig. 7.28).
Lesions may become completely atrophic and histologically there is flat-
tening of the epidermis, variable number of colloid bodies, and pigment
incontinence with almost no inflammation. If colloid bodies are rare, distinc-
tion from poikiloderma may be very difficult. Fig. 7.22
Lichen planus: note the hyperkeratosis, hypergranulosis, and irregular acanthosis.
Fig. 7.20 Fig. 7.23

Lichen planus: this view shows characteristic eosinophilic cytoid bodies associated Lichen planus: the hypergranulosis is clearly related to the acrosyringium. There is
with basal cell liquefactive degeneration and a lymphohistiocytic infiltrate. marked basal cell liquefactive degeneration. Note the fibrin deposition.
Fig. 7.24 Fig. 7.27

Lichen planus: the acanthosis is irregular and often has a saw-toothed appearance. Atrophic (resolving) lichen planus: there is hyperkeratosis, epidermal flattening, and
a slight residual lymphohistiocytic infiltrate.
Fig. 7.25
Lichen planus: close-up view of Figure 7.24 showing basal cell liquefactive
degeneration and cytoid bodies.
Fig. 7.28
Atrophic (resolving) lichen planus: in addition to the lymphohistiocytic infiltrate,
there are excessive numbers of fibroblasts and increased papillary dermal collagen.
In lesions of annular lichen planus the typical histologic features are only
seen in the periphery at the advancing edge of the lesion.
In micropapular lichen planus the changes are so focal that the diagnosis
may be missed if serial sections are not examined.
Lichen planopilaris in its early stages shows an infiltrate surrounding the
lower hair follicle and papilla, follicular dilatation, and keratin plugging (Fig.
7.29).52,54 The adjacent interfollicular epithelium may or may not show a typ-
ical lichenoid infiltrate (Fig. 7.30). Basal cell hydropic degeneration, cytoid
body formation, and pigmentary incontinence are also sometimes evident. In
advanced scalp lesions, the hair follicles are destroyed and replaced by ver-
tically orientated fibrous scars, reminiscent of the fibrous streamers seen in
pseudopélade of Brocq.
Lichen planoporitis represents a rare variant in which lichenoid/interface
changes are centered on the acrosyringium and eccrine sweat duct as it enters
the epidermis. Squamous metaplasia of the ductal lining epithelium may be
a feature.127
Fig. 7.26 In lichen planus actinicus, the annular borders of the macules show typi-
Lichen planus: melanin pigment is present within macrophages (pigmentary cal features of lichen planus. In the center of the lesions, however, the epithe-
incontinence). lium is atrophic, thin, and flattened, although the lymphohistiocytic infiltrate
A B
Fig. 7.29
Lichen planopilaris: (A, B) there is marked follicular dilatation and plugging accompanied by a bandlike folliculocentric infiltrate. This patient presented with scarring alopecia
and typical lichen planus lesions elsewhere.
B
A
Fig. 7.30
Lichen planopilaris: (A, B) there is a strikingly folliculocentric bandlike infiltrate associated with keratin plugging. The interfollicular epidermis is unaffected.
remains. Foci of parakeratosis and eczematization within the follicular epi-

thelium have also been described. Lichen nitidus-like lesions may sometimes
be seen (see below).
Lichen planus pigmentosus is characterized by epidermal thinning accom-
panied by basal cell vacuolization, pigmentary incontinence, and a superficial
dermal lichenoid lymphohistiocytic infiltrate.4
Hypertrophic lichen planus is characterized by more marked hyperkera-
tosis and acanthosis, with the epithelium sometimes showing pseudoepithe-
liomatous hyperplasia such that misdiagnosis as squamous cell carcinoma is
a distinct possibility, particularly if clinical information is not available (Figs
7.31–7.33).73 A number of changes not seen in ordinary lichen planus may be
observed and include parakeratosis, spongiosis, necrotic keratinocytes above
the basal cell layer, and eosinophils and plasma cells in the dermal infiltrate.
These changes may raise the possibility of a lichenoid drug eruption. The dif-
ferential diagnosis is not difficult, as lichenoid drug eruptions tend to be more
generalized and are not usually associated with hypertrophic changes.
The oral lesions of lichen planus, although often displaying the classical
features, may show parakeratosis; occasionally, alternate foci of both are Fig. 7.31
evident. In contrast to the cutaneous lesions, the epithelium is sometimes Hypertrophic lichen planus: note the hyperkeratosis, focal wedge-shaped hypergranulosis,
rather thin and the saw-toothed pattern indistinct. There is typically basal very marked irregular acanthosis, and superficial dense bandlike infiltrate.
Fig. 7.32 Fig. 7.34

Hypertrophic lichen planus: there is very marked irregular acanthosis. Note the Bullous lichen planus: oral lesion showing separation of the squamous epithelium
hypergranulosis. from the lamina propria. Note the bandlike infiltrate.
Fig. 7.35
Lichen planus: brilliant
green fluorescence
indicates the presence
Fig. 7.33 of fibrin. By courtesy
Hypertrophic lichen of the Department of
planus: there is basal cell Immunofluorescence,
liquefactive degeneration Institute of Dermatology,
with cytoid bodies. London, UK.
Direct immunofluorescence studies on skin biopsies from patients with

cell hydropic degeneration. Basement membrane thickening due to the depo- lichen planus usually reveal a linear fibrillar band of fibrin at the dermoepi-
sition of fibrin-rich eosinophilic amorphous material is commonly present. dermal junction (Fig. 7.35). The cytoid bodies may be highlighted non-
The cellular infiltrate, in addition to lymphocytes and histiocytes, frequently specifically by the use of antisera, mainly to IgM, but also to IgG, IgA and C3
contains plasma cells. Dysplasia may be seen. (Fig. 7.36). A lichen planus ‘specific antigen’, which is present in the prickle
Unlike skin involvement, esophageal lesions show parakeratosis. Variable cell and granular cell layers, has been demonstrated by indirect immunofluo-
epithelial atrophy and/or mild thickening are usually seen and the saw-toothed rescence of patients' serum with fetal skin.128 Whether this is of pathogenetic
pattern of acanthosis is not a feature.28,32–34 As with oral lesions, plasma cells significance is unknown. Direct immunofluorescence of lichen planopilaris
often accompany the lymphocytic infiltrate. reveals follicular, linear basement membrane zone labeling with immunoglob-
Vesicular or bullous lesions are subepidermal and occur due to excessive ulin (primarily IgG or IgA).129 Fibrin may also be present. The nosological
edema developing in association with the basement membrane zone damage implications of this observation are uncertain. Indirect immunofluorescence
complicating basal cell hydropic degeneration (Fig. 7.34). for circulating antibasement membrane zone antibodies is negative.
interferon-alpha therapy.8,9 Occasionally, papules may be encountered on the

palms and soles.3–12 Familial cases have been rarely described.13,14 Lichen niti-
dus can spontaneously resolve within a few months or persist indefinitely.2
Mucous membrane involvement presenting as grayish-yellow papules has
also been described.4 Nail involvement, which is extremely rare, presents as
thickening with ridges, rippling, terminal splitting, striations, and pits.2,4
Keratodermic, vesicular, hemorrhagic, purpuric, and perforating variants
may rarely be encountered.2,15–19 Perforating lichen nitidus shows a predilec-
tion for the forearms and fingers and may be trauma related.17,20
Actinic lichen nitidus refers to the development of lichen nitidus on sun-
exposed sites, usually during the summer months. In some cases, involvement
is predominantly facial and it may present in black patients.21 It shows con-
siderable overlap with actinic lichen planus (see above).22,23
Fig. 7.36
Lichen planus: cytoid
bodies labeled positively
for IgM. By courtesy
Immunofluorescence,
London, UK.
Lichen planus should be differentiated from other diseases showing a
lichenoid infiltrate and hydropic degeneration of the basal layer of the epi-
thelium.130 Thus lichen planus may be indistinguishable from lichenoid Fig. 7.37
keratosis and their distinction is entirely dependent on clinicopathological Lichen nitidus: numerous tiny papules are present on the chest of a young child.
correlation. In many cases of lichenoid keratoses, there are other associated By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
changes including focal spongiosis and parakeratosis. Atrophic lesions may
be confused with poikiloderma and chronic discoid lupus erythematosus. A
lichen planus-like morphology is typical of the early stages of chronic graft-
versus-host disease (GVHD).
Poikiloderma shows epidermal atrophy, with loss of the ridge pattern and
no tendency to a saw-toothed appearance. In those examples associated with
mycosis fungoides, the lichenoid infiltrate contains variable numbers of atypi-
cal lymphocytes and mycosis fungoides cells.
Chronic discoid lupus erythematosus is associated with epidermal atro-
phy and follicular plugging. The inflammatory cell infiltrate is patchy with a
tendency to periappendageal location. A positive lupus band test is a helpful
discriminator.
Lichen planus may easily be mistaken for a lichenoid drug reaction, par-
ticularly in the absence of clinical information. Histological features favoring
the latter include high-level cytoid bodies and eosinophils within the dermal
infiltrate.
Lichen nitidus
Clinical features
Lichen nitidus is a rare but distinctive dermatosis, which shows an equal sex
incidence.1 Children and young adults are predominantly affected. It presents Fig. 7.38
clinically as an eruption of pinhead-sized, flesh-colored, shiny, flat-topped Lichen nitidus: numerous
tiny papules are present
or dome-shaped papules and shows a predilection for the arms, chest, abdo-
on the penis. The genitalia
men, and genitalia (Figs 7.37, 7.38).1–5 A positive Koebner's phenomenon are commonly affected.
is typically present.5 The condition is usually localized and asymptomatic, From the collection of the
although occasionally there may be mild or even intense pruritus.2 Rarely, late N.P. Smith, MD, the
generalized lesions have been described.2,6,7 An association with generalized Institute of Dermatology,
lesions and Down's syndrome has been documented, as has been a case after London, UK.
Lichen nitidus is recognizable by a characteristic histology in many cases. The
classic papule is sharply circumscribed and occupies the space of only four
or five dermal papillae. It is often depressed in the center and composed of
atrophic epidermis, frequently covered by a parakeratotic tier and overlying
a cellular infiltrate (Figs 7.39–7.42). Clawlike extensions of epidermal ridges
mark the lateral boundaries of the lesion. The epithelium shows basal cell
hydropic degeneration, and cytoid bodies may be a feature. The inflamma-
tory component consists of lymphocytes, histiocytes, and variable numbers
of epithelioid cells. Giant cells are sometimes a feature and true granulomata
may occasionally be found, although caseation is never present.24 In addition
to red blood cell extravasation, purpuric variants may show increased vascu-
larity with vessel wall thickening and hyalinization.18 In rare cases, a promi-
nent lymphocytic inflammatory infiltrate can extend down the hair follicle
and eccrine glands, making the distinction from lichen striatus challenging.24
A follicular variant of lichen nitidus may be seen and mimics lichen spinulo-
sus histologically.25 However, rarely, lichen nitidus and lichen spinulosus may
coexist clinically.26
Fig. 7.41
Lichen nitidus: the infiltrate consists of lymphocytes, histiocytes, and epithelioid
cells. Ill-defined noncaseating granulomata are not uncommon.
Fig. 7.39
Lichen nitidus: scanning view showing a typical small, circumscribed lesion occupying Fig. 7.42
only a couple of dermal papillae. Note the clawlike epidermal lateral borders. Lichen nitidus: there are multiple lesions of lichen nitidus with an associated
granulomatous component. The patient also had typical lichen planus lesions. By
courtesy of R. Margolis, MD, St Elizabeth's Hospital, Boston, USA.
Palmar lesions may be identical to those seen elsewhere or show a more

diffuse bandlike upper dermal lymphohistiocytic infiltrate with associated
giant cells and focal parakeratosis.3,10–12,27
Fibrin can be detected at the basement membrane zone by immunoflu-
orescent techniques, but immunoglobulin deposition is not a feature.28,29
Immunophenotypic studies show that there is a marked excess of CD4+
cells (helper/inducer T cells) over CD8+ cells (cytotoxic/suppressor T cells).28
Langerhans cells are conspicuous.30 These findings are similar to those
described for lichen planus.
Ultrastructural examination reveals rather non-specific findings includ-
ing epidermal intercellular edema, subepidermal edema, colloid bodies,
decreased numbers of desmosomes, and disruption or reduplication of the
lamina densa.31–33 Perivascular electron-dense deposits (the nature of which is
unknown) have been described in purpuric variants.8
Comment
Lichen nitidus may coexist with lichen planus or predate it and lichen niti-
Fig. 7.40 dus-like lesions may be found in patients with typical lichen planus, but it is
Lichen nitidus: note the parakeratosis and bandlike infiltrate. unlikely that the conditions are closely related.34,35 Wickham's striae are not
a feature of lichen nitidus and mucosal involvement is exceptional.2,4 Lichen expression, suggesting the absence of localized antigenic stimulation as seen
nitidus is associated with parakeratosis and epidermal atrophy, in contrast in lichen planus.2,12 These studies suggest that lichenoid keratosis is an entity
to the orthohyperkeratosis and acanthosis seen in lichen planus. The saw- distinct from lichen planus despite the similarities in histology.
toothed appearance of the lower border of the epidermis seen in lichen planus Despite this, histologically, as its name suggests, the features are similar to
is not a feature of lichen nitidus and immunofluorescence for immunogloblins those of lichen planus. Thus there is hyperkeratosis, wedge-shaped hypergran-
is negative. Epithelioid cells and giant cells are characteristic of lichen nitidus ulosis, variable acanthosis, and basal cell liquefactive degeneration sometimes
and are not typically a feature of lichen planus. Three patients with Crohn's accompanied by lymphocytic exocytosis (Figs. 7.44, 7.45).2,3,5 Foci of parak-
disease were reported to develop lichen niditus; however it remains to be eratosis are also frequently seen.1,2 Although the saw-toothed acanthosis of
seen if lichen nitidus is truly an extragastrointestinal finding of this disease.36 lichen planus is sometimes evident, more often the epithelium merely shows
Another patient developed lichen nitidus after hepatitis B vaccine injection.37 broadened, widened, and irregular epidermal ridges.4 The basal epidermal
The significance of this is uncertain. layers may sometimes show very minor degrees of cytological atypia, includ-
ing cellular and nuclear enlargement with conspicuous nucleoli, but these
Lichenoid keratosis changes represent regenerative phenomena.3 Dysplasia as seen in lichenoid
actinic keratosis is not a feature of a lichenoid keratosis. Colloid bodies are
usually conspicuous in both the epidermis and dermis and pigmentary incon-
Clinical features
tinence is often marked (Figs 7.46–7.48).1,2,7 Apoptotic keratinocytes can
Lichenoid keratosis (benign lichenoid keratosis, lichen planus-like keratosis, be prominent and may be associated with inatraepidermal blister formation
solitary lichen planus) is not uncommon and usually presents as a solitary, with subepidermal vesiculation. Epidermal pallor and dermal edema can be
0.3–2-cm diameter, sharply demarcated, erythematous, violaceous, tan or seen in cases with only slight or no acanthosis and an interface population of
brown papule or plaque (Fig. 7.43).1,2 Occasionally, multiple lesions may lymphocytes along the junction with vacuolar degeneration. Foci of atrophy
be present.2,3 It is usually of short duration and shows a predilection for the can be occasionally encountered.2 In some cases a combination of lichenoid
face (particularly the cheeks and nose), neck, upper trunk (especially the pre- and spongiotic changes may be seen.
sternal area), forearm, and dorsum of the hand.2,4–8 The surface is often scaly.
Lesions are commonly asymptomatic, but mild pruritus has sometimes been
documented.8 Patients are frequently Caucasian, but occasionally blacks are
affected.2,7,8 Females develop these lesions more commonly than males, usu-
ally in their fourth to seventh decades.2,5
Lichenoid keratosis is often clinically misdiagnosed as a seborrheic keratosis,
superficial basal cell carcinoma, squamous cell carcinoma, actinic keratosis or
Bowen's disease.5

The precise nature of lichenoid keratosis is uncertain. In the past, it was
regarded as a solitary lesion of lichen planus or thought to have an actinic
pathogenesis.9–11 It was also proposed to represent an immunological or regres-
sive response to a pre-existent epidermal lesion similar to the phenomenon
encountered with a ‘halo’ nevus.2 The frequent association of solar lentigines
or, less commonly, seborrheic keratoses in the adjacent epithelium has been
cited as evidence in favor of this hypothesis.4–6,8 Recent studies have shown
that the lymphocytic infiltrate in lichenoid keratosis to be immunophenotypi-
cally distinct from lichen planus. The lymphocytes in lichenoid keratosis are
predominantly CD8-reactive in contrast to lichen planus. More CD20-positive
B cells are usually seen in lichenoid keratosis. Furthermore, the lymphocyte Fig. 7.44
infiltrate in lichenoid keratosis lacks the cutaneous lymphocyte antigen (CLA) Lichenoid keratosis: scanning view showing hyperkeratosis, hypergranulosis,
irregular acanthosis, and a bandlike chronic inflammatory infiltrate.
Fig. 7.43 Fig. 7.45

Lichenoid keratosis: there is scaling overlying a slightly raised erythematous plaque. Lichenoid keratosis: in this field there is basal cell liquefactive degeneration. Cytoid
By courtesy of the Institute of Dermatology, London. bodies are present.
A dense chronic inflammatory cell infiltrate is typically present in the

superficial dermis. Although this characteristically has a lichenoid distri-
bution, on some occasions it may be more discrete and predominantly
perivascular in location.4,7 The infiltrate consists largely of lymphocytes and
histiocytes, but small numbers of plasma cells and eosinophils are occasion-
ally present. Exceptionally, a few atypical lymphocytes (enlarged with hyper-
chromatic, irregular, contoured nuclei) which are CD30 and CD3 reactive
can be also seen.2 The adjacent dermis sometimes shows lentigo and solar
elastosis, which is usually mild if present. Features suggestive of mycoses
fungoides such as Pautrier abscesses, dermal–epidermal tagging and mild
lymphocytic atypia have been rarely noted in benign lichenoid keratosis.13
Clinicopathological correlation and careful follow-up are essential in such
cases to avoid misdiagnosis.
Immunofluorescence findings, which are similar to those of lichen planus,
comprise deposits of IgM and, less commonly, IgG outlining cytoid bodies.5
Many conditions show lichenoid histology and therefore come into the differ-
ential diagnosis. Most prominently, these include lichen planus and lichenoid
Fig. 7.48
drug reactions. Lichenoid keratosis: basal cell liquefactive degeneration is evident in addition to
If clinical information is available, differentiation from lichen planus cytoid bodies. Note the parakeratosis.
should present little difficulty. Lichen planus is characterized by large num-
bers of lesions in contradistinction to the single papule or plaque of lichenoid
keratosis. In addition, lichen planus is usually itchy. Parakeratosis and dermal
plasma cells with eosinophils are not a feature of lichen planus, but are typi-
cal of lichenoid keratosis.7
Both actinic keratoses and squamous cell carcinoma in situ may some-
times show a lichenoid inflammatory cell reaction. Dysplasia by definition
is not a feature of lichenoid keratosis.1,2 Inflamed seborrheic keratosis and
porokeratosis can have a prominent lichenoid reaction. The absence of
horn cyst formation, squamous epidermal eddies, and laminated stratum
corneum keratin helps distinguish these lesions from seborrheic keratosis,
while the absence of cornoid lamella excludes porokeratosis. Melanocytic
lesions with halo phenomenon can become a diagnostic consideration and
require examination of the dermis and dermoepidermal junction for mel-
anocytic nests. In difficult cases, additional step sections or S-100 protein
immunohistochemical study can prove useful. Finally, the presence of scat-
tered CD30-positive lymphocytes in some cases of lichenoid keratosis may
raise the histological differential diagnosis of lymphomatoid papulosis.
However, the paucity of these enlarged CD30-positive cells, the absence of
a deep infiltrate, and the clinically history of a solitary lesion is reassuring
for lichenoid keratosis.2
Fig. 7.46
Lichenoid keratosis: in this early lesion, there is more uniform acanthosis.
Lichen striatus
Clinical features
Lichen striatus (Blaschko linear acquired inflammatory skin eruption
(BLAISE)) is an uncommon, usually asymptomatic, dermatosis of unknown
etiology, affecting the limbs or neck in which lesions typically follow Blaschko's
lines.1–8 Infrequently, the condition is pruritic.6–9 It is self-limiting, normally
disappearing within months to a year of onset. It shows a female predomi-
nance (2–3:1) and, although it may occur at any age, it most often presents
in children aged 5–15 years.2,5,7,8 Rarely, lichen striatus has been described
in adults (adult Blaschkitis, see below).4,10,11 Occurrence during pregnancy is
very rare.12 A family history is rarely encountered, suggesting a genetic pre-
disposition and/or a common environmental etiology in such cases.2,6,8,13,14 It
is associated with seasonal variation with most series reporting the majority
of patients presenting in spring and summer,2,7 with the exception of one large
series where the majority of patients presented in the winter 8,13 Case cluster-
ing has been documented.2
Lesions, usually solitary and unilateral, present as erythematous or flesh-
colored lichenoid or sometimes psoriasiform scaly papules, which coalesce
into a continuous or interrupted linear or curved band, 1–3 cm wide and
often covering the whole length of a limb, either lower or upper extremi-
Fig. 7.47 ties (Figs 7.49, 7.50).2,8 Occasionally, multiple lesions have been recorded,
Lichenoid keratosis: there is interface change with cytoid bodies. as has bilaterality.8,15,16 Presentation at two different sites and at multiple
sites may exceptionally occur.17 Nail changes, which may affect a single nail,
include onycholysis, longitudinal ridging, splitting, and nail loss.8,1,18,19 An
exceptional case of lichen striatus with bilateral nail dystrophy has been
described.20 Lichen striatus is not associated with Koebner's phenomenon.
Hypo- or hyperpigmentation sometimes follows resolution, which may be
marked in people with pigmented skin.8 Lichen striatus is associated with
atopy in up to 60% of patients.1,6–8

The etiology of this condition is unknown although case cluster-
ing and seasonality raises the possibility of an environmental or infec-
tive basis in conjunction with an abnormal host response.2,21 The
development of lesions along Blaschko's lines also raises the possi-
bility of a cell-mediated autoimmune reaction to an abnormal clone
of cells. Blaschko's lines are believed to represent the direction along
which epidermal growth centers expand during early skin develop-
ment.1 It has been suggested that the distribution of lesions in lichen
striatus may reflect a postzygotic abnormality such as somatic mutation
affecting localized stem cells.1 An intriguing case following trauma in
an adult has been reported.22 Further exceptional cases associated with
solarium use, varicella infection, and hepatitis B vaccine have been
described.23–25
The histological features of lichen striatus may be non-specific and show
changes of mild chronic non-specific dermatitis.26 In an established lesion,
however, the changes often consist of an admixture of spongiotic dermatitis
with lichenoid and interface features (Fig. 7.51).27 Thus, there is often par-
akeratosis with a normal or slightly acanthotic epidermis accompanied by Fig. 7.50
intercellular edema, lymphocytic exocytosis, and keratinocyte necrosis (Figs Lichen striatus: the arms
are sometimes affected.
7.52–7.54). Satellite cell necrosis may sometimes be a feature and transepi-
The condition most often
dermal elimination of keratinocyte debris (perforating lichen striatus) has presents in children. By
occasionally been documented.4,28 Intraepidermal Langerhans cell vesicles courtesy of the Institute
have exceptionally been described.27 A heavy lymphohistiocytic infiltrate is of Dermatology, London,
present in the superficial dermis and also surrounds the vessels of the superfi- UK.
cial and deep vascular plexuses and sometimes also the cutaneous adnexae.4,27
Eosinophils and plasma cells are uncommon.27
Some biopsies may be indistinguishable from lichen planus. In those

cases where there is follicular involvement, the features can resemble
those of lichen planopilaris, and old lesions sometimes simulate lichen
nitidus.
By immunohistochemistry, the majority of the intraepidermal lympho-
cytes are of a CD8+ cytotoxic phenotype.4,27 The dermal lymphocytes
consist of an admixture of CD4+ and CD8+ subtypes. CD7 is typically
conserved.25 Intraepidermal Langerhans cells may be normal, increased or
decreased.27
Nail changes include slight spongiosis with exocytosis, focal hyper-
granulosis, dyskeratosis, and a bandlike lymphohistiocytic infiltrate
affecting the proximal nail fold, nail bed, and nail matrix dermis.18
Adult Blaschkitis
Clinical features
Adult Blaschkitis (acquired relapsing self-healing Blaschko dermatitis) is a
rare, relapsing linear eruption with a mean age of onset of 40 years, predomi-
nantly affecting males.1–14 Lesions, which are pruritic papules and vesicles,
Fig. 7.49 affect multiple sites, particularly the trunk, following Blaschko's lines and
Lichen striatus: a typically resolve in days or weeks.1 The condition, which may be unilateral or
linear band of scaly more commonly bilateral, recurs over the ensuing months or years.
hyperpigmented papules
is present on the inner Pathogenesis and histological features
aspect of the leg, a
commonly affected
The etiology is unknown. Abnormalities in chromosome 18 in cells from
site. By courtesy of involved skin in comparison to normal-appearing skin has been described
R.A. Marsden, MD, in a female patient with adult Blaschkitis, supporting a link with cutaneous
St George's Hospital, genetic mosaicism.13 Association with a drug has been cited in one case and
London, UK. emotional stress has been reported to precede relapses.11,12
Fig. 7.51 Fig. 7.53

Lichen striatus: scanning view showing hyperkeratosis, focal parakeratosis, and Lichen striatus: there is
irregular acanthosis. A heavy inflammatory cell infiltrate is present in the upper spongiosis and marked
dermis. There is conspicuous pigmentary incontinence. Case courtesy of S. Lyle, lymphocytic exocytosis.
MD, Beth Israel Deaconess Medical Center, Boston, USA. Case courtesy of S.
Lyle, MD, Beth Israel
Deaconess Medical
Center, Boston, USA.
Fig. 7.52 Fig. 7.54

Lichen striatus: note the
Lichen striatus: in this field, there is parakeratosis, hyperkeratosis, spongiosis, and
spongiosis, basal cell
interface change. Note the pigment incontinence and intense chronic inflammatory
liquefactive degeneration,
cell infiltrate. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center,
and pigmentary
Boston, USA.
incontinence. Case
courtesy of S. Lyle, MD,
Beth Israel Deaconess
Medical Center, Boston,
USA.
Histologically, adult Blaschkitis is characterized by spongiotic changes;

lichenoid features are absent and no deep involvement of adnexal structures Keratosis lichenoides chronica
is seen.6,8 A rare case with interface changes has been reported.10
Clinical features
Differential diagnosis Keratosis lichenoides chronica (Nekam's disease, lichen ruber verrucosus et
It resembles lichen striatus and it has been suggested that there is no justifi- reticularis) is a very rare, chronic inflammatory dermatosis that combines
cation for separating the two entities.15 However, it differs clinically by the the features of a seborrheic dermatitis-like eruption of the scalp and face
presence of vesicles, its truncal distribution, and relatively rapid resolution. with a progressive lichenoid papulonodular dermatosis affecting the trunk,
Relapsing courses are typical. Pruritus is rare in lichen striatus. Lichen stria- buttocks, and limbs.1–6 Patients usually present in the third to fifth decades
tus predominantly affects young children although rare cases similar to adult although exceptionally reports of pediatric involvement have been docu-
Blaschkitis but affecting children have been described. mented, some with possible familial association.7–9 It is usually persistent and
typically does not respond to treatment although improvement in the summer

may sometimes be seen.5
Facial and scalp lesions are erythematous, greasy and scaly, and bear no
resemblance to those found on the trunk and extremities, which are ery-
thematous or violaceous lichenoid scaly papules in a confluent, reticulate,
or linear distribution. The latter may suggest Koebner's phenomenon (Figs
7.55, 7.56). Papulonodular and infiltrated plaques are sometimes also pres-
ent. Lesions are typically bilateral, symmetrical, and usually asymptomatic
although rarely pruritus may be intense. Scarring is not a feature. Associated
features include oral papules and ulceration, ocular lesions (blepharitis, con-
junctivitis, anterior uveitis, and iridocyclitis), laryngeal nodules, palmoplantar
keratoderma, and nail changes including yellow discoloration and dystro-
phy (longitudinal ridging, nail plate thickening, onycholysis, and paronychia)
(Fig. 7.57).1,10–14 Genital involvement including penile and scrotal papules,
chronic balanitis, and phimosis has been documented.6,10,11
Keratosis lichenoides chronica has been described in association with a
number of systemic diseases including chronic infections (toxoplasmosis,
tuberculosis, and viral hepatitis), kidney disease, and lymphoma.3,15–17

Although the precise nature of keratosis lichenoides chronica is uncertain,
some authors regard it as a variant of hypertrophic lichen planus.10,18
Histologically, the lichenoid eruption is characterized by hyperkeratosis
and parakeratosis, variable acanthosis, and epidermal atrophy associated
with a bandlike lymphohistiocytic infiltrate in the superficial dermis, often
with conspicuous melanophages.11 Neutrophils may be prominent in the
stratum corneum. Perifollicular/acrosyringotropic and perivascular chronic
inflammation may also be evident. Epidermal basal keratinocytes show Fig. 7.56
hydropic degeneration, and cytoid body formation has been described.11,18 Keratosis lichenoides chronica: close-up view of solitary lichenoid papules and a
confluent plaque. By courtesy of R.A. Marsden, MD, St George's Hospital,
Many necrotic keratinocytes are present.1 Exceptionally, amyloid deposition
London, UK.
has been documented.19
The dermal infiltrate consists of lymphocytes, histiocytes, and variable
plasma cells and eosinophils.11
Direct immunofluorescence highlights the cytoid bodies.18
The scalp and facial lesions show the features of a chronic dermatitis,
namely spongiosis with exocytosis and patchy parakeratosis. A perivascular
chronic inflammatory cell infiltrate of lymphocytes, histiocytes, and plasma
cells may be present in the upper dermis.5
Fig. 7.55
Keratosis lichenoides
chronica: there
are erythematous
hyperkeratotic lichenoid
lesions in a linear and
reticular distribution. By Fig. 7.57
courtesy of R.A. Marsden, Keratosis lichenoides chronica: plantar involvement showing disfiguring exophytic,
MD, St George's Hospital, hyperkeratotic verrucous plaques. By courtesy of R.A. Marsden, MD, St George's
London, UK. Hospital, London, UK.
Erythema dyschromicum perstans

Clinical features
Erythema dyschromicum perstans (dermatosis cenicienta, ashy dermatosis) is
an acquired, usually asymptomatic, disfiguring dermatosis which occurs par-
ticularly in Latin American (especially Mexican) populations and in Asians.1–7
It was originally named dermatosis cenicienta after the clinical appearance of
affected patients – los cenicientos (the ash-colored ones).1 However, white-
skinned races may rarely be affected.8 It is of unknown etiology, shows a
female predilection, and can develop at any age although the majority of
patients are in their first three decades.2,9 Presentation in infancy has been
documented.10
Patients develop oval, irregular or polycyclic, gray macules with ery-
thematous, indurated, inflammatory borders of 1–2 mm. The lesions extend
peripherally, show a tendency to coalesce, and often affect large areas of the
integument (Figs 7.58–7.60). With progression, the eruption develops a gray-
blue color and loses the erythematous border, which is sometimes replaced by
a hypopigmented periphery. It is usually symmetrical, and particularly affects
the trunk, proximal extremities and, to a lesser extent, the face and neck.2 Fig. 7.58
Erythema dyschromicum
The palms and soles, scalp, nails, and mucous membranes do not appear to
perstans: this patient
be involved.6 shows irregularly
distributed gray
macules. By courtesy
Pathogenesis and histological features of R.A. Marsden, MD,
The etiology is unknown. Cases have followed HIV infection and there is a St George's Hospital,
report of simultaneous development of vitiligo and erythema dyschromicum London, UK.
perstans. The significance of these observations is doubtful.11,12 Increased sus-
ceptibility with HLA-DRB1*0407 in Mexican patients has been reported.13
Sections from the inflammatory border show hyperkeratosis and an epi-
dermis of normal thickness or somewhat atrophic, accompanied by basal cell
hydropic degeneration and cytoid body formation (Fig. 7.61). Pigmentary
incontinence is marked and a mild perivascular or lichenoid inflamma-
tory cell infiltrate is present in the superficial dermis (Fig. 7.62). Sections
from the central gray area show epidermal atrophy, follicular hyperkera-
tosis, and pigmentary incontinence. The dermal inflammatory infiltrate is
composed of both CD4 and CD8 T cells, usually with CD8 forms slightly
predominating.14
Direct immunofluorescence reveals non-specific staining of the cytoid
bodies with IgG, IgM, and C3.15–17 Fibrinogen may be present at the der-
moepidermal junction.16 The immunocytochemical studies are therefore simi-
lar to lichen planus. The epidermal keratinocytes express Ia antigen and the
lymphocytic population comprises both helper/inducer and suppressor/cyto-
toxic phenotypes similar to lichen planus.17,18
Ultrastructural findings are non-specific, comprising intra- and interepi-
dermal edema with cytoplasmic vacuolation, separation of keratinocytes,
retraction of desmosomes, cytoid body formation, focal gaps in the kera-
tinocyte basal lamina, and pigment-laden histiocytes in the papillary
dermis.16,19,20
The precise relationship of erythema dyschromicum perstans to lichen
planus is uncertain. The histological, immunological, and ultrastructural
findings certainly suggest that they are closely related.15,16 Typical lichen Fig. 7.59
Erythema dyschromicum perstans: in this patient there is extensive involvement of
planus may precede the development of erythema dyschromicum per-
the face, neck, and trunk. By courtesy of J. Tschen, MD, Baylor College of Medicine,
stans and sometimes the two conditions have presented simultaneously, Houston, USA.
although some of the documented cases may have represented lichen
planus pigmentosus.21,22
Lichenoid and granulomatous dermatitis The extremities and trunk are most often involved, followed by the head and
neck region. Clinically, the lesions present as lichenoid papules
Clinical features
These lesions were described in 2000 by Magro and Crowson to have features Pathogenesis and histology
of both lichenoid and granulomatous dermatitis.1 There is a slight female Various etiologic agents included drug, coexisting medical illnesses, and
predominance (21:15) affecting a broad range of ages (5–86 years old). infections have been implicated. Similar to any lichenoid disorder, there is a
Interface dermatoses 237
Fig. 7.60
perstans: in this patient
with more advanced
Fig. 7.62
disease, there is a
generalized bluish
perstans: note the
discoloration. By
hydropic degeneration,
cytoid body, and pigment
incontinence.
UK.
Interface dermatoses
Definitions
There is such considerable variation in the literature as to the exact defini-
tions and interrelationships between erythema multiforme (particularly the
‘major’ variant), Stevens-Johnson syndrome, and toxic epidermal necroly-
sis that it is often difficult or impossible to be certain to which disease the
authors are actually referring!1–5 The consensus paper published in 1993 by
Bastuji-Garin is used as a basis for classification since the authorship included
most of the major players at that time in this difficult subject.1
Classification of an individual patient depends upon the precise morphol-
ogy and pattern of individual lesions and the extent of skin involvement
(detached and detachable epidermis) as a percentage of total body surface
area at the worst stage of the illness.
• Target lesions are defined as sharply demarcated and round, less than
3.0 cm in diameter and comprising three distinct zones, namely a central
erythematous or purpuric disc with or without a blister, surrounded
by a raised edematous ring, in turn bordered by an erythematous rim
(Fig. 7.63).1 Target lesions are typically distributed in an acral location,
are often seen following a herpetic infection, and are characteristic of
erythema multiforme. Typical target lesions are not seen in patients with
Fig. 7.61 widespread epidermal detachment.
Erythema dyschromicum perstans: there is hyperkeratosis and marked pigmentary • Raised atypical target lesions are ill-defined, round, palpable lesions
incontinence. with only two zones including a central raised edematous area with an
erythematous border.
• Flat, atypical target lesions are ill-defined, round lesions with only two
bandlike infiltrate of lymphocytes and histiocytes. The histiocytes are vari- nonpalpable zones. The center may be blistered (Fig. 7.64).
ably described as loosely aggregated and superficially located, cohesive gran- • Macules with or without blisters are defined as nonpalpable,
ulomata, diffuse interstitial granulomatous inflammation, scattered solitary erythematous or purpuric macules with irregular shape and size and
giant cells, and granulomatous vasculitis.1 Cases associated with drugs also often confluent. Blisters often occur on all or part of the macule.
may display parakeratosis, keratinocyte necrosis, acrosyrinogeal accentua- This lesion is characteristically seen in patients with widespread
tion, red cell extravasation, granulomatous vasculitis, eosinophils, and plas- epidermal detachment who have a history of drug ingestion.
macellular infiltrate sparing the deep dermis.1,2 Lymphocyte atypia may also Working on this basis, the following definitions have been proposed:1
be a feature in examples associated with cutaneous lymphoma or lymphoma- • Bullous erythema multiforme is characterized by < 10% detachment,
tous drug reactions.1 typical target lesions, and sometimes raised atypical target lesions.
including children, and shows a slight male predilection.1–8 All races may
be affected. It is self-limiting and commonly recurrent (recurrent erythema
multiforme), although rarely continuous episodes of erythema multiforme
have been described (persistent erythema multiforme).9–13 Very occasionally,
epidemics are seen, as for example in military camps.4 The eruption shows
seasonal variation with many patients developing the condition in spring and
summer.
It presents as symmetrically distributed, fixed, discrete erythematous
round maculopapules 1–2 cm in diameter which appear in crops on the
acral regions, particularly the elbows, the knees, and extensor aspects of
the extremities (Figs 7.65–7.67). Sometimes, the face, palms and soles,
flexural extremities, and perineum (Fig. 7.68) are affected.2 The scalp is
rarely involved.14 Typically, the center of the lesions becomes ischemic to
produce a bluish discoloration (the classic iris or target lesion) which may
eventually blister. Although lesions are often present for up to 7 days, the
entire episode is usually over by 6 weeks or less.14 Lesions often number
a hundred or more. Resolution may be associated with postinflammatory
hyperpigmentation.
Oral lesions are common and are usually mild, typically presenting as mul-
Fig. 7.63 tiple ulcers, which may involve the entire oral cavity, or predominantly affect
Target lesion: characterized by a central blister surrounded by an edematous ring
the buccal mucosa and tongue (Figs 7.69, 7.70).15 Target lesions on the lips
and an outer erythematous border. By courtesy of R.A. Marsden, MD, St George's
may also be encountered.
In many patients, episodes of erythema multiforme are recurrent, develop-
ing as often as five times each year. Such cases are almost invariably due to
herpes simplex infection. Particular clinical features of this variant include a
• Stevens-Johnson syndrome is characterized by > 10% detachment, flat positive Koebner's phenomenon, photodistribution, grouping of lesions over
atypical target lesions, and erythematous macules in addition to blisters the elbows and knees, and nail fold involvement.8
and erosions affecting one or more mucous membranes. In the older literature, a variant of erythema multiforme was recognized
• Overlap Stevens-Johnson syndrome/toxic epidermal necrolysis is (erythema multiforme major) in which patients developed severe mucosal dis-
characterized by 10–30% detachment, atypical target lesions, and flat ease including oral, ocular, and anogenital lesions. In keeping with the current
erythematous macules. thinking on this complex topic, such cases are now included in the spectrum
• Toxic epidermal necrolysis is characterized by > 30% detachment with of Stevens-Johnson syndrome.1,2
flat atypical target lesions and/or erythematous macules. Rarely, toxic Rarely, patients (usually females) may develop erythema multiforme in asso-
epidermal necrolysis may develop as large epidermal sheets in the absence ciation with discoid or systemic lupus erythematosus – Rowell syndrome.
of erythematous macules.
Erythema multiforme The etiology in the overwhelming majority of cases is past or present infec-
tion with herpes simplex virus (HSV) types I and II. In many patients, dis-
Clinical features ease is subclinical. In some studies the relationship is strongest in patients
Erythema multiforme is a relatively common condition, which predominantly with recurrent disease. Occasionally, Mycoplasma infection is of etiological
affects younger individuals (particularly in their second to fourth decades), importance. Although many other viral and bacterial infections have also
Fig. 7.64
Flat atypical target lesion: characterized by only two components, a central Fig. 7.65
edematous area or blister surrounded by a zone of erythema, these lesions may Erythema multiforme: multiple lesions on the hand, a typical site of presentation.
be seen in erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
necrolysis. By courtesy of the Institute of Dermatology, London. London, UK.
Fig. 7.66 Fig. 7.68

Erythema multiforme: multiple ulcerated lesions on the hands. From the collection Erythema multiforme: note the presence of erythema and erosion on the labium
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. minus. By courtesy of P. Morgan, MD, London, UK.
Fig. 7.69
Erythema multiforme: multiple erosions are present on the labial mucosa. By
courtesy of P. Morgan, MD, London, UK.
Fig. 7.67
Erythema multiforme: more extensive involvement in an adult with large
erythematous lesions. The blisters have ruptured. By courtesy of the Institute of
Dermatology, London.
been implicated including orf, cowpox, Epstein-Barr virus, streptococcus,

meningococcus, Histoplasma, and various childhood illness immunizations,
it is uncertain whether these truly represent erythema multiforme or whether
they might be better classified as some other dermatosis, including Stevens-
Johnson syndrome.4,14,16 Erythema multiforme has also been described as
a side effect of a number of drugs including sulfonamides, trimethoprim-
sulfamethoxazole combinations, penicillin, barbiturates, the oral con-
traceptive pill, TNF-α antagonists, bortezomib, sorafenib, and anti- Fig. 7.70
retroviral drugs in HIV patients.4,1,17–20 An interesting association with Erythema multiforme: there is a large ulcer on the buccal mucosa. By courtesy of
ciprofloxacin after alcohol ingestion has been described.21 The antineoplastic P. Morgan, MD, London, UK.
drug paclitaxel has not only been associated with erythema multiforme but
may trigger a photosensitive variant of the disease.22 Furthermore, the erup-
tion has also been associated with photocontact dermatitis to ketoprofen.23
A single association with HPV vaccination has been reported.24 A localized
contact dermatitis to a henna tattoo has also triggered the disease.25 Erythema
multiforme has also been associated with internal malignancy, including
lymphoma, and may follow radiotherapy.26,27
Although cultures of skin lesions in erythema multiforme are generally
negative for herpes simplex, viral DNA has been identified within the epi-
dermis of skin lesions by polymerase chain reaction (PCR); in situ hybrid-
ization and immunohistochemistry detecting viral components are often
positive.13,16,28–35 Viral DNA is absent from healed lesions.31 Viral gene
expression correlates with lesion development.29 Since there is no evidence
of a viremia, it is thought that viral DNA is transported to the skin within
circulating lymphocytes rather than directly through the bloodstream or
via centrifugal neuronal spread.31,34 Why it localizes to specific sites in the
skin is unknown but this may be related to ultraviolet (UV) exposure. It is
likely that an episode of erythema multiforme develops as a delayed hyper-
sensitivity (and/or cytotoxic) reaction to herpes viral antigens including
DNA polymerase expressed on the surface of keratinocytes. The identifi- Fig. 7.71
Erythema multiforme: early lesion showing hyperkeratosis, basal cell hydropic
cation of IFN-γ in active skin lesions suggests a delayed hypersensitivity
degeneration, and occasional cytoid bodies.
reaction with involvement of variable cytokines recruiting additional lym-
phocytes and macrophages to amplify the inflammatory reaction.35,36 It
has been postulated that HSV DNA polymerase might also be associated
with increased expression of transforming growth factor-beta (TGF-β) and
p21waf, thereby accounting for cell growth arrest and apoptosis.37 Viral
antigens do not persist in lesional skin after resolution of the eruption and
therefore in patients with recurrent disease, repeat transportation of viral
DNA to the skin must occur.
Erythema multiforme is associated with an increased incidence of
HLA-B15 (B62), HLA-B35, and HLA-DR53, particularly in recurrent
disease.38–41 Patients with limited mucosal involvement show an increased
frequency of HLA-DQB1*0302 compared with patients in whom
mucosal lesions predominate, when HLA-DQB1*0402 is more com-
monly identified.41
Erythema multiforme is characterized by a combination of basal cell
hydropic degeneration and keratinocyte apoptosis accompanied by a heavy
superficial dermal lymphohistiocytic infiltrate associated with lymphocytic
exocytosis and satellite cell necrosis.16,42–46 An exceptional case in which the
predominant cells were histiocytes mimicking Kikuchi's disease has been
described.47
Apoptotic keratinocytes are rounded, intensely eosinophilic, and often
anucleate, although residual pyknotic forms may be present (Figs 7.71, Fig. 7.72
7.72). Their distribution may be focal, involving only an occasional and often Erythema multiforme: close-up view of basal cell hydropic degeneration.
basally located keratinocyte, or it can affect the entire epidermis, thereby
resembling toxic epidermal necrolysis (Lyell's syndrome) (Fig. 7.73). Marked
basal cell hydropic degeneration sometimes results in subepidermal clefting
or vesiculation (Fig. 7.74). Intra- and intercellular intraepidermal edema is
evident and spongiotic vesiculation can be a feature (Fig. 7.75).
In biopsies from early lesions, the changes may be predominantly dermal
with marked edema of the papillary dermis accompanied by a chronic inflam-
matory cell infiltrate and red cell extravasation (Fig. 7.76), thereby account-
ing for the clinical appearance of purpura.
The inflammatory cell infiltrate in erythema multiforme usually comprises
lymphocytes and histiocytes; neutrophils are sparse or absent. Eosinophils
may sometimes also be present.48 Leukocytoclasis is not seen.
Histological features, similar to those of the skin lesions, typify involve-
ment of the mucous membranes with spongiosis and intracellular edema.
These lesions tend to be more obvious and, therefore, intraepithelial blisters
are sometimes conspicuous.
With immunohistochemistry, the infiltrate consists predominantly of
helper (CD4+ Vβ2+) lymphocytes with a lesser number of cytotoxic lym-
phocytes and admixed macrophages.49,50 Keratinocytes express intracellu-
lar adhesion molecule-1 (ICAM-1) and HLA-DR, the latter thought to be
induced by IFN-γ of activated CD4+ T-helper 1 (Th1) cell derivation.49,51
TNF-α is not expressed in HSV-associated lesions.37 Circulating soluble Fas is Fig. 7.73
thought to be an mediator of apoptosis, as in toxic epidermal necrolysis and Erythema multiforme: marked apoptosis has resulted in intraepidermal vesiculation.
S tevens-Johnson syndrome. Autantibodies to desmoplakin 1 and 2 may also

play a role in erythema multiforme major.16
Erythema multiforme shows considerable overlap with Steven-Johnson
syndrome and toxic epidermal necrolysis. In erythema multiforme, how-
ever, there are commonly more marked inflammatory changes than seen in
Stevens-Johnson syndrome and toxic epidermal necrolysis in which the epi-
dermal changes of widespread apoptosis are the predominant feature.
Erythema multiforme may also on occasion be confused with fixed drug
eruption, acute graft-versus-host disease (GVHD), and connective tissue
diseases such as systemic or subacute cutaneous lupus erythematosus and
dermatomyositis. Presence of mucin and evidence of chronicity such as hyper-
keratosis and parakeratosis are useful clues for connective tissue disease. The
presence of conspicuous eosinophils would be in favor of a drug reaction.
Focal interface change combined with an absence of significant eosinophils
and follicular involvement is thought helpful for distinguishing between
GVHD and erythema multiforme. None of the findings is considered abso-
lutely pathognomonic of any entity and clinicopathological correlation will Fig. 7.76
most often ensure their distinction with ease. Erythema multiforme: early lesion showing interface change and marked upper
dermal edema.
Toxic epidermal necrolysis and

Stevens-Johnson syndrome
The original description of toxic epidermal necrolysis included two unrelated
conditions:1
• the scalded skin syndrome seen in infants and young children and due to
staphylococcal infection with toxin production,
• a drug hypersensitivity reaction, predominantly affecting adults, now
regarded as the sole representative of this entity.
Clinical features
Classification of a blistering disorder as toxic epidermal necrolysis (Lyell's
syndrome) or Stevens-Johnson syndrome is based upon the extent of detached
or detachable skin at the worst stage of the illness.2 In the former condition,
30% or more skin is involved whereas in the latter less than 10% is affected
(Figs 7.77, 7.78). An intermediate category where 10–30% of the skin is
involved has also been recognized.3–5
Toxic epidermal necrolysis and Stevens-Johnson syndrome are very rare
conditions, with reported incidences ranging from 0.93 to 1.3 cases per mil-
Fig. 7.74
Erythema multiforme: in this example, subepidermal vesiculation is present. lion population in Europe and 0.5 in the United States.6–9 They represent
severe drug hypersensitivity reactions except for those instances in which
GVHD develops a toxic epidermal necrolysis-like appearance.7,10 While prior
studies have shown there is no racial predilection, there is some evidence
of genetic susceptibility to this condition. Patients with HLA-B*1502 and
HLA-B*5801 are associated with carbamazepine-induced Stevens-Johnson
syndrome and allopurinol-induced Stevens-Johnson syndrome among the
Han Chinese, respectively. 5,11,12 The elderly are predominantly affected, but
the condition may present at any age, including children, infants, and the
newborn.13–15 In the last group, mucosal lesions may sometimes be the sole
manifestation of the disease.16 Prior studies have shown that females are
affected more often than males (2:1) but more recent reports suggest that this
may be changing, with more male and HIV/AIDS patients being reported.4,15
In children the sex ratio is equal.
Patients typically present with a short prodromal illness of pyrexia, sore
throat, muscle ache, headache, anorexia, nausea, vomiting, and burning
eyes, soon followed by the development of a painful rash most often start-
ing on the face, neck, and shoulders before becoming more generalized with
trunk and proximal limb accentuation.4,5,15–18 The eruption consists of irregu-
lar, erythematous, and sometimes purpuric or necrotic, flat, atypical target
lesions. In some patients, an exanthematous, morbilliform eruption is initially
Fig. 7.75 seen.19 Occasionally, typical target lesions overlapping with erythema multi-
Erythema multiforme: early lesion showing spongiosis, lymphocytic exocytosis, and forme may be a feature.9 In any event, this early stage is soon followed by the
cytoid bodies. development of flaccid, fluid-filled bullae (Fig. 7.79). These rapidly ulcerate,
Fig. 7.79
Toxic epidermal necrolysis: early stage showing multiple large fluid-filled blisters.
By courtesy of R. Reynolds, MD, Harvard Medical School, Boston, USA.
Fig. 7.77
Stevens-Johnson syndrome: this patient developed Stevens-Johnson syndrome
following sulfonamide therapy. By courtesy of R.A. Marsden, MD, St George's
Fig. 7.80
Toxic epidermal necrolysis: there is widespread erythema and numerous blisters
Fig. 7.78
are evident. By courtesy of I. Zaki, MD, and S. Dalziel, MD, University Hospital,
Stevens-Johnson syndrome: this condition is distinguished from toxic epidermal
Queen's Medical Centre, Nottingham, UK.
necrolysis by there being less than 10% of the skin involved. Note the tense
blisters. By courtesy of the Institute of Dermatology, London, UK.
lesions, esophageal stricture, hepatitis, and pancreatitis are occasional man-

ifestations.21–23 Tracheobronchial involvement is fairly common and adult
leaving painful raw erosions similar to scalding (Figs 7.80–7.83). Nikolsky's respiratory distress syndrome is an important and potentially life-threatening
sign is positive. Eventually, the whole body, with the exception of the hair- complication.17 Anemia and leukopenia are typically seen.
bearing scalp, may become affected. The mortality of Stevens-Johnson syndrome is approximately 5%, whereas
Toxic epidermal necrolysis/Stevens-Johnson syndrome is a multisystem the more extensive skin involvement in toxic epidermal necrolysis is reflected
disease. The mucous membranes are affected in all patients and sometimes in a higher mortality of up to 40%.17,22,24–26 Causes of death include sepsis
represent the presenting manifestation.17 The oropharynx, eyes, genitalia, (particularly due to Staphylococcus aureus and Pseudomonas aeruginosa),
and anus show particular involvement, in descending order of frequency.4,5,19 heart failure, pulmonary embolism, septic shock, disseminated intravascular
Ocular lesions are especially important, as they are a cause of significant long- coagulation, and gastrointestinal bleeding.19 Increased age, a high proportion
term morbidity in 40–50% of survivors.4,20 Patients may manifest conjunctivi- of skin loss, deteriorating renal function,22 and extensive involvement of the
tis, synechiae, the sicca syndrome, trichiasis, and keratitis.19 Gastrointestinal bronchial epithelium4 are all associated with a poor prognosis.
Fig. 7.83
Toxic epidermal necrolysis: healing is commonly followed by postinflammatory
hyperpigmentation. From the collection of the late N.P. Smith, MD, the Institute of
Toxic epidermal necrolysis may also evolve in the setting of acute

Fig. 7.81 GVHD. Although some of these cases are undoubtedly due to an adverse
Toxic epidermal necrolysis: note the generalized blistering resembling scalding. drug reaction, a proportion represents a specific and severe manifestation
By courtesy of I. Zaki, MD, and S. Dalziel, MD, University Hospital, Queen's Medical of acute GVHD. This is associated with a very poor outlook and high
Centre, Nottingham, UK. mortality.10,30
Toxic epidermal necrolysis/Stevens-Johnson syndrome is an important
complication of HIV infection and is seen in up to 1 in 1000 acquired immu-
nodeficiency syndrome (AIDS) patients per year.31 The high incidence relates
in part to the frequent use of sulfonamides in these patients.32 Patients with
systemic lupus erythematosus are also particularly at risk.15
Exceptionally, toxic epidermal necrolysis has been documented in adults fol-
lowing an infection including hepatitis A and Mycoplasma pneumoniae.4,33,34
The precise mechanisms involved in the pathogenesis of toxic epidermal
necrolysis are unclear. Affected patients in sulfonamide-related cases are com-
monly slow acetylators, and detoxification of resultant reactive drug metabo-
lites is impaired.17,35,36 Although the condition may result from a direct action
in some cases, it is thought to be more likely that drug metabolites function
as haptens and induce an indirect cellular immune reaction to keratinocytes.
Patients with AIDS are deficient in glutathione and, as a result, persistence of
such reactive metabolites may explain the increased incidence of this disease
in these patients.36
Toxic epidermal necrolysis is associated with an increased incidence of
HLA-B12: 50% compared with 26% in the normal population.37 As men-
tioned above, specific HLA types are associated with Stevens-Johnson syn-
drome in certain racial populations.
Fig. 7.82 Although the exact pathogenesis of the disease is not clear, it has been
Toxic epidermal necrolysis: this is a serious potentially life-threatening condition.
demonstrated that the inflammatory cells in the blisters are cytotoxic T lym-
This is a particularly severe example. From the collection of the late N.P. Smith, MD,
the Institute of Dermatology, London, UK.
phocytes and natural killer cells.38 The main cytotoxic protein expressed is
granulysin and this protein seems to be a major player in the induction of
disseminated keratinocyte necrosis. When the protein is injected into the skin
of mice, blisters closely simulating those seen in toxic epidermal necrolysis/
Pathogenesis and histological features Stevens-Johnson syndrome develop.38
Toxic epidermal necrolysis/Stevens-Johnson syndrome almost always represents The histological features are those of variable epidermal apoptosis associ-
an adverse drug reaction.13,17,27 However, in children, infection with Mycoplasma ated with basal cell hydropic degeneration or subepidermal vesiculation (Figs
pneumoniae has sometimes been implicated in the latter condition.5,16 Etiological 7.84–7.87).39,40 Lymphocytic exocytosis may be present and satellite cell
agents include sulfonamides, anticonvulsants (phenytoin, barbiturates, and necrosis is sometimes apparent.41,42 Sweat duct epithelium is also involved,
carbamazepine), antibiotics (aminopenicillins, quinolones, and cephalosporins), and hair follicles may also be affected, although much less often (Fig. 7.88).13
nonsteroidal antiinflammatory agents (phenylbutazone, oxyphenbutazone, A light, predominantly perivascular infiltrate of lymphocytes, macrophages,
isoxicam, and piroxicam), and allopurinol.17,19 HIV antiretroviral agents have also and melanophages is present in the superficial dermis, which also is com-
been implicated.28 Patients with such adverse reactions may show a positive patch test monly edematous (Figs 7.89, 7.90). Small numbers of eosinophils may be
to the offending drug and lymphocyte transformation may be demonstrable.27,29 present.
With immunohistochemistry, the dermal infiltrate consists predomi-

nantly of CD4+ T-helper cells, whereas in the epidermis CD8+ cells are most
numerous.41,43,44 Histiocytes may be conspicuous.45 Langerhans cells are
depleted. Keratinocytes express HLA-DR. Keratinocyte cell death is thought
to result from the combined effects of cytolytic enzymes including perforin
and cytokines such as soluble TNF-α and IL-6.18,39,45–47 Fas ligand-mediated
apoptosis is believed to be of major importance in the final development of
necrolysis.4,5,18,39,45–47
Staphylococcal scalded skin syndrome is an important clinical differential
diagnosis. The typical histological finding of a subcorneal pustule in this con-
dition makes the distinction easy. In addition, staphylococcal scale skin syn-
drome does not demonstrate full-thickness necrosis.
Toxic epidermal necrolysis/Stevens-Johnson syndrome may sometimes be
indistinguishable from severe erythema multiforme. Marked lymphocytic
exocytosis, apoptosis predominantly affecting the lower epidermis, intense,
lichenoid dermal chronic inflammation with extension along the superficial
and deep vascular plexuses, and prominent erythrocyte extravasation are
Fig. 7.86
more in favor of erythema multiforme.40,48 This histological distinction is also Toxic epidermal necrolysis: this field shows the floor of the blister. There are no
mirrored to some extent by the etiology. Thus, those cases that result from an inflammatory cells in this example.
Fig. 7.87
Toxic epidermal necrolysis: medium-power view showing necrosis of the full
Fig. 7.84 thickness of the roof of the blister.
Toxic epidermal necrolysis: low-power view showing subepidermal blistering.
Fig. 7.88
Fig. 7.85 Toxic epidermal necrolysis: follicular involvement showing basal cell hydropic
Toxic epidermal necrolysis: the roof of the blister is completely necrotic. degeneration and apoptosis.
poikiloderma. Histologically, poikiloderma is characterized by hyperkerato-

sis, epidermal atrophy with basal cell liquefactive degeneration, pigmentary
incontinence, telangiectasia, and a variable superficial dermal lymphohistio-
cytic infiltrate (Figs 7.91, 7.92).
Poikiloderma of Civatte
Poikiloderma of Civatte (poikiloderma of head and neck, Derbyshire neck) refers
to a fairly common progressive and irreversible disorder in which typical poiki-
loderma presents in a photodistribution, predominantly affecting the sides of the
face and neck and the ‘V’ of the chest (Fig. 7.93).1–4 Middle-aged and elderly
women, menopausal females, are predominantly affected. Possible etiological
factors include hormonal effects, phototoxicity or photoallergy possibly due to
perfumes or fragrances.4–6 Recently, familial cases have been documented.4
In addition to the typical features of poikiloderma, solar elastosis is often very
marked.3 In some biopsies, however, the appearances can be very non-specific.
Fig. 7.89
Toxic epidermal necrolysis: there is a perivascular lymphohistiocytic infiltrate.
Fig. 7.91
Poikiloderma: there is basal cell hydropic degeneration and a very light perivascular
Fig. 7.90 lymphohistiocytic infiltrate.
Toxic epidermal necrolysis: note the apoptosis and pigment incontinence.
infection tend to be more inflammatory than those that represent an adverse

drug reaction, in which the changes are predominantly epidermal.48 The pres-
ence of eosinophils does not seem to distinguish between drug- and infection-
related causes within this histological spectrum.40
Toxic epidermal necrolysis resulting from an adverse drug effect and that
presenting in a background of severe GVHD are indistinguishable.
Paraneoplastic pemphigus
Erythema multiforme-like histological features are an integral feature of para-
neoplastic pemphigus.
Poikiloderma
Poikiloderma (Gr. poikilos, spotted, mottled, varied) is a clinical descriptive
term applied to skin showing slight scaling, atrophy, variable pigmentation,
and telangiectasia. It is a feature of a number of conditions including lupus
erythematosus, dermatomyositis, large plaque parapsoriasis, poikiloderma
of Civatte, poikiloderma congenitale, Bloom's syndrome, Cockayne's syn- Fig. 7.92
drome, dyskeratosis congenita, and DNA mitochondrial syndrome-associated Poikiloderma: close-up view.
Mitochondrial DNA syndrome-associated hands.6 While occasionally reported, mental retardation is not usually a fea-
ture of this syndrome.1 The disease is associated with the development of
poikiloderma cutaneous squamous cell carcinoma and more rarely basal cell carcinoma.2,4
Photodistributed poikiloderma has been documented in a number of mito- Bowen's disease has also been described.7
chondrial DNA syndromes, particularly Pearson's syndrome, which also There is also an increased risk of internal malignancies, particularly tib-
includes failure to thrive, exocrine pancreas insufficiency, severe renal tubule ial osteosarcoma and multicentric osteosarcoma (7–32%).1,2,8–10 An associa-
dysfunction, and bone marrow suppression.1 Other dermatological manifes- tion with duodenal stenosis and annular pancreas has been described in one
tations of mitochondrial DNA syndromes include acrocyanosis, dry brittle patient.11 The life span of the patient, however, is generally normal.
hair, vitiligo, hyperpigmentation, and anhidrosis.2–7
Rothmund-Thomson syndrome
Clinical features
This rare syndrome, which has been described in Asians and blacks as well as
Caucasians, has an autosomal recessive mode of inheritance. In contrast to the
earlier finding of an equal sex incidence, the more recent literature suggests a
predilection for males (2:1).1,2 It usually presents between the third and sixth
months of life (hence the term ‘poikiloderma congenitale’) as a reticulated,
erythematous rash – sometimes described as marmoreal (L. marmor, marble) –
on the face, which eventually spreads to involve the extremities and the but-
tocks (Figs 7.94–7.96).2 The trunk and flexural aspects are usually spared.1
Affected infants are photosensitive and, therefore, there is often a history of
sun exposure before the development of skin lesions.3,4 This is later replaced
by reticular, linear, or punctate foci of atrophy.4 Telangiectasia is present and
areas of hypo- and hyperpigmentation may be noted. The poikilodermatous
change is seen most frequently at sun-exposed sites.1
Fig. 7.94
A variety of other manifestations may be observed, including variable alo- Rothmund-Thomson
pecia particularly involving the scalp, eyebrows and eyelashes, and seen most syndrome: there is
often in females. This is present in up to 80% of patients.1 Gastrointestinal a marked mottled
problems including chronic emesis and diarrhea may be seen in infancy.2 hyperpigmentation
Juvenile, subcapsular (unilateral or bilateral) cataracts are common and skel- predominantly affecting
etal abnormalities include short stature, osteopenia, pathological fractures, the peripheries. By
dislocations, irregular metaphyses, abnormal trabeculation, and stippled ossi- courtesy of the Institute
fication of the patellae.2 Small hands with shortened digits are frequently of Dermatology, London,
seen.5 Frontal bossing, saddle nose, and prognathism are characteristic.1 UK.
Absent or malformed radii are seen in 10–20% of patients and bifid or absent
thumb may also be present.1,2,6 Nail dystrophy, dental abnormalities (par-
ticularly conical-shaped teeth with caries), and hypogonadism may also be
detected. Hyperkeratotic warty or verrucous lesions sometimes develop on
the extensor surfaces, particularly overlying joints and especially the feet and
Fig. 7.95
Rothmund-Thomson
syndrome: there is
symmetrical involvement
of the legs. By courtesy
Fig. 7.93 of the Institute of
Poikiloderma of Civatte: note the mottled hyperpigmentation in a characteristic Dermatology, London,
distribution. By courtesy of the Institute of Dermatology, London, UK. UK.
and typically develops in infancy. Café-au-lait spots are a common manifes-

tation and discrete areas of hypopigmentation are usual.3 A peculiar high-
pitched, squeaky (so-called '’Mickey Mouse’) voice is sometimes a feature.5
Male infertility is common.3 Patients may suffer impaired concentration,
short-term memory, and general mental organizational disability.5
Bloom's syndrome is typified by an inherent propensity to chromosomal
abnormalities, in particular, sister chromatid exchange. There is an associ-
ated increased incidence of most malignancies, especially acute leukemia,
non-Hodgkin's lymphoma, colon carcinoma, breast carcinoma, and cutane-
ous squamous cell carcinoma. Patients are prone to develop multiple primary
tumors, which often develop at an early age (third decade). As a result, death
by age 30 usually occurs due to cancer.4,6 They may also suffer immunode-
ficiency (diminished IgG, IgA, IgM) and are therefore at an increased risk
of childhood infections, pulmonary infections, and chronic lung disease.5,7
There is also an elevated risk of adult onset-like diabetes mellitus.8

The gene for Bloom's syndrome, BLM, which has been mapped to 15q21.3,
Fig. 7.96 is a member of the RecQ helicase protein family, responsible for unwinding
Rothmund-Thomson syndrome: there is atrophy in addition to hyperpigmentation. DNA and RNA.9–15 It has been identified as representing part of the BRCA1-
By courtesy of the Institute of Dermatology, London, UK. associated genome surveillance complex, which is mutated in families with
hereditary breast cancer.16 The protein functions as a 3′-5′ DNA helicase and
may be involved specifically in allowing sister chromatid separation during
mitosis.12,17 DNA helicases have essential roles in genetic recombination,
transcription, DNA replication, and repair.15 Mutation of the BLM gene
Pathogenesis and histological features results in genomic instability. Bloom's syndrome is associated with increased
Rothmund-Thomson syndrome, in some patients at least, has been shown sensitivity to alkylating agents, increased spontaneous chromosome breakages,
to be associated with a mutation in the RECQL4 gene, a member of the increased interchromatid exchange (including sister chromatid exchange,
DNA helicase family (see Bloom's syndrome).9,12–15 Cytogenetic analysis has 6–10-fold), increased somatic cell mutation frequency, and reduced replication
revealed mosaicism in a subpopulation including trisomy 8.2 The underlying fork elongation rate.4,11 Mutations include missense, nonsense, frameshift,
defect in Rothmund-Thomson syndrome is unknown. While most investiga- and genomic deletions, most of which result in premature translation
tions have failed to demonstrate abnormal sensitivity to UVA or UVB, there terminations and resultant defective Bloom's syndrome protein with impaired
have been occasional recent reports of reduced unscheduled DNA synthesis function.14 Multiple defective nuclear enzymes including DNA ligase I have
following irradiation of cultured fibroblasts with UVB and UVC.3,16 More been identified.18 Monosomy 7 and deletions of the long arm of chromosome
recent studies suggest a role for RECQL4 in repairing DNA induced by UV 7 are found in the majority of patients with myeloid leukemia.19 A mouse
irradiation.17 Other investigations have demonstrated that RECQL4 is also model recapitulates many aspects of the human disease syndrome, including
involved in DNA replication.18–20 hematopoietic malignancies.20
No recognized diagnostic test for this disorder is available and diagnosis
is based primarily on the polioderma rash.15 Mutational screening for the
RECQL4 gene is possible and can correlate with certain aspects of the syn-
drome, but additional genes may also be involved.21
The histological features of poikiloderma include hyperkeratosis, epi-
dermal atrophy, liquefactive degeneration of the basal epidermal cells, and
telangiectasia. Pigmentary incontinence may be present and a perivascular
chronic inflammatory cell infiltrate is sometimes evident in the superficial
dermis. The latter sometimes also shows elastic tissue fragmentation and
depletion or absence of cutaneous appendages.1 The squamous cell carcino-
mas show typical features.
An examination of scalp has revealed hypopigmented vellus hairs without
cortices.6
Bloom's syndrome
This rare chromosomal instability syndrome (also known as congenital Fig. 7.97
telangiectatic erythema with dwarfism) has an autosomal recessive mode of Bloom's syndrome:
inheritance and is particularly seen in East European (Ashkenazi) Jews. When characteristic facies
found in non-Jews, there is a high incidence of parental consanguinity. It rep- includes ‘pinched’
resents a genetically homogenous single locus disease unassociated with any features. Marbled
apparent heterogeneity.1 erythema of the cheek
and crusted lesions
Clinical features involving the lower
lip. By courtesy of D.
There is a characteristic appearance with microcephaly, dolichocephaly, and Atherton, MD, Institute
small, narrow ‘pinched’ facies, and stunted growth leading to severe dwarf- of Dermatology and
ism.2,3 An erythematous rash with telangiectasia develops predominantly on Children's Hospital at
the face (in particular the ‘butterfly’ area) and is exacerbated by sunlight Great Ormond Street,
(Fig. 7.97).4 The rash may also affect the backs of the hands and forearms London, UK.
The cutaneous lesions are typified by a lupus erythematosus-like histol-

ogy. There is epidermal atrophy accompanied by liquefactive degeneration
of the basal layer with cytoid body formation. A lymphohistiocytic infil-
trate is present in the superficial dermis. Telangiectatic blood vessels are
evident.
Cockayne's syndrome
This is a very rare disorder with an autosomal recessive mode of inheritance
and a male predominance (4:1) with the majority of cases reported to be of
British ancestry. It is a multisystem disease associated with premature aging and
particularly affects the skin, teeth, eyes, skeleton, and central nervous system.1
Clinical features
Children appear to be normal at birth and have an unremarkable early devel-
opment. However, usually in the second year of life, they show photosensi-
tivity and acquire a ‘butterfly’ rash (as in lupus erythematosus) on the malar
region, which with time is associated with scarring and hyperpigmentary
changes. These features, in association with prognathism, sunken eyes, loss of
subcutaneous fat, and nasal atrophy (‘beaked’ nose), give the children a char-
acteristic progeria-like or bird-headed appearance (Fig. 7.98).2–4 Fine hair
and anhidrosis may also be evident.1
Ocular lesions include corneal opacity, cataract, retinal degeneration, and
optic atrophy with resultant blindness.1 ‘Salt and pepper’ pigmentation of the
fundus is characteristic.2
Patients usually suffer from progressive sensorineural deafness.1 The patients Fig. 7.98
are dwarfs and have disproportionately long limbs with enlarged hands and Cockayne's syndrome: the features include prominent ears, prognathism, a
‘beaked’ nose, and flexion contractures.By courtesy of D. Atherton, MD, Institute of
feet.2 Microcephaly is common and radiological examination reveals thick-
Dermatology and Children's Hospital at Great Ormond Street, London, UK.
ening of the skull bones. Kyphosis, ankylosis, and flexion contractures are
frequent complications, and dental abnormalities include malocclusions and
caries. Involvement of the central nervous system presents as microcephaly,
normal pressure hydrocephalus, mental subnormality, ataxia, choreoatheto-
sis, spasticity, myoclonus, and gait disturbance.1,2,5 Renal function is usually The cerebral lesions are characterized by loss of white matter, cerebellar cor-
impaired.6 tical atrophy, hydrocephalus, and widespread calcification.5,21 Histologically,
Patients with Cockayne's syndrome have an increased incidence of infec- there is demyelination and gliosis. Iron-laden neurons, neurofibrillary tan-
tions and usually die within the third decade. gles, and giant, bizarre astrocytes have also been reported.21,22 Severe athero-
An unusually severe form with early onset and quick death associated with sclerosis resulting in occasional strokes can occur. 21
abnormal thymidine dimer repair (and hence showing overlap with xero- The kidney shows global sclerosis due to marked basement membrane (type
derma pigmentosum) has recently been described.5,7 IV) collagen deposition associated with tubular atrophy and interstitial fibrosis.6
Prenatal diagnosis of Cockayne's syndrome is now possible.8
Dyskeratosis congenita
Pathogenesis and histological features Clinical features
The two genes responsible for Cockayne's syndrome (CSA and CSB) have This is a rare, but important, systemic illness with poor prognosis and high
been cloned, with most cases due to mutations in CSB.9–11 CSA encodes a mortality. It has a predominantly X-linked recessive mode of inheritance
WD (Trp-Asp) protein, which interacts with a number of proteins including and occurs mainly in males (6:1), although both autosomal dominant
p44 protein, a subunit of transcription/DNA repair factor IIH (TFIIH).12 CSB and recessive variants are also recognized.1–5 The condition consists
belongs to the yeast SNF2/SW12 protein family, which is of importance in predominantly of a complex triad of skin pigmentation, nail, and mucosa
gene transcriptional activation.12 Unlike CSA, CSB is devoid of helicase activ- abnormalities. There is also an increased incidence of malignancy including
ity. CSB protein interacts with CSA and excision repair enzyme XPG. It may hematological and solid tumors.1,2,6
also have a role in response to hypoxic injury and in chromatin structure.11 The skin acquires a widespread reticular pigmentation with associated
A mouse model of this syndrome has been developed.13 poikiloderma, which at first appears most prominently on the face, neck,
Patients with Cockayne's syndrome have an impaired DNA excision/ and the ‘V’ neck region of the upper chest, but later becomes generalized
repair mechanism and are hypersensitive to the effects of UV radiation with (Fig. 7.99).1,4 During childhood the nails become dystrophic and are often
an inability to promote normal levels of DNA and RNA synthesis following lost (Fig. 7.100). There may also be palmoplantar hyperkeratosis associated
UV irradiation.14–17 The specific defect resides within repair of mutations in with hyperhidrosis, development of epiphora, early loss of dentition, caries,
transcriptionally active genes rather than in excision/repair mechanisms in poor growth, sparse hair, bullous eruptions, lacrimal duct stenosis, and men-
general.18,19 There are five complementation groups identifiable by cell fusion tal subnormality.1–3,7 A reduced diffusion capacity develops from pulmonary
studies: CSA, CSB, XPB, XPD, and XPG.5,11 XPB, XPD, and XPG differ from fibrosis.2
groups CSA and CSB by showing an increased incidence of skin cancer.12 Premalignant leukoplakia involving particularly the mouth and anus is an
Cockayne's syndrome may also coexist with trichothiodystrophy.20 important complication, with a significant risk of squamous cell carcinoma
Biopsy of the malar rash shows epidermal atrophy associated with basal developing in these lesions.2,5 The urethra and vagina may also be affected.
cell hydropic degeneration. A chronic inflammatory cell infiltrate is present Hematological manifestations include thrombocytopenia, aplastic anemia,
in the superficial dermis. pancytopenia, myelodysplasia, and acute myeloid leukemia.7–9
The grave outlook of dyskeratosis congenita relates particularly to the with a striking predisposition to develop rearrangements.2,14 Dyskeratosis
development of infections complicating aplastic anemia, malignancy, and congenita therefore appears to result from defective telomerase activity with
pulmonary complications.2,10 resultant impaired stem cell turnover or proliferative activity.4,15 This is sup-
The clinical features of this disease are most severe in males with the ported by the finding that telomeres are markedly shortened and that this
X-linked variant. There is considerable variation in autosomal variants and develops at an early age.6,16
in some of these patients symptoms may be very mild, allowing a normal life The autosomal dominant variant has similarly recently been shown to be
expectancy.2 associated with a mutation of the RNA component of telomerase TERC,
telomerase enzyme TERT – both part of the shelterin telomere protection
Pathogenesis and histological features complex TIN2.4,6
Dykeratosis congenita is characterized by mutations in genes involved in Finally, the autosomal recessive variant has been associated with mutation
telomere function, with the effected gene depending on the mode of inheri- in the NOP10/NHP2 genes that regulate telomerase.6
tance.6 X-linked recessive dyskeratosis congenita is due to mutations of the The histological features of the pigmentary changes are non-specific, show-
DKC1 gene, which has been mapped to Xq28.11 The mutations, which are ing only pigmentary incontinence.
predominantly missense, result in single amino acid substitutions in dyskerin, Biopsies of the mucosal lesions show an acanthotic epithelium with or
a nucleolar protein believed to be responsible for site-specific pseudouridy- without dysplastic changes. In the latter case, great care must be taken to
lation of ribosomal RNA. It is also associated with mutations in the TERC, exclude the presence of squamous cell carcinoma.
TERT, NOP10, and NHP2 genes involved in telomere function.12,13 Not all
cases have a known genetic cause. There is marked chromosomal instability Graft-versus-host disease
Clinical features
Graft-versus-host disease (GVHD) represents a complex multisystem major
complication of organ transplantation, usually bone marrow, that particu-
larly affects the skin, intestine, and liver. It develops when transplanted immu-
nocompetent donor T lymphocytes are activated, proliferate, and respond
to foreign host major histocompatibility complex (MHC)-histoincompatible
antigens in a background of recipient immunosuppression.1–9 In the context
of identical class I HLA antigens, as may be seen in sibling donors, class II
HLA antigens (HLA-DR, -DP, and -DQ) and minor histocompatibility anti-
gens are of major pathogenetic significance.1,2 These latter HLA antigens are
expressed on host epithelial cells following pregraft irradiation or chemother-
apy, thereby focusing the donor lymphocyte immune response on the skin,
liver, and intestinal tract.1,10,11
GVHD is a very serious complication of allogeneic bone marrow trans-
plantation and morbidity and mortality is very high.12 It may also follow
solid organ transplantation, develop in severely immunodepressed patients
after transfusion of nonirradiated blood or blood products, or complicate
transplacental transfer of maternal lymphocytes into an immunodeficient
fetus.13–15
Fig. 7.99 The clinical features of GVHD develop as a consequence of donor
Dyskeratosis congenita: typical poikilodermatous pigmentation on the neck. By T lymphocyte-mediated reactions to host tissues. Successful bone marrow
courtesy of D. Atherton, MD, Institute of Dermatology and Children's Hospital at transplantation is dependent upon compatibility of the ABO system blood
Great Ormond Street, London, UK. groups and histocompatibility antigens (HLA). The D locus (HLA class II)
is of particular importance; successful transplantation has occurred in the
presence of identical D loci with dissimilarities at the A and B loci. However,
the development of GVHD is not totally dependent upon HLA incompatibility
as it can develop in 35% of cases with identical A, B, and D loci, suggesting the
additional importance of the minor histocompatibility antigens (miH).2,16
Development of acute GVHD appears to be a consequence of HLA dis-
parity, sex mismatch, increasing patient age, and the presence of infection.7
While the skin is a major target organ in GVHD and one of the first involved
organs, the liver and gastrointestinal tract are also affected.9,17 Manifestations
include malaise, nausea and vomiting, diarrhea, malabsorption, and abnor-
mal liver function. Additionally, patients with GVHD have an increased risk
of opportunistic infections, which are an important cause of morbidity and
mortality.
Historically, GVHD was conventionally subdivided into two subgroups by
time after transplantation:
• Acute GVHD occurs within the first 3 months following transplantation
(most often presenting between 2 and 6 weeks).2,17–19
• Chronic GVHD presents after the third month.
However, changing transplantation practices have resulted in delayed
and even atypical presentations of GVHD. In 2005, the National Institutes
Fig. 7.100 of Health Consensus Development Project on Criteria for Clinical Trials in
Dyskeratosis congenita: there is dystrophy of the nails with marked atrophy of the Chronic Graft-versus-Host Disease proposed new criteria to standardize the
surrounding skin. By courtesy of D. Atherton, MD, Institute of Dermatology and diagnosis of chronic GVHD and also account for these new GVHD presenta-
Children's Hospital at Great Ormond Street, London, UK. tions, dividing it into four groups:17,19–21
• Classic acute GVHD: acute GVHD presenting within 100 days after
HCT or donor leukocyte infusion,
• Persistent, recurrent or late onset acute GVHD: acute GVHD occurring
more than 100 days after transplation without chronic GVHD
symptoms,
• Classic chronic GVHD: chronic GVHD without features of acute GHVD
regardless of timing from transplantation,
• Overlap syndromes: both acute and chronic GVHD features present
regardless of timing from transplantation.
The classical features of acute and chronic GVHD are presented below.
The other two categories show similar features and are defined by the clinical
context in which they occur, that is their timing relative to transplantation.
Acute GVHD
Acute GVHD develops in between 6% and 90% of patients who undergo
bone marrow transplantation.22 The incidence relates particularly to HLA
mismatch, the age of the patient, and the conditioning regimen protocols
used.1,2 Additional risk factors of importance include sex mismatch, i.e., when
the donor is a female (particularly if multiparous) and the recipient is male,
use of radiation and/or high dosage chemotherapy prior to transplantation,
prior blood transfusions, prior splenectomy, viral infections, and inadequate
immunosuppression.2
It presents with the sudden onset of fever and malaise, which are rap-
idly followed by cutaneous signs including facial erythema and a gener-
alized morbilliform, maculopapular rash characteristically affecting the
palms and soles (Figs 7.101, 7.102). Mucosal lesions may also be a feature Fig. 7.101
(Fig. 7.103). The skin lesions particularly affect the upper half of the body Acute graft-versus-host disease: chest and arm showing widespread macular
and the back of the neck; ears and shoulders are sites of predilection.1,7,18,19 erythema with fine telangiectasia and mild scaling. By courtesy of R. Touraine, MD,
Lichen planus-like features may sometimes supervene. Additional cutane- Hôpital Henri Mondor, Paris, France.
ous lesions include purpura, petechiae, desquamation, and a folliculitis-like
appearance.7,19
More severe variants include erythroderma or even a toxic epidermal
necrolysis-like reaction. The latter has a poor prognosis and may be a mani-
festation of a drug reaction or represent a true component of acute GVHD.
It usually affects a large surface area, shows mucosal involvement, and is
associated with severe liver and gastrointestinal lesions.23,24 Mortality is very
high (50% and higher, especially if untreated), related to the effects of ther-
apy in addition to the lesions themselves.12,25 In the event of survival of acute
GVHD, the rash may resolve completely or merge into the features of chronic
GVHD. It is often difficult on clinical grounds (and histologically) to dif-
ferentiate between acute GVHD, viral disorders, and cytotoxic/adverse drug
reactions.
The clinical manifestations of acute GVHD are traditionally divided into
four stages:1,2,17,18
• Stage I: Maculopapular eruption affecting up to 25% of surface area.
Bilirubin levels of 2–3 mg/dL and diarrhea in excess of 500 mL/day.
• Stage II: Maculopapular erythema affecting 25–50% of surface area.
Bilirubin levels of 3–6 mg/dL and diarrhea in excess of 1000 mL/day.
• Stage III: Generalized erythroderma. Bilirubin levels of 6–15 mg/dL and
diarrhea in excess of 1500 mL/day. Fig. 7.102
• Stage IV: Toxic epidermal necrolysis. Bilirubin levels of 15 mg/dL or more Acute graft-versus-host disease: this vivid palmar erythema is characteristic.
and diarrhea exceeding 1500 mL/day. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
Chronic GVHD
Chronic GVHD develops in 10% of all patients undergoing allogeneic bone fasciitis have also been described.30–32 In addition, a variety of presentations
marrow transplantation and in 30–70% of all long-term survivors.26 Systems have been reported which can be subtle, especially in the early phase. These
involved include the skin, eyes, mouth and esophagus, liver, genitalia, muscle, include xerosis, ichthyosis, follicular prominence, pityriasiform, eczematous,
and peripheral and central nervous systems.7 Virtually all chronic GVHD psoriasiform lesions, annular lesions similar to urticaria or erthyema annu-
patients exhibit skin manifestations and 90% develop oral lesions.2 Some lare centrifigum, a morbilliform papulosquamous rash, and even erythro-
develop chronic GVHD de novo (30%); others show a gradual progression derma.33 Risk factors for developing chronic GVHD include prior episode of
of continuous acute GVHD into the chronic variant (32%).2 Occasionally, acute GVHD, increasing age, sex mismatch, i.e., when the donor is a female
chronic GVHD may follow a period of resolution of acute GVHD, after an (particularly if multiparous) and the recipient is male, and use of non-T-cell
interval of quiescence (36%).2 Chronic GVHD can occur as a lichen planus- depleted bone marrow.2,34
like eruption or show features of a poikilodermatous or sclerodermatous reac- Although early in chronic GVHD the lesions are typically lichenoid and later
tion.27–29 A discoid lupus erythematosus-like reaction is rare. Polymyositis and sclerodermatous, in some patients these features may appear simultaneously.2
Fig. 7.103 Fig. 7.104

Acute graft-versus-host disease: note the erosions on the buccal mucosa. By Early chronic graft-versus-host disease: there are widespread, almost confluent
courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France. hyperpigmented lichenoid papules. Associated erosion of the epidermis gives an
appearance similar to toxic epidermal necrolysis (Lyell's syndrome). By courtesy of
R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
UV irradiation, trauma, and infection with herpes zoster virus or Borrelia can
precipitate chronic GVHD.2
The early chronic GVHD lesion commonly has a classic lichenoid appear-
ance with typical erythematous or violaceous polygonal papules sometimes
showing Wickham's striae (Fig. 7.104). The periorbital region, ears, palms,
and soles are sites of predilection.2 Oral mucosal lesions include typical net-like
lacy white lesions, and ulcerated areas may also develop (Figs 7.105–7.107).
The cheeks, tongue, palate, and lips are sites of predilection.2 Symptoms of
Sjögren's syndrome are also often present. Onycholysis and cicatricial alope-
cia may be features. The rash is sometimes less typical, appearing as a desqua-
mative active dermatitis or as follicular hyperkeratosis. As mentioned above,
the findings can sometimes be subtle, such as xerosis.33
The late phase of chronic GVHD is typically sclerodermatous and usu-
ally presents 8–18 months after transplantation (Figs 7.108–7.110). The
development of a poikilodermatous rash is followed by induration, atro-
phy, and sclerosis.30 The resultant features resemble morphea or systemic
sclerosis; chronic ulceration, particularly involving pressure points, can
be an unpleasant complication. Blisters may occasionally develop.30 The
development of cutaneous squamous cell carcinoma has occasionally been
documented.31,32
Chronic GVHD has a mortality of up to 40%. Causes of death include Fig. 7.105
Early chronic graft-versus-host disease: there are diffuse widespread lichenoid
infection, cachexia, and liver failure.2
changes of the lips. By courtesy of R. Touraine, MD, Hôpital Henri Mondor,
Systemic features include chronic hepatitis, diarrhea with malabsorption,
Paris, France.
bronchiolitis obliterans, peripheral entrapment neuropathy, and polymyosi-
tis.2 Opportunistic infections are also of major importance.
Pathogenesis and histological features result in increased recognition of histoincompatible MHC antigens by donor
GVHD is mediated by the combined effects of donor T lymphocytes (CD4+ T-cells.1 The superficial dermal endothelial cells express E-selectin, α4β1
T cells responding to MHC class II antigens and CD8+ T cells to class I anti- integrin, αLβ2 integrin, ICAM-1, platelet endothelial cell adhesion mole-
gens) and cytokines including IL-1, TNF-α, IFN-γ and GM-CSF.1,2,11,35–43 The cule-1 (PECAM-1), and vascular cell adhesion molecule-1 (VCAM-1) which
development of acute GVHD depends upon a complex interplay between mediate lymphocyte adhesion to the endothelium and facilitate recogni-
host immunosuppression, tissue damage as a result of pregraft induction tion, activation, and response to MHC molecules.1,47–49 The mechanisms
therapy, and donor lymphocyte proliferation and activation with consequent of cell injury and death result from both cytotoxic T cell and possibly NK
injury and death of susceptible host tissues.1 cell-mediated cytotoxic effects and the actions of cytokines. The former
The lymphocytes may be of CD4+ or CD8+ immunophenotype and com- includes cytolytic actions mediated by perforin and granzyme B, and apop-
monly there is an admixture. Both Th1 and Th2 CD4+ subtypes are rep- tosis through the Fas-Fas ligand pathway.50,51 IL-1, IL-2, IL-6 and TNF-α are
resented. The former produce IL-2 and IFN-γ and are thought to promote thought to be of particular importance in mediating cytotoxicity.1 Raised
GVHD, the latter produce IL-4, IL-6 and IL-10 and are believed to be pro- serum TNF-α correlates with GVHD and antibodies to TNF-α or its recep-
tective, although this has been contested.44 Natural killer (NK) cells may also tor protect against the disease.1,52–54 Recently, regulatory T cells (Treg) have
be of importance although their presence appears to be variable.45 B cells are been postulated to play a role in GVHD. Treg are decreased in patients with
absent. Activated keratinocytes following induction chemotherapy or irradia- GVHD and their role remains to be elucidated.17 Studies suggest a role for
tion produce TNF-α and IL-1 and express ICAM-1 and HLA-DR.46 This may B cells in GVHD.55
Fig. 7.106 Fig. 7.108

Early chronic graft-versus-host disease: florid reticulate white striae on the buccal Late chronic graft-versus-host disease: note the grossly hyperpigmented sclerotic
mucosa are evident. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, limb. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
France.
Fig. 7.107 Fig. 7.109

Early chronic graft-versus-host disease: there are erosive changes on the tongue. Late chronic graft-versus-host disease: hyperpigmented sclerotic plaques are present
By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France. on the back. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
Deposition of IgM and C3 at the dermoepidermal junction and around The acute lesion of GVHD is characterized by focal or diffuse basal cell
the superficial vasculature in up to 39% of patients with acute GVHD sug- hydropic change (Figs 7.111–7.114).58 Apoptotic and dyskeratotic keratinocytes,
gests that humoral responses play a significant role in the pathogenesis of at all levels of the epidermis and associated with adjacent lymphocytes (satellite
GVHD.56 cell necrosis), are characteristic.17,59,60 Isolated cytoid bodies are also frequently
The development of chronic GVHD is dependent on a variety of factors evident. Lymphocytic exocytosis is invariably present and spongiosis is sometimes
including, antihost tissue activity of donor T cells and the development of a feature. Microvesiculation at the dermoepidermal junction occasionally occurs.
autoimmunity.2,57 The infiltrate consists predominantly of CD8+ T cells; NK Follicular involvement is a common feature and the hair bulge region is typically
cells are usually absent.2 As with acute GVHD, TNF-α and IL-1 are the major affected.61,60 Langerhans cells are often reduced in number. Vascular changes include
cytokines implicated.2 endothelial cell swelling with sloughing, and intimal and perivascular lymphocytic
Fig. 7.110 Fig. 7.112

Late chronic graft-versus-host disease: there is mottled hypo- and hyperpigmentation Acute graft-versus-host disease: high-power view showing basal cell liquefactive
with gross atrophy and scaling. By courtesy of R. Touraine, MD, Hôpital Henri degeneration. Diagnosis is entirely dependent on the clinical history.
Mondor, Paris, France.
infiltration. Blood vessel proliferation has also been described. Perivascular edema
and nuclear dust may additionally be present and mast cells are also conspicu-
ous.62,63 Eosinophils are sometimes present and this finding does not necessarily
indicate a drug reaction. Therefore, the histologic presentation of GVHD is broad
and no finding can be considered pathognomonic for GVHD.12,19
The toxic epidermal necrolysis-like lesions are characterized by severe
epidermal necrosis in association with subepidermal vesiculation. Evidence
of sweat gland involvement is commonly present.64,65 Keratinous plugging
of the acrosyringium may therefore be seen and the excretory ducts often
show cytopathic-degenerative and proliferative changes.65 The former com-
prises basal cell hydropic degeneration, lymphocytic infiltration, and apop-
tosis. Follicular involvement is a not uncommon additional manifestation.66
The histological features of acute GVHD may be subdivided into four stages,
which have prognostic significance (Table 7.1).66–68
The histology of chronic GVHD is typically lichenoid in appearance and is
indistinguishable from idiopathic lichen planus (Fig. 7.115). These features
are hyperkeratosis, hypergranulosis, irregular acanthosis, basal cell hydropic
degeneration, cytoid body formation, pigmentary incontinence, and a ban- Fig. 7.113
Acute graft-versus-host disease: high-power view lesion showing parakeratosis,
basal cell hydropic degeneration, and apoptosis.
Fig. 7.111
Acute graft-versus-host disease: evolving lesion showing basal cell hydropic Fig. 7.114
degeneration and scattered apoptotic keratinocytes. The dermis contains dilated Acute graft-versus-host disease: high-power view showing parakeratosis, apoptosis,
blood vessels and a light perivascular chronic inflammatory cell infiltrate. and satellite cell necrosis.
Table 7.1
Grading of acute graft-versus-host disease
Grade Feature
I Focal or diffuse vacuolar alteration of basal cells
II Vacuolar alteration of basal cells; spongiosis and
dyskeratosis of epidermal cells
III Formation of subepidermal cleft in association with
dyskeratosis and spongiosis
IV Complete loss of epidermis
Reproduced with permission from Lerner et al. (1974) Transplantation Proceedings, 6,

367–371.
Fig. 7.116
Late chronic graft-versus-
host disease: there is
dense fibrosis of the
dermis with tethering of
the subcutaneous fat.
Appendages are absent.
These appearances
are reminiscent of
scleroderma.
some extent in favor of an adverse drug reaction, in reality there are no real
discriminators between adverse drug reactions and acute GVHD.74 In short,
the regular practice of skin biopsy to differentiate between GVHD, drug reac-
tions, chemotherapy effect, and viral infection is extremely difficult and of
dubious clinical value in some cases.
Acute GVHD may be indistinguishable from erythema multiforme and,
Fig. 7.115 in more severely affected patients, toxic epidermal necrolysis. Recently,
Early chronic graft-versus-host disease: the hyperkeratosis, hypergranulosis, the intriguing report of bile pigment deposition in the stratum corneum in
irregular acanthosis, and basal cell hydropic degeneration are indistinguishable from patients with GVHD offers a possible line of approach to making this impor-
idiopathic lichen planus. tant distinction.75
The early changes of chronic GVHD may be indistinguishable from lichen
planus. However, the dermal infiltrate is usually less conspicuous than that
in lichen planus and sometimes contains plasma cells and eosinophils. The
presence of satellite cell necrosis may be a diagnostic pointer towards chronic
dlike lymphohistiocytic infiltrate obscuring the dermoepidermal interface. GVHD.
In contrast to idiopathic lichen planus, satellite cell necrosis is often present In the absence of clinical information it is usually not possible to dis-
in the early phase of chronic GVHD and the infiltrate sometimes contains tinguish the features of late chronic GVHD from morphea or systemic
plasma cells and eosinophils. Squamous metaplasia of the eccrine sweat ducts sclerosis.
has been described.60,65 The histological features of the eruption of lymphocyte recovery are indis-
The late stage of chronic GVHD is characterized by epidermal atrophy tinguishable from acute GVHD. The differential diagnosis of acute GVHD
with abolition of the ridge pattern and scarring of the superficial and deep includes engraftment syndrome. This syndrome can occur 10–14 days after
dermis, with loss of the adnexal structures (Fig. 7.116) imparting a scle- transplantation but before peripheral lymphocytes are seen. It presents with
rodermoid feature including eosinophilic fasciitis, panniculitis, morphea-like a fever, hepatitis, intestinal symptoms, and an erythmatous maculopapular
changes, and lichen sclerosus.60,69,70 Features of the early stage of chronic eruption similar to acute GVHD. Some also require the presence of weight
GVHD, i.e., hydropic basal cell degeneration, cytoid body formation, and gain and pulmonary edema. Whether or not this represents a hypoacute
a chronic inflammatory cell infiltrate, may or may not be evident. Dermal GVHD is uncertain. The etiology is unknown although it is postulated that
mucin deposition has also been documented.71 the damage may be caused by cytokines released from recovering and degran-
Hepatic changes include bile duct atypia with necrosis, periportal inflam- ulating neutrophils. G-CSF, GM-CSF, female gender, breast cancer, and other
mation, focal hepatocyte necrosis, and cholestasis.9 Gastrointestinal lesions hematopoietic and drugs have been implicated as risk factors for developing
show individual crypt cell necrosis accompanied by a mild chronic inflamma- this condition.17,76
tory cell infiltrate.60,72,73 In summary, no histological feature is pathognomonic for graft-versus-
host disease and clinical correlation is essential. Therefore, in the appropri-
Differential diagnosis ate clinical population, a positive biopsy can be very predictive despite subtle
The features of acute GVHD can be reproduced by cytotoxic drugs such as non-specific histologic findings. A negative biopsy is less reassuring. Some
cyclophosphamide and by radiotherapy. Viral infections also enter the dif- have advocated the use of a four-tier diagnostic system of no GVHD, possible
ferential diagnosis, as does an adverse drug reaction, for example, to anti- GVHD, consistent with GVHD, and definite GVHD, a practical proposal
biotic therapy. Although the presence of conspicuous eosinophils argues to that reflects the realities of daily practice.60
Pityriasis lichenoides orrhagic and ultimately develop necrosis and ulceration (Fig. 7.120).
Healing is usually associated with the development of superficial varioli-
form scars. Postinflammatory hyper- or hypopigmentation is not uncommon
Clinical features (Fig. 7.121).9,11 The rash is often polymorphic, individual patients having
Pityriasis lichenoides (Gr. pityron, bran + iasis; lichen; Gr. eidos, form) lesions at varying stages of evolution. Patients may be pyrexic and sometimes
is an uncommon dermatosis of unknown etiology, although a hypersen- lymphadenopathy is present.1
sitivity reaction to a number of infectious agents including adenovirus, The chronic lesions are typified by numerous, lichenoid, brownish-red,
toxoplasmosis, Epstein-Barr virus, and Mycobacterium pneumoniae have scaly papules, 3–10 mm across, the scale being most noticeable peripher-
been proposed.1–4 The condition has also been documented in association ally, sometimes referred to as the mica scale (Figs 7.122, 7.123). These
with a range of autoimmune conditions such as rheumatoid arthritis, hypo- lesions usually heal without scarring, but are sometimes associated with
thyroidism, and pernicious anemia.3,4 Two cases of pityriasis lichenoides hypopigmentation, which may be the most prominent feature in dark-
chronica (PLC) associated with adalimumab therapy for Crohn's disease skinned races.
and a case induced by infliximab have been described.5,6 The term includes
a spectrum of disease manifestations, ranging from the acute ulcerone-
crotic lesions of pityriasis lichenoides et varioliformis acuta (PLEVA, also
known as Mucha-Haberman disease or acute guttate parapsoriasis) to the
more chronic scaly papules of pityriasis lichenoides chronica (chronic gut-
tate parapsoriasis); there is often clinical overlap.7–10 In addition, a febrile,
ulceronecrotic variant (febrile ulceronecrotic Mucha-Habermann disease)
is recognized.3–8
Pityriasis lichenoides in more recent studies lacks strong sex predominance
in adults. However, some studies have shown more of a male predominance in
pediatric populations.11–14 It most often occurs in childhood (5–10 years of
age) and early adulthood, second or third decade.11–14
Lesions show a propensity to involve the arms, legs, trunk, and buttocks
(Fig. 7.117). The upper limbs appear to be involved more often than the
lower and the flexor more commonly than the extensor surfaces. They can
begin as small macules that progress to papules. PLC is typically asymp-
tomatic while PLEVA is associated with burning and pruritis.9 The onset
is usually insidious and the course fluctuating and episodic, patients expe-
riencing recurrent crops of lesions, with the exception of the ulcronecrotic
variant which is rapid. Duration of the rash is quite variable: although
many patients are free of lesions by 3–6 months, others show great per-
sistence of the disease, often for many years.11 The disease shows some
seasonal variation, with lesions worsening in winter and showing improve- Fig. 7.118
ment in sunlight. Although pityriasis lichenoides is traditionally divided Pityriasis lichenoides acuta: typical lesions with pustulation are present on the arm,
into acute and chronic variants, not uncommonly both types of lesions can a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.
be seen in the same patient, indicating a possible connection between PLC
and PLEVA.9
In the more acute form of the disease, the initial lesions are crops of
pink papules (Figs 7.118, 7.119). These may become vesicular or hem-
Fig. 7.119
Pityriasis lichenoides
acuta: early lesions
are erythematous and
Fig. 7.117 papular. By courtesy
Pityriasis lichenoides acuta: erythematous papules and crusted lesions are present of the Institute of
on the buttocks and thighs. In severe cases, lesions may be very extensive. Dermatology, London,
By courtesy of the Institute of Dermatology, London, UK. UK.
Fig. 7.121
Pityriasis lichenoides acuta: healed lesion showing scarring and hypopigmentation.
Fig. 7.122
Pityriasis lichenoides chronica: widespread scaly papules are present on the
chest and arms. From the collection of the late N.P. Smith, MD, the Institute of
B Dermatology, London, UK.
Fig. 7.120
Pityriasis lichenoides acuta: (A) necrotic and ulcerated lesions are present;
(B) close-up view. By courtesy of the Institute of Dermatology, London, UK.
Although there are case reports of lymphoma (mycosis fungoides) devel-

oping in patients with pityriasis lichenoides, this is a rare event; however, see
below.15–17
The rare febrile ulceronecrotic variant is associated systemic features
including fever, muscle weakness and pain, malaise, lymphadenopathy, arthri-
tis, myocardial involvement, and neuropsychiatric manifestations.3–8,11,18,19
Widespread cutaneous manifestations include large 2–6-cm ulceronecrotic
lesions, hemorrhagic and necrotic papules, and erythema multiforme-like
lesions.3,4,11

Immunofluorescence examination of biopsies from fresh purpuric lesions
commonly detects IgM and C3 in the walls of the superficial dermal blood
vessels and along the dermoepidermal junction in both the acute and chronic Fig. 7.123
forms of the disease.20–22 A high proportion of patients have elevated cir- Pityriasis lichenoides chronica: the characteristic mica scale. By courtesy of the
culating immune complexes.23,24 Cytotoxic suppressor T cells constitute the Institute of Dermatology, London, UK.
majority of the infiltrate in pityriasis lichenoides acuta et varioliformis.25,26

Lesser numbers are seen in pityriasis lichenoides chronica. These (and the
overlying keratinocytes in addition to nearby endothelial cells) have been
shown to express HLA-DR.26 In contrast to lymphomatoid papulosis, the
Ki-1 (CD30) activation antigen is generally not expressed in pityriasis
lichenoides acuta except perhaps in overlap cases.27 Macrophages are also
numerous. Langerhans cells are diminished in number. Clonal T-cell receptor
gene rearrangements have been described in small numbers of patients with
pityriasis lichenoides acuta raising the possibility of overlap with cutaneous
T-cell lymphoma.28,29 Exceptionally, pityriasis lichenoides acuta may progress
to cutaneous T-cell lymphoma.11,30,31 As a result, some have suggested that
PLEVA may represent a host response to a developing T-cell lymphoprolifera-
tive disorder in some cases.11
The histopathological features of pityriasis lichenoides are similar in both
variants, although in the acute form the changes are usually more severe.
Both are characterized by varying proportions of epidermal and dermal
changes.32–35
The chronic lesions of pityriasis lichenoides are characterized by par-
akeratosis in which there are sometimes small collections of lymphocytes
reminiscent of the Munro microabscesses of psoriasis (Figs 7.124, 7.125). Fig. 7.125
Pityriasis lichenoides chronica: note the parakeratosis, acanthosis, and perivascular
The epidermis may show slight acanthosis and usually small numbers of
and interstitial chronic inflammatory cell infiltrate.
necrotic keratinocytes are present accompanied by a hint of interface change
(Fig. 7.126). Spongiosis is often a feature. There is a perivascular chronic
inflammatory cell infiltrate in the superficial dermis (Fig 7.127). Red cell
extravasation is often present but is usually not marked.
The acute lesions of pityriasis lichenoides show similar epidermal features,
but on a much exaggerated scale. Marked inter- and intracellular edema
accompanied by keratinocyte necrosis and interface change frequently result
in vesiculation and ulceration (Figs 7.128, 7.129). Exocytosis is usually
prominent and intraepidermal red blood cells are characteristic. The upper
dermis is edematous and contains a chronic inflammatory cell infiltrate (Fig.
7.130). This is usually perivascular and varies from sparse to dense; typically,
it has a wedge-shaped appearance, extending deeply into the reticular
dermis, although this is only seen in biopsies from established lesions. The
infiltrate consists of lymphocytes with an admixture of histiocytes. Red cell
extravasation is usually conspicuous. The blood vessels of the superficial
dermis are dilated and congested. Although the endothelial cells are often
blurred or swollen, fibrinoid necrosis indicating necrotizing vasculitis is
rarely seen (Fig 7.131).
Fig. 7.126
Pityriasis lichenoides chronica: high-power view showing basal cell hydropic
degeneration.
Fig. 7.124 Fig. 7.127

Pityriasis lichenoides chronica: scanning view showing hyperkeratosis with Pityriasis lichenoides chronica: in this high-power view there is a lymphohistiocytic
parakeratosis and acanthosis. infiltrate and melanophages are present.
Fig. 7.128 Fig. 7.130

Pityriasis lichenoides acuta: this low-power view shows an ulcerated papule with Pityriasis lichenoides acuta: this high-power view shows a lymphohistiocytic
overlying crust. infiltrate. Red cell extravasation can also be seen.
Fig. 7.129 Fig. 7.131

Pityriasis lichenoides acuta: there is basal cell hydropic degeneration and apoptosis. Pityriasis lichenoides acuta: high-power view showing fibrinoid necrosis affecting
the dermal vasculature.
In febrile ulceronecrotic Mucha-Habermann disease, the features are those
of very severe pityriasis lichenoides acuta and are often accompanied by the
changes of leukocytoclastic vasculitis.11,36–38 papulosis were documented.2 In the light of our current understanding of
In the earlier literature, patients having clinical and histological features these two conditions, it is now apparent that such patients clearly were suf-
of both pityriasis lichenoides et varioliformis acuta and lymphomatoid fering from lymphomatoid papulosis.
Superficial and deep perivascular Chapter
See
for references and
additional material
inflammatory dermatoses
8
Chronic superficial dermatitis 259 Tumid lupus erythematosus 269 Pregnancy prurigo 277
Toxic erythema 261 Perniosis 270 Urticarial vasculitis 278
Erythema annulare centrifugum 261 Chilblain lupus erythematosus 272 Tumor necrosis factor receptor-associated
periodic syndrome 280
Erythema gyratum repens 263 Pigmented purpuric dermatoses 273
Eosinophilic, polymorphic and pruritic
Lymphocytic infiltrate of the skin 264 Lichen aureus 275
eruption associated with radiotherapy 280
Reticular erythematous mucinosis 265 Pruritic urticarial papules and plaques of
Viral exanthemata 280
pregnancy 276
Polymorphous light eruption 267
Chronic superficial dermatitis

Clinical features
Chronic superficial dermatitis (digitate dermatosis, superficial scaly dermatitis,
small-plaque parapsoriasis, persistent superficial dermatitis) is a not uncom-
mon condition, which presents as erythematous scaly persistent patches,
showing a predilection for the limbs and trunk. While the lesions may be
round or oval, they often have a finger-like appearance, hence the alternative
designation of digitate dermatosis (Figs 8.1, 8.2).1 The patches are usually
a few centimeters in greatest dimension, but may sometimes be much larger.
They are associated with a fine ‘cigarette-paper’ scale that often has a pale
white, tan or yellowish color (Fig. 8.3). The disorder is most commonly
encountered in middle-aged adults and shows a predilection for men. The
patient is usually otherwise asymptomatic. Coexistence with ulcerative colitis
has been reported in one patient.2 Lesions tend to chronicity, often persisting
for many years. While development of mycosis fungoides has been reported
in a patient with chronic superficial dermatitis, it is most likely that these
represent separate disease processes rather than disease progression.3
Fig. 8.1
Chronic superficial dermatitis: this patient shows digitate erythematous lesions in a
Histological features characteristic distribution. By courtesy of the Institute of Dermatology, London, UK.
Biopsy shows a superficial perivascular lymphocytic infiltrate (Figs 8.4, 8.5).
The infiltrate is of variable density but is often very sparse. Cytological aty-
the changes described above do not represent chronic superficial dermatitis.
pia is absent. The epidermis often shows foci of spongiosis. A confluent lin-
Delayed-type hypersensitivity reactions are more commonly associated with
ear band of parakeratosis spanning multiple rete ridges is a characteristic
these histological appearances. Many other diseases similarly cause such
finding.
non-specific biopsy findings including viral exanthems and connective tissue
The infiltrate is largely composed of CD4+ T lymphocytes with a minor
disease. Therefore, clinical correlation is necessary to e stablish the diagnosis.
population of CD8+ T-suppressor cells (Fig. 8.6).2 In a small series, the CD4
The main clinical differential diagnosis is with mycosis fungoides and,
to CD8 ratio ranged from 2 to 4.4. The T cells are generally reactive for
accordingly, most biopsies are obtained to exclude this possibility. The
CD2, CD3, and CD5 (Fig. 8.7). CD7 expression is variable and may be
patches in chronic superficial dermatitis tend to be uniform in size, shape, and
absent. Scattered CD68 reactive macrophages and CD1+ Langerhans cells
color, contrasting vividly with the greater variability of those of mycosis fun-
can be seen.
goides. The presence of spongiosis favors a diagnosis of chronic superficial
dermatitis; however, mycosis fungoides may also be associated with signifi-
Differential diagnosis cant spongiosis and this feature does not reliably distinguish these disorders.
The histological features in chronic superficial dermatitis are entirely non-specific. In Diagnostic pointers favoring early mycosis fungoides include the presence of
fact, the constellation of histological findings is among the most often encountered atypical lymphocytes, epidermotropism, and lymphocytes aligned along the
by the dermatopathologist. Certainly, the vast majority of biopsies that show basal cell layer of the epidermis (‘tagging’).
260 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.2 Fig. 8.4

Chronic superficial Chronic superficial dermatitis: there is parakeratosis, acanthosis, and a superficial
dermatitis: these uniform, perivascular infiltrate.
linear lesions had been
present for many years.
By courtesy of the
London, UK.
Fig. 8.5
Chronic superficial
dermatitis: there is very
Fig. 8.3 slight intercellular edema.
Chronic superficial dermatitis: closer examination shows that the lesions appear The infiltrate consists
somewhat wrinkled and have a fine scale. By courtesy of R.A. Marsden, MD, of lymphocytes and
St George's Hospital, London, UK. histiocytes.
Immunohistochemistry should be viewed with caution. Loss of T-cell superficial dermatitis is mycosis fungoides.5 The observation that chronic
expression may support a diagnosis of mycosis fungoides provided there superficial dermatitis rarely, if ever, evolves into (or declares itself as) frank
are histological features in favor of the diagnosis and if the clinical con- mycosis fungoides has led some authors to cast doubt on this view.6 More
text is appropriate. Loss of CD7 expression, however, may be seen in reac- recent publications have asserted that chronic persistent dermatitis does
tive conditions and this feature is therefore not reliable. Occasionally, only not progress to mycosis fungoides.7 It is perhaps more likely that some
careful review of the clinical information, taken in conjunction with the cases of very early mycosis fungoides cannot be reliably distinguished from
histological features of previous biopsies (if available) allows for defini- chronic superficial dermatitis. Recently, clonal T-cell gene rearrangements
tive diagnosis. It is important to note that some investigators have dem- have been demonstrated in circulating lymphocytes in blood but not in skin
onstrated cases of chronic superficial dermatitis with clonal T-cell gene of patients with digitate dermatitis.8 Clearly, long-term follow-up studies
rearrangements by polymerase chain reaction (PCR).4 One case with a are necessary to resolve the significance of clonality in putative cases of
clonal T-cell population resolved, underscoring the growing appreciation chronic superficial dermatitis.
that clonality and malignancy are not necessarily synonymous.4 Therefore, Pityriasis lichenoides may also be confused with chronic superficial der-
it appears that demonstration of a clonal T-cell population may not suf- matitis. Spongiosis without interface changes favors the latter. Pityriasis
fice to reliably distinguish chronic superficial dermatosis from early myco- lichenoides is associated with either vacuolar or lichenoid interface changes
sis fungoides in all cases. In the past, others have concluded that chronic in the absence of spongiosis.9
Toxic erythema 261
earlier literature frequently classified different diseases together under these

appellations.1 Therefore, to avoid confusion, it is encouraged that these terms
are not used in referring to specific diseases.
Erythema annulare centrifugum

Clinical features
Erythema annulare centrifugum has an incidence of 1 per 100 000 and may
be associated with certain underlying factors, including:
• Connective tissue disorders, e.g., Sjögren's syndrome,1,2
• Drugs, e.g., penicillin, salicylates, amytriptyline, etizolam, gold, sodium
thiomoalate, hydroxychloroquine sulfate, piroxicam, finasteride,
hydrochlorothiazide and thiacetazone,3–11
• Bacterial infections, e.g., Mycobacteria, Streptococcus, Escherichia coli,12
• Viral infection, e.g., Epstein-Barr virus, HIV, herpes simplex and zoster,
molluscum contagiosum,13–16
• Fungal infection, e.g., dermatophytoses, Candida,17–19
• Parasites, e.g., helminthes,20
• Arthropods,21
• Sarcoidosis,22
• Hypereosinophilic syndrome,23
Fig. 8.6
Chronic superficial
• Bullous dermatosis, e.g., linear IgA dermatosis,24,25
dermatitis: the infiltrate is
• Autoimmune disease, e.g., polyglandular autoimmune disease type 1 as well
composed predominantly as autoimmune progesterone dermatitis and autoimmune hepatitis,26–28
of CD4+ T-helper cells. • Pregnancy.29,30
Many of these associations are likely to be coincidental and, in most
cases, no underlying etiology is identified.31–35 It is unclear whether erythema
annulare centrifugum is a distinctive entity or simply represents the clinical
expression of a number of inflammatory dermatoses such as hypersensitivity
reactions sharing common histological features.36
Mahood and colleagues emphasized that many earlier reports of neopla-
sia associated with erythema annulare centrifugum are questionable since
different subtypes of annular erythemas were often classified together.31,37,38
However, more recent cases have documented erythema annulare cen-
trifugum in patients with underlying malignancy, once again raising the issue
of an association with neoplasia. Erythema annulare centrifugum in patients
with non-small cell lung carcinoma, carcinoma of breast, colon and prostate,
chronic lymphocytic leukemia, and Hodgkin's lymphoma have been reported
in the last decade.14,39–44 In a recent large series, carcinoma was present in 6
of 66 (13%) patients.45 Of these, two had leukemia (acute myelogenous and
acute lymphoblastic); one patient had non-Hodgkin's lymphoma; and three
cases were associated with carcinoma (lung, rectal, and hepatocellular).45
Erythema annulare centrifugum has been reported in all age groups, includ-
ing infants and neonates, but is most commonly seen in young adults.46,47 A
recent large series found that the lower extremities, particularly the thighs,
were the most frequent site of involvement.45 Nearly 50% of patients in this
series had lower extremity involvement. The trunk was affected in 28% of
patients and the upper extremity in 16%. The hands, feet, and face are usu-
Fig. 8.7 ally spared. Head and neck involvement was seen in only 8% of patients.
Chronic superficial Laboratory investigation sometimes reveals a peripheral eosinophilia.31
dermatitis: in this Although individual lesions persist for weeks to a few months before resolv-
example, there is no ing, a course of relapses and remissions over months to years is common and
significant loss of CD7 an annually and seasonally recurring form has recently been reported.48 Kim
expression. et al. found that lesions lasted from 3 days to 18 years with a mean duration
of 2.8 years.45
The lesions take the form of annular erythematous bands, which may
Toxic erythema spread outwards or remain stationary (Figs. 8.8, 8.9). They are well cir-
cumscribed with raised edges, and slight scaling that tends to trail behind the
Toxic erythema, annular erythema, and gyrate erythema are terms used by advancing margin.49 With time, central clearing is seen. Arcuate and polycy-
dermatologists to describe a number of diseases that share common clinical clic variants are therefore occasionally evident.31 Lesions may be mildly pru-
and histological appearances. Clinically, the terms imply annular erythema- ritic. Vesiculation is rare.32
tous lesions. Pathologists often also use these same terms (particularly gyrate Some authors have divided the disease into two distinct subtypes: superfi-
erythema) in a generic manner to describe an inflammatory lesion with a cial and deep gyrate erythema.45
‘cuffed’ perivascular lymphocytic infiltrate. Although such nomenclature • The superficial variant is associated with pruritus and has a trailing scale.
may be used as a descriptor (as one might use terms such as ‘lichenoid’, for • The deep variant is characterized by erythematous annular lesions with
example), it should not be taken to imply a specific disease. It is likely that the indurated borders but lack a scale.
Fig. 8.8
Erythema annulare centrifugum: bilateral annular lesions are present on the
buttocks. From the collection of the late N.P. Smith, MD, The Institute of Fig. 8.10
Dermatology, London, UK. Erythema annulare
centrifugum: the
superficial and deep
vasculature is surrounded
by a dense infiltrate.
Fig. 8.9
Erythema annulare centrifugum: close-up view. From the collection of the late N.P.
Smith, MD, The Institute of Dermatology, London, UK.
Fig. 8.11
Erythema annulare centrifugum: the infiltrate is composed of mature lymphocytes
and histiocytes.
A spectrum of non-specific histological findings is seen in erythema annulare
centrifugum. As noted above, deep and superficial variants are recognized.45 Differential diagnosis
In the superficial variant, a well-demarcated perivascular infiltrate of Given that the histological features of erythema annulare centrifugum are not
lymphocytes and histiocytes, often described as having a ‘coat sleeve'’ or distinctive, it is critical to correlate the biopsy and clinical findings. Clinical
‘pipe-stem’ appearance, is confined to the superficial dermis (Figs 8.10, 8.11). information is necessary to distinguish this disorder from other gyrate
The overlying epidermis often may be normal; however, epidermal changes erythemas, pityriasis rosea, hypersensitivity reactions, lupus erythematosus,
including mild spongiosis, slight and focal basal layer vacuolar degeneration, viral exanthemata, and Jessner's lymphocytic infiltrate. In cases with significant
mounds of parakeratosis or hyperkeratosis are encountered in approximately epidermal changes, a silver stain to exclude a fungal infection is also advised.
50% of patients.14,45 Clinically, erythema annulare centrifugum may resemble psoriasis. The presence
In the deep subtype of erythema annulare centrifugum, the perivascular of parakeratotic mounds associated with neutrophils would favor a diagnosis
infiltrate involves both the superficial and deep plexuses.14,32–34,45 Epidermal of psoriasis. In contrast to cutaneous lupus erythematosus, interface changes
changes are usually absent or minimal. are not usually well developed and immunofluorescence studies are negative.
In both variants, the degree of inflammation is variable; however, the Erythema chronicum migrans also enters the differential diagnosis. The presence
density of inflammation tends to be greater in the deep variant. The vast of plasma cells would be in favor of the latter condition. Histochemical stains
majority of cells are lymphocytes; however, a minor component of histiocytes for spirochetes may be positive but are cumbersome and difficult to interpret.
and eosinophils may be seen. PCR is a more realiable and easy test to confirm the diagnosis.
Toxic erythema 263
Erythema gyratum repens

Clinical features
Erythema gyratum repens (L. repens, to crawl or creep) is an extremely rare
and clinically distinctive figurate eruption usually associated with an under-
lying malignancy. The most commonly associated neoplasm is carcinoma
of the lung; other affiliated tumors include carcinoma of the uterus and
cervix, esophagus, stomach, kidney, and breast as well as essential thrombo-
cythemia.1–11 Treatment of the cancer may be associated with remission of the
cutaneous eruption, while tumor recurrence or metastases can be accompa-
nied by a relapse.2 Rarely, the condition develops in the absence of an under-
lying malignancy.12–17 It may disclose underlying pulmonary tuberculosis. In
one patient with no evidence of malignancy, the rash resolved a few days after
removal of a cavitary tuberculoid lung lesion.14
Ichthyosis may accompany erythema gyratum repens.18 A report of a
patient with transitional cell carcinoma of the kidney who developed erythema
gyratum repens and ichthyosis comes as no surprise since both conditions are
associated with malignancy. The combination of ichthyosis, palmoplantar
keratosis, and erythema gyratum repens, in the absence of malignancy, has Fig. 8.13
also been reported.19 Erythema gyratum repens: the eruption may sometimes have a bizarre appearance.
Erythema gyratum repens-like eruptions have also been described in the By courtesy of R. Cerio, MD, The London Hospital, London, UK.
presence of connective tissue diseases. Typical erythema gyratum repens devel-
oped in a patient with cutaneous subacute lupus erythematosus following are usually spared.33 Postinflammatory hyperpigmentation may be a feature.1
hydroxychloroquine treatment.20,21 The authors of this report concluded that Hyperkeratosis of the palms and soles is also sometimes present.3,12 Males are
the patient's rash represented a peculiar pattern of involvement by subacute affected twice as commonly as females.3 Patients are usually in their seventh
lupus which they designated subacute lupus gyratum repens. An erythema gyra- decade.20
tum repens-like eruption has also been described in association with Sjögren's
syndrome, neutrophilic dermatosis, leukocytoclastic vasculitis, in patients with Pathogenesis and histological features
lupus erythematosus, and in the setting of u rticarial vasculitis.22–25 Erythema gyratum repens may have an immunological pathogenesis, since
Caputo et al. reported linear IgA dermatosis, erythema, and an erup- granular deposits of IgG and C3 have been found at the basement mem-
tion resembling erythema gyratum repens in a patient without malignancy.26 brane zone of both involved and uninvolved skin in a patient with associ-
Bullous pemphigoid may be associated with erythema gyratum repens and ated bronchial carcinoma and in involved non-sun-exposed skin in another
an erythema gyratum repens-like eruption has been documented in a patient unassociated with neoplasia.16,34–36 In a separate patient, although basement
with treated and resolving psoriasis and with epidermolysis bullosa acquisita membrane zone immunofluorescence was negative, epidermal nuclear label-
accompanied by ulcerative colitis.27–31 ing was identified.37 Caux et al. reported one patient with squamous cell car-
Erythema gyratum repens has been described in patients with hypereo- cinoma of the lung who had immunoreactants at the basement membrane of
sinophilic syndrome, also with no evidence of neoplasia.32 involved and normal non-sun-exposed skin. In addition, this patient showed
The eruption, which may precede the malignancy by months, takes the staining of IgG, IgM, and C3 along the basement membrane of the bron-
form of concentric bands of erythema in an annular or gyrate arrange- chus.35 However, the immunoreactants did not localize to the tumor.
ment (Figs 8.12, 8.13). These bands have been described as having a ‘tim- The appearances in erythema gyratum repens are not diagnostic. They
ber grain’ or ‘zebra-like’ pattern and they move (up to about 1 cm) daily.33 include hyperkeratosis, parakeratosis, acanthosis, and spongiosis, together
Scaling occurs and there may be pruritus. Lesions often commence on the with a superficial perivascular lymphohistiocytic infiltrate in the papillary
arms and legs, but frequently become generalized.1 The hands, feet, and face dermis (Figs 8.14, 8.15).2
Fig. 8.12
Erythema gyratum repens:
the presence of annular
erythematous parallel
bands with scaling is
characteristic. From the
Smith, MD, The Institute Fig. 8.14
of Dermatology, London, Erythema gyratum repens: there is hyperkeratosis, acanthosis and a mild perivascular
UK. chronic inflammatory cell infiltrate.
Fig. 8.15 Fig. 8.17

Erythema gyratum repens: spongiosis is present. Jessner's lymphocytic infiltrate: central clearing has resulted in this circinate lesion.
As noted above, the histological features are non-specific and vary from coexist.1 The disease tends to affect adults, particularly in the third to fifth
patient to patient. Fortunately, the clinical features are so distinctive that con- decades. Although some authors have found a predilection for males, 54%
fusion with other disorders is unlikely. Obviously, any patient with features of patients in a large series were female and the overall gender distribution
of erythema gyratum repens should be very carefully evaluated for an under- appears to be equal.1,3 Rarely, the condition presents in children.9–11 Lesions
lying neoplasm. often resolve within weeks or months, but relapses are not uncommon and, in
many patients, the disorder persists for years. The eruption is not character-
Lymphocytic infiltrate of the skin (Jessner) ized by seasonal variation. The evidence available suggests that lymphocytic
infiltrate of the skin is a distinctive dermatosis. It does not evolve into lupus
Clinical features erythematosus, polymorphous light eruption or lymphoma.1
Jessner's lymphocytic infiltrate of the skin is an uncommon dermatosis of Pathogenesis and histological features
unknown etiology, although a relationship with sun exposure, at least in the
early stages, is occasionally documented.1 Lesions, which may be single or The etiology of this curious condition is unknown. Although some patients
more often multiple, occur most often on the face, neck, back, and upper notice a relationship with sun exposure, many do not, and lesions not uncom-
chest, and present as 1–2-cm diameter, asymptomatic, discoid or annular, ery- monly develop on covered sites.
thematous or brownish papules or plaques that often show central clearing to Braddock and coauthors found that natural killer cell lytic activity and anti-
produce circinate lesions (Figs 8.16, 8.17).1–4 Familial cases have occasion- body-dependent cell-mediated cytotoxicity was decreased.10 This same group
ally been documented.5–8 identified increased levels of circulating immune complexes in patients with
In contrast to discoid lupus erythematosus, with which it is sometimes lymphocytic infiltrate of skin. In two patients immune complexes decreased
confused, there is no hyperkeratosis, telangiectases or follicular plugging, to normal levels following treatment but became elevated during recurrence
and scarring is not a feature. Rarely, however, the two diseases appear to of disease following treatment.10,11 Based on these observations, these inves-
tigators concluded that immune defects might be important in the pathogen-
esis of Jessner's lymphocytic infiltrate. Of interest, similar findings have been
observed in patients with reticular erythematous mucinosis. Clearly, further
study is necessary to determine the pathogenesis of this disease.
The epidermis is typically unaffected. Within the superficial and mid der-
mis is a perivascular and, much less commonly, a perifollicular infiltrate of
mature lymphocytes (Figs 8.18, 8.19). Occasional histiocytes and scattered
plasma cells may also be present and sometimes there is an increase in dermal
ground substance.12 Lymphoid follicles are not a feature.
The infiltrate consists predominantly of T cells, most often of the CD4+
helper subtype (Fig. 8.20). Occasionally, however, CD8+ suppressor T cells
constitute the majority of cells.3,13–16 Leu 8 is commonly expressed but human
leukocyte antigen (HLA)-DR is not present. B cells are relatively sparse in
number or are absent.
Lymphocytic infiltrate of the skin differs from discoid lupus erythematosus
by the absence of epidermal changes, scarring, and a negative lupus band
test. Immunohistochemistry may sometimes be helpful. The infiltrate in lym-
phocytic infiltrate is HLA-DR negative in contrast to discoid lupus erythe-
Fig. 8.16 matosus in which the lymphocytes and often the keratinocytes are HLA-DR
Jessner's lymphocytic infiltrate: there are multiple erythematous plaques on this positive.17 Leu 8 (immunoregulatory T-cell) expression is also more frequently
young man's cheek. By courtesy of the Institute of Dermatology, London, UK. seen in lymphocytic infiltrate.13,18 In one study, the average percentage of Leu
Reticular erythematous mucinosis 265
8 positive lymphocytes was 65% in lymphocytic infiltrate of skin and only

15% in discoid lupus erythematosus.18 The presence of CD20+ B cells favors
lupus erythematosus, which tends to be composed of a mixture of B and T
cells. In contrast, T cells predominate in lymphocytic infiltrate of skin.14,19,20
One group of investigators has suggested that the presence of plasmacytoid
monocytes favors a diagnosis of lymphocytic infiltrate of skin over lupus ery-
thematosus. They found plasmacytoid monocytes to be present in 58% of
patients with lymphocytic infiltrate of skin but only in 7% of patients with
discoid lupus erythematosus.21 Others, however, have not been able to cor-
roborate this finding.19 The presence of significant dermal mucin would sup-
port lupus erythematosus. Reliable distinction between lymphocytic infiltrate
of the skin and tumid lupus erythematosus may be difficult and frequently
impossible since lymphocytic infiltrate may sometimes be accompanied by
excess dermal mucin. It has therefore been speculated that these entities rep-
resent a continuous disease spectrum rather than different diseases.22 The
finding that a subset of patients with lymphocytic infiltrate of the skin also
had a confirmed diagnosis of lupus erythematosus lead one group to specu-
late whether lymphocytic infiltrate of the skin could represent a variant of
lupus erythematosus.4
Fig. 8.18 Epidermal Langerhans cells are often increased in lymphocytic infil-
Lymphocytic infiltrate of Jessner: a heavy chronic inflammatory cell infiltrate cuffs
trate whereas they are frequently reduced in number in discoid lupus
the vessels in the superficial and mid dermis.
erythematosus.13
Lymphocytic infiltrate may often be distinguished from chronic lympho-
cytic leukemia/lymphocytic lymphoma by careful evaluation of cellular mor-
phology. The benign lymphocytic infiltrate is composed of non-neoplastic
lymphocytes with small, regular, and hyperchromatic nuclei. In chronic lym-
phocytic leukemia/lymphocytic lymphoma the nuclei are larger, irregular, and
paler staining, and a nucleolus may be visible. Regardless of these subtle cyto-
logical differences, if the possibility of low-grade lymphoma exists, immuno-
histochemical studies should be performed. Most often, well-differentiated
lymphomas are of B-cell lineage.
Lymphocytic infiltrate is usually histologically indistinguishable from poly-
morphous light eruption although early lesions of the latter may show edema
of the papillary dermis. It should be noted, however, that sometimes the two
conditions may coexist. In cases where the diagnosis is in doubt, phototesting
may be necessary. One group of investigators has found the presence of plas-
macytoid monocytes to favor lymphocytic infiltrate of the skin over polymor-
phous light eruption.21 However, this has not been confirmed (see above).
Histologically, lymphocytic infiltration of Jessner also shows some over-
lap with reticular erythematous mucinosis. Mucin deposition, however, is
not generally a feature of lymphocytic infiltrate of the skin, although it may
Fig. 8.19 be evident. Furthermore, the infiltrate in reticular erythematous mucinosis is
Lymphocytic infiltrate of Jessner: the infiltrate is composed almost entirely of small usually mild.
lymphocytes.
Reticular erythematous mucinosis

Clinical features
This rare chronic dermatosis, which shows a female predominance (2:1), has
been described worldwide.1 Although it may affect a wide age range, it most
frequently develops in the second to fourth decades.2 Rarely, it is encoun-
tered in children.2 Familial presentation is exceptional.3 It usually presents
as a persistent, reticulate, urticated, macular, and sometimes papular, ery-
thema with an irregular, but well-defined border. The lesions typically occur
on the central chest and upper back (Figs 8.21–8.23).4–6 Less commonly,
they can be found on the face, arms, abdomen, and groins, but the peripher-
ies are spared.1,7,8 Patients frequently notice an exacerbation in the sun, but
the relationship between sunlight and the disease (if any) is not well under-
stood.2,6–11 Although patients are usually asymptomatic, some report pruritus
or burning following exposure to sunlight. There is no evidence of systemic
involvement.
Occasional patients have more infiltrated papules and plaques; this was
originally described as plaquelike cutaneous mucinosis, but is now accepted
as a variant of reticular erythematous mucinosis.12,13 Of particular interest,
Fig. 8.20 the plaquelike form of the disease has been documented in association with
Lymphocytic infiltrate of Jessner: the majority of lymphocytes express CD4 (T-helper carcinoma of the breast and colon and one patient suffered from essential
cells). thrombocytosis in addition to carcinoma of the lung.13,14
Fig. 8.21
Reticular erythematous mucinosis: erythematous reticular eruption in a characteristic
distribution in a young woman. By courtesy of the Institute of Dermatology, London, UK.
Fig. 8.23
Reticular erythematous mucinosis: closer view of previous figure. Macular elements
predominate. From the collection of the late N.P. Smith, MD, The Institute of
if any, has not been defined. It is, of course, tempting to postulate that they
are related but data to support such a conclusion are not yet established.
The presence of monoclonal IgG (kappa) paraproteinemia has been
reported in one patient.19

The pathogenesis of reticular erythematous mucinosis is not well understood.
Phototoxicity likely plays some role in the disease, either directly or indi-
rectly. Braddock and coauthors found that natural killer cell lytic activity
and antibody-dependent cell-mediated cytotoxicity were decreased.20 This
same group found increased levels of circulating immune complexes. Of
interest, two patients were observed to have circulating immune complexes
that decreased with treatment only to become elevated during recurrence of
disease following treatment.20 Based on these observations, the investigators
concluded that immune defects may be of importance in the pathogenesis. Of
interest, similar findings have been observed in patients with Jessner's lym-
phocytic infiltrate (see above). Clearly, further study is necessary regarding
Fig 8.22 the precise pathogenetic basis of this disease.
Reticular erythematous mucinosis: location in the lower back is unusual. From the The epidermis may be slightly flattened or appear normal. Within the der-
collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK. mis there is moderate vascular dilatation associated with a marked mono-
nuclear perivascular and often perifollicular infiltrate composed mainly of
T-helper lymphocytes (Figs 8.24, 8.25).6,13,20–22 Excess mucin (predominantly
Patients with this condition have an increased risk of thyroid disease, hyaluronic acid) is usually present in the upper dermis but in more chronic
arthritis, and diabetes mellitus.2 In a series of nine patients, one patient lesions it is sometimes absent (Fig. 8.26). The mucin stains positively with
had evidence of Hashimoto's disease while another had hyperthyroidism.13 Alcian blue (pH 2.5) and colloidal iron, but is usually not metachromatic with
A patient with reticular erythematous mucinosis and myxedema in the setting toluidine blue. The collagen fibers are separated, but appear morphologically
of Hashimoto's thyroiditis has also been described.15 normal. Fragmentation of elastic fibers is sometimes a feature.7 There is no
Reticular erythematous mucinosis in patients with human immuno- evidence of fibroblastic proliferation, but by immunohistochemistry increased
deficiency virus (HIV) infection has also been documented.16,17 Of inter- numbers of factor XIIIa-positive dermal dendrocytes have been identified.23
est, other cutaneous mucinoses that have been described in association A few cases with positive direct immunofluorescence have been reported.
with HIV infection include scleredema and lichen myxedematosus.17 IgM-reactive papillary dermal cytoid bodies were documented in one case.20
Furthermore, deposition of mucin in the bone marrow of patients with Rare examples show staining for IgM along the dermal–epidermal junc-
acquired immunodeficiency syndrome (AIDS) is a common finding.18 The tion.2,10,24 The significance of these findings is unclear but may be further
pathogenetic relationship between these various forms of mucin deposition, evidence of an immunological basis for the pathogenesis of this condition.24
Polymorphous light eruption (including juvenile spring eruption and lambing ears) 267
Ultrastructural studies are largely unhelpful. Other than demonstrating

conspicuous and dilated rough endoplasmic reticulum within dermal fibro-
blasts, electron microscopy merely serves to confirm the light microscopic
observation of widely separated fascicles of collagen fibers.21 In a number
of reports tubuloreticular structures were identified within the cytoplasm of
endothelial cells.7,25,26 Although at one time these were thought to represent
paramyxoviruses, more recent studies suggest that they may be derived from
infolded endoplasmic reticulum. They have also been identified in pretibial
myxedema, lupus erythematosus, dermatomyositis, malignant atrophic papu-
losis, and various lymphomas.27
The principal clinical and pathological differential diagnoses include lupus
erythematosus and polymorphous light eruption. Distinguishing between
lupus erythematosus and reticular erythematous mucinosis may be very diffi-
cult, particularly as one condition may evolve into the other.28 Histologically,
reticular erythematous mucinosis lacks the epidermal changes of lupus ery-
thematosus and the immunofluorescent findings are usually, but not always,
negative.7–9 As noted above, there are a few reports in which granular
Fig. 8.24
Reticular erythematous mucinosis: there is a perifollicular and perivascular infiltrate
immunoglobulin deposition at the dermoepidermal junction has been iden-
in the upper and mid dermis. tified.2,10,24 The presence of several immunoreactants favors a diagnosis of
lupus erythematosus. Clinical and serological studies are also necessary to
establish a diagnosis of lupus erythematosus.
In polymorphous light eruption, mucin deposition is much less striking and
is limited to the papillary dermis.29 Perifollicular inflammation is not a feature
of polymorphous light eruption. In addition, epidermal changes of spongiosis –
sometimes with vesiculation in papular and eczematous lesions and mild basal cell
hydropic change in the plaque variant – serve as further distinguishing features.30
Polymorphous light eruption resolves once exposure to sunlight has ceased, in
contrast to reticular erythematous mucinosis where the lesions persist.
Histologically, reticular erythematous mucinosis also shows some overlap
with lymphocytic infiltrate of Jessner.2 Mucin deposition, however, is not gen-
erally a feature of the latter condition and the inflammatory cell infiltrate is
always more prominent.
Polymorphous light eruption (including

juvenile spring eruption and lambing ears)
Clinical features
Fig. 8.25 Polymorphous (polymorphic) light eruption, which is the most common
Reticular erythematous mucinosis: the infiltrate consists of mature lymphocytes photodermatosis, usually presents in young people as recurrent erythematous
with a lesser number of histiocytes. papules, vesicles and/or plaques following exposure to ultraviolet (UV) light
(Figs 8.27, 8.28).1–6 The face, chest, upper back, and extremities are the most
common sites of involvement.5 Most patients have multiple lesions.5 In one
study of 138 patients, the mean age at onset was 26 years.5 There is a predilec-
tion for young women, with 89% of patients being female.7,8 The vast majority
of lesions are associated with pruritus. Most patients require less than 30 min-
utes of sun exposure to elicit clinical features.5 Onset following light exposure
typically takes 18–24 hours. Either the UVA or UVB part of the light spectrum
may cause lesions.2,9 Lesions are caused by UVA light in 56% of cases, UVB
in 17%, and both UVA and UVB ranges in 26% of cases.2 However, some
authors have not been able to elicit lesions with UVB light.4 Exposure result-
ing in sunburn is not necessary for the development of the condition.4 Some
patients report symptoms resulting from light exposure through glass.4
Polymorphous light eruption most often occurs in patients with fair skin;
however, dark-skinned individuals can also be affected. The disease is more
common in people residing in northern latitudes. One study showed that the
prevalence rates for London (UK) and Perth (Australia) were 14.8% and
5.2%, respectively.10 In a recent retrospective analysis, however, the incidence
of photosensitivity reactions and polymorphous light eruption in particular
was found to be roughly comparable for dark-skinned and Caucasian
individuals.11 The pinpoint papular variant of polymorphous light eruption
Fig. 8.26 has only recently been recognized and appears to be particularly common
Reticular erythematous mucinosis: increased dermal mucin (hyaluronic acid) separates on dark skin.11,12 It is characterized by numerous grouped, small, 1–2-mm
the collagen fibers (Alcian blue stain). papules, which may be accompanied by small vesicles in the acute phase.13
authors concluded that the risk of lupus erythematosus was not increased in
patients with polymorphous light eruption. Authors of another study, how-
ever, have suggested that a subgroup of patients with polymorphous light
eruption may be at an elevated risk for lupus erythematosus.15
Juvenile spring eruption appears to be either a variant of polymorphous
light eruption or a closely related disorder.16–21 In one study, the prevalence was
6.7% with a male predominance.16 The lesions are characterized by erythema-
tous papules and vesicles located on sun-exposed portions of the helix of the
ear following light exposure. They tend to be pruritic. In one study, 4 of 18
patients also had lesions of typical polymorphous light eruption.17 As its name
implies, the lesions tend to occur in the spring. A positive family history is
present in some patients.19 A disorder, clinically and histologically reminiscent
of juvenile spring eruption, has also been reported to develop in farmers at the
time of lambing and calving. It is provisionally termed ‘lambing ears’.22

The pathogenesis of polymorphous light eruption is poorly understood.
Study of adhesion molecule expression has led some authors to propose that
polymorphous light eruption is immunologically mediated.23 Specifically,
Fig. 8.27
Polymorphous light eruption: patients present with erythematous papules and
vascular endothelial expression of endothelial leukocyte adhesion molecule-1
vesicles on sun-exposed skin. From the collection of the late N.P. Smith, MD, (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and keratinocyte
The Institute of Dermatology, London, UK. and endothelial expression of intercellular adhesion molecule-1 (ICAM-1) in
biopsies of induced lesions has been documented.23 The authors noted that
their results were similar to those seen in delayed-type hypersensitivity reac-
tions. In addition, reduced skin infiltration by neutrophils following UVB
exposure was noted.24 However, the triggering antigen(s) are unknown.23 It
appears that polymorphous light eruption may be a heritable disorder. In one
study, 46% of patients reported a positive family history.7
Histologically, a perivascular lymphohistiocytic infiltrate is present in the
superficial and sometimes deep dermis (Figs 8.29, 8.30).25–27 A characteristic,
but not uniformly present feature, is papillary dermal edema, which is often
marked. The presence of massive papillary dermal edema may be associated
with subepidermal or intradermal vesicle formation.
Papular and papulovesicular lesions may show epidermal acanthosis,
spongiosis, occasional dyskeratotic cells, and lymphocyte exocytosis.25,27
Spongiosis may sometimes become so severe as to lead to intraepidermal ves-
icle formation.25 Other authors, however, have not found spongiosis to be a
significant feature.26 Basal cell vacuolization, usually mild, is found in some
cases.25,27,28 Periadnexal involvement by a chronic inflammatory cell infiltrate
Fig. 8.28
Polymorphous light eruption: the eruption is typically symmetrical and is usually
pruritic. By courtesy of the Institute of Dermatology, London, UK.
It appears that the incidence of polymorphous light eruption is much more

common than is demonstrated by contact with healthcare workers. In one
survey, 21% of workers in a Swedish pharmaceutical company had symp-
toms consistent with polymorphous light eruption; however, only 3% had
sought medical attention for their symptoms.7
Biopsy of experimentally induced lesions shows similar histological fea-
tures compared to clinical lesions.4 Given the role of sun exposure in its
pathogenesis, it comes as no surprise that polymorphous light eruption is
most often seen in spring and summer.4 In addition, it is not uncommon for
the first sign of disease to manifest during a vacation to southern latitudes.
The features, which develop after a latent period of hours to days, commonly
subside completely within days and heal without sequelae.1 However, once
the disease is established, persistence for many years is common.3 Overall,
Fig. 8.29
however, there is diminution of light sensitivity over time, but this process
Polymorphous light
often takes years.3 In a large study, the mean disease duration of the condition eruption: there is papillary
was 10.5 years.5 Patients with a duration of up to 53 years have been stud- dermal edema and a
ied.7 The distribution of lesions often changes with time.5 dense superficial and deep
One study showed that thyroid disease was present in 14% of patients.14 perivascular inflammatory
This same study found lupus erythematosus in only 2 of 94 patients. The cell infiltrate.
Tumid lupus erythematosus 269
and giant cells is a conspicuous feature that favors actinic reticuloid. Finally,
the finding of large atypical, hyperchromatic cerebriform lymphoid cells and
blast forms is characteristic of actinic reticuloid.
Tumid lupus erythematosus

Clinical features
Lupus erythematosus is discussed in detail in Chapter 17 and the reader is
referred there for a comprehensive discussion of the disease. In this section
only the tumid variant of lupus erythematosus is discussed.
Tumid lupus erythematosus (lupus erythematosus tumidus) is a rare mani-
festation of lupus that some authors believe to be sufficiently characteristic
to justify classification as a distinctive subtype of chronic cutaneous lupus
erythematosus.1 However, the lack of an agreed-upon diagnostic gold stan-
dard makes this designation somewhat controversial. Further study and
refinement of criteria for inclusion into this subtype of lupus and to allow for
reliable distinction from other inflammatory dermatoses is necessary.
Raised erythematous plaques, which have been described as ‘succulent’,
Fig. 8.30 characterize the clinical lesions.1 Follicular plugging is not a feature.2 Annular
Polymorphous light eruption: incipient subepidermal vesiculation is evident. Note and gyrate forms are seen in some patients.1 The sun-exposed areas such
the red cell extravasation and lymphocytic infiltrate.
as the face, chest, arms, and shoulders are most commonly affected.1–4 In
the largest series published to date, patients with this clinical appearance
may be present in papular and papulovesicular lesions.25 Some authors have accounted for 16% of the total number of patients seen in a large cutane-
reported increased eosinophils and neutrophils; however, others have not ous lupus clinic.1 Approximately equal numbers of male and female patients
confirmed this observation.25,26 Papillary dermal erythrocyte extravasation are affected, in contrast to the preponderance of females affected by other
is commonly present.25 Finally, features secondary to scratching, such as subtypes of cutaneous lupus.2,4 In this variant, young adults are most often
hyperkeratosis and acanthosis, may be seen.27 encountered but presentation in childhood is rare.4,5 In most patients, lesions
Immunofluorescence studies have shown that immunoreactants (C3, IgG, can be reproduced by exposure to UVA or UVB light.1,3,6 Development of
and IgM) may be present along the basement membrane zone.3 However, tumid lupus erythematosus has also been reported following highly active
when staining is evident, it is usually weak.3 antiretroviral therapy in the setting of HIV as a manifestation of immune
Juvenile spring eruption of the ears is characterized by a perivascular lym- restoration as well as in the setting of estrogen and infliximab treatment.7–9
phohistiocytic infiltrate often associated with subepidermal vesicle formation.20 Unusual and rare presentations include unilateral distribution in addition to
In early lesions, helper-inducer T lymphocytes predominate and increased symmetrical involvement of both elbows.10,11
numbers of dermal Langerhans cells are present.26 With chronicity, cytotoxic
suppressor T cells become more conspicuous. Histological features
Biopsy shows a superficial and perivascular ‘cuffed’ lymphocytic infiltrate
Differential diagnosis (Fig. 8.31).12 Periadnexal involvement is also seen in many cases. Abundant
It should be noted that there is considerable variability in both the clini- dermal mucin is commonly present (Fig. 8.32).2,12,13 In contrast to other
cal and histological descriptions of polymorphous light eruption. This has variants of lupus erythematosus, epidermal changes (e.g., follicular plugging,
led some authors to suggest that polymorphous light eruption likely repre- vacuolar interface changes, and thickened basement membrane) are generally
sents a group of related disorders rather than a single entity.25,26 Phototesting, not apparent.1,2,12
therefore, is probably the best ‘gold standard’ for establishing the diagnosis.
Compared with reticular erythematous mucinosis, mucin deposition is absent
or much less prominent in polymorphous light eruption. Clinically, polymor-
phous light eruption resolves once exposure to sunlight has ceased in contrast
to the persistent lesions of reticular erythematous mucinosis.
Histologically, polymorphous light eruption also shows some overlap with
other causes of gyrate erythema such as lymphocytic infiltration of Jessner.
The presence of marked papillary dermal edema, when present, favors poly-
morphous light eruption. A clinical history of documentation of resolution
of lesions with cessation to light exposure may sometimes be the only way to
distinguish these entities. In cases where the diagnosis is in doubt, phototest-
ing may often be necessary.
The histological features of lupus erythematosus are sometimes difficult
to distinguish from polymorphous light eruption, particularly when the lat-
ter is associated with positive immunofluorescence. However, most cases of
polymorphous light eruption are negative with immunofluorescence testing.
When immunoreactants are present, usually only weak staining is observed.
Careful clinical and serological evaluation should resolve any confusion
between these conditions.
Actinic reticuloid is another eruption associated with exposure to UV light.
Compared with polymorphous light eruption, actinic reticuloid is more typi-
cally associated with a dense cellular interstitial infiltrate involving the pap- Fig. 8.31
illary and reticular dermis, and sometimes extending into the subcutaneous Tumid lupus erythematosus: there is a perivascular lymphocytic infiltrate. The
fat. It is composed of lymphocytes, histiocytes, variable numbers of eosino- collagen fibers are separated by excess dermal mucin. By courtesy of J. Cohen,
phils, and plasma cells. The presence of multinucleate stellate myofibroblasts MD, Dermatopathology Laboratory, Tucson, Arizona, USA.
As can be seen from the above discussion, tumid lupus erythematosus is

a controversial entity. To some extent, the problem is a matter of seman-
tics and definitions. Indeed, some authors have taken the position that
reticular erythematous mucinosis and Jessner's lymphocytic infiltrate of
the skin would be more appropriately regarded as tumid lupus.18 Clearly,
further studies are necessary to more clearly define the clinicopathologi-
cal features of tumid lupus erythematosus and its distinction from similar
entities.
Perniosis, atypical chilblains and cold

equestrian panniculitis
Clinical features
Perniosis (chilblains) is characterized by sensitivity to cold, damp weather
and is therefore seen during the cold months of the year. The disease seems to
be more common in environments where inadequate heating is problematical
for a few months of the year and is less common in localities characterized by
Fig. 8.32 harsh frigid winters where adequate home heating is the norm.1 Exposure to
Tumid lupus erythematosus: the mucin is Alcian blue positive. By courtesy of
cold water sometimes appears to play a role.2
J. Cohen, MD, Dermatopathology Laboratory, Tucson, Arizona, USA.
Patients present with painful, erythematous nodules on the distal extremi-
ties, especially the fingers and the toes (Fig. 8.33).1,3 Other exposed sites,
Direct immunofluorescence staining fails to demonstrate reactivity.1 such as the nose and ears, may also be affected (Fig. 8.34). Lesions may be
The infiltrate cell infiltrate consists of a mixture of CD4+ and CD8+ reac- complicated by blister formation or ulceration. In most patients, the condition
tive T lymphocytes.2,14 remits during summer but often recurs during winter months. Patients with
anorexia nervosa may be at increased risk of developing perniosis.4,5
Differential diagnosis Horse-riding enthusiasts who wear tight clothing during cold weather may
The concept of tumid lupus erythematosus has been expanded in a recent develop similar lesions on the thighs (Fig. 8.35). This disease is associated
large series of patients.1 Whether there is justification for classification of with panniculitis and has been termed ‘equestrian cold panniculitis’.6
the disorder in these patients as a variant of lupus erythematosus or not is Patients with lesions that persist into warmer seasons appear to be at a
debatable. None met the criteria for lupus erythematosus and most did not higher risk of developing lupus erythematosus.7 One group has designated
have significantly elevated antinuclear antibodies (ANA). However, occa- patients with some criteria, but not meeting diagnostic thresholds for con-
sional patients have been shown to develop skin lesions consistent with dis- nective tissue diseases such as lupus erythematosus, as having ‘atypical
coid lupus erythematosus, including prominent e pidermal changes.13,15 chilblains’.7 This subset of patients appears to be at higher risk of developing
In addition to patients similar to those described by Kuhn et al.,1 patients unequivocal features of connective tissue disease. It is reasonable to evaluate
that do fit the criteria for discoid lupus erythematosus (DLE), subacute cuta- all patients with perniosis for evidence of lupus erythematosus. Occasionally,
neous lupus erythematosus (SCLE) or systemic lupus erythematosus (SLE) patients with perniosis who present without clinical manifestations of
rarely develop lesions that show a dense superficial and deep perivascular and connective tissue disease eventually develop SLE.8
periappendigeal infiltrate in the absence of significant epidermal changes.16
Distinction of these subgroups of tumid lupus from lymphocytic infiltrate of
Jessner and polymorphous light eruption based on histological examination
alone may be difficult if not impossible.17 Some authors have suggested that
some cases reported as lymphocytic infiltrate of Jessner or reticular erythema-
tous mucinosis, in fact, represent tumid lupus.18
The histological features of tumid lupus erythematosus may be difficult to
distinguish from polymorphous light eruption. The latter condition, which is
the most common photodermatosis, usually presents in young people, par-
ticularly females, as recurrent, erythematous papules, vesicles and/or plaques
following exposure to UV light. Lesions, which develop after a latent period
of hours to days, commonly subside completely within days and heal with-
out sequelae.19 A dense perivascular lymphohistiocytic infiltrate, often
associated with papillary dermal edema, is present in the superficial and
sometimes deep dermis.20 The presence of significant papillary dermal edema
favors polymorphous light eruption. Furthermore, the latter often has focal
epidermal changes, particularly spongiosis and lacks dermal mucin.
Lymphocytic infiltrate of the skin (Jessner) may be difficult to distinguish from
tumid lupus erythematosus.3 In such cases, immunocytochemistry may some-
times be helpful. The infiltrate in lymphocytic infiltrate is HLA-DR negative in
contrast to lupus erythematosus in which the lymphocytes and often the kera-
tinocytes are HLA-DR positive.21 Leu 8 (immunoregulatory T-cell) expression Fig. 8.33
Perniosis: erythematous
is also more frequently seen in lymphocytic infiltrate.21 Epidermal Langerhans
nodules are present over
cells are often increased in number in lymphocytic infiltrate whereas they are the fingers. From the
frequently reduced in discoid lupus.22 The presence of significant amounts of collection of the late N.P.
dermal mucin favors a diagnosis of tumid lupus erythematosus. Smith, MD, The Institute
Erythema annulare centrifugum differs from tumid lupus by the lack of of Dermatology, London,
significant dermal mucin. UK.
Perniosis, atypical chilblains and cold equestrian panniculitis 271
Fig. 8.36
Perniosis: there is hyperkeratosis, acanthosis, and a heavy lymphocytic infiltrate.
Note the marked subepidermal edema.
Fig. 8.34
Perniosis: in this patient,
the nose is affected.
From the collection of the
late N.P. Smith, MD, The
London, UK.
Fig. 8.37
Perniosis: there is marked subepidermal edema and red cell extravasation.
Fig. 8.35
Equestrian cold
panniculitis: tender
erythematous lesions on
buttock and thigh.
By courtesy of the
London, UK.

The pathogenesis of perniosis is not well understood. Clearly, cold is
a requirement for development of symptoms. Tight clothing may play a
role in the development of perniosis at nonexposed sites. In some patients,
particularly children, the presence of cryoproteins may play a role in the
disease.9
Biopsy reveals a cuffed perivascular lymphocytic infiltrate with variable
vascular fibrinoid change (Figs 8.36–8.38). The inflammatory infiltrate Fig. 8.38
may be superficial but often extends into the deep dermis and subcutaneous Perniosis: the infiltrate consists largely of lymphocytes.
Fig. 8.39 Fig. 8.40

Perniosis: this example shows a heavy mural infiltrate consistent with lymphocytic Chilblain lupus erythematosus: resolving perniosis involving the tips of the thumb, ring,
vasculitis. and little fingers. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
a dipose tissue. In some cases it is difficult to demonstrate strict criteria for Approximately 15% of patients develop SLE, particularly those who
lymphocytic vasculitis (Fig. 8.39). In other examples, however, fibrinoid develop discoid and perniotic lesions simultaneously and those with DLE-
vascular damage with thrombi is extensive. Papillary dermal edema, which erythema multiforme-like syndrome in addition to perniosis.1,2,8 Patients with
may be marked, is often present.10 Interface changes, either vacuolar interface severe chilblains that persist into warmer seasons appear to be at higher risk
or lichenoid dermatitis, may sometimes be seen.11 A chronic inflammatory of lupus erythematosus compared to those with the idiopathic form.9 Patients
infiltrate around sweat glands has occasionally been noted.7 with some criteria, but not meeting diagnostic thresholds for connective tissue
Biopsy of cold panniculitis shows a perivascular chronic inflammatory disease, have been designated as having ‘atypical chilblains’.9 These individ-
infiltrate that tends to be prominent at the dermal–subcutaneous tissue uals appear to be at higher risk of eventually developing frank connective
junction.6 tissue disease.9 Based on the above observations, it is clear that patients with
The inflammatory infiltrate is mostly composed of CD3+ T cells with a minor perniosis should be evaluated for evidence of lupus erythematosus.
subpopulation of CD20+ B cells and scattered CD68+ macrophages.11,12
Differential diagnosis Pathogenesis and histological features

The biopsy findings are non-specific and other diseases causing cuffed While the pathogenesis of sporadic disease remains elusive, mutations in the
perivascular lymphocytic reactions and lymphocytic vasculitis enter into the DNA exonuclease TREX1, located on chromosome 3, have recently been
differential diagnosis. The diagnosis is rendered only after careful clinical cor- reported in the autosomal dominant familial form of chilblain lupus.4–7 The
relation. Patients often have some features of, but fail to meet criteria for, function of TREX1 is the digestion of single-stranded DNA. Recent work has
connective tissue disease.7 Also, lesions very similar, or identical, to perniosis shown that lack of TREX1 function may lead to accumulation of reverse tran-
may be seen in patients with cutaneous or systemic lupus erythematosus.8,11,13 scribed DNA with subsequent stimulation of interferon production, which
Frank lymphocytic vasculitis and interface changes appear to be more com- ultimately may be a trigger for autoimmunity.10,11 Mutations in TREX1 have
mon in patients with chilblain lupus erythematosus than in idiopathic chil- also been reported in other autoimmune disorders such as Aicardi-Goutieres
blains; however, the presence or absence of these findings may not be reliable syndrome, an encephalopathy characterized by basal ganglia calcification and
discriminators.7,11 A positive lupus band test or antinuclear antibodies favors white matter alterations.6,12 The development of chilblains is not infrequently
a diagnosis of chilblain lupus erythematosus.7 seen in patients with this syndrome with clinical and histological findings
similar to chilblain lupus erythematosus.13,14
Biopsy reveals a cuffed perivascular lymphocytic infiltrate with edema, red cell
Chilblain lupus erythematosus extravasation, and variable vascular fibrinoid change (Fig. 8.41). Some biopsies
show frank lymphocytic vasculitis. The inflammatory infiltrate often extends into
Clinical features the deep dermis and subcutaneous adipose tissue. Interface epidermal changes,
Lupus erythematosus is discussed in detail in Chapter 17 and the reader is ranging from focal vacuolar changes to a lichenoid tissue reaction, are often
referred there for a comprehensive discussion of the disease. In this section, present.2,15 Chronic inflammation around sweat glands is sometimes seen.9
only chilblain lupus erythematosus (lupus pernio) will be discussed. The infiltrate is mostly composed of T cells, occasional macrophages, and
Chilblain lupus erythematosus may be a manifestation of either discoid scattered B cells.
or systemic lupus erythematosus and shares many clinical and histological
similarities with idiopathic chilblains (Fig. 8.40). It develops almost Differential diagnosis
exclusively in females during the winter months.1 Lesions are characterized Other diseases associated with a ‘cuffed’ perivascular lymphocytic infiltrate
by itchy, painful, erythematous or blue-purple papules, plaques, and nodules and lymphocytic vasculitis must be considered in the differential diagnosis.
on the fingers, heels, and soles of the feet; the hands, calves, knees, knuckles, The diagnosis is rendered only after careful clinical and serological corre-
elbows, nose, and ears are less often affected.2 Hyperkeratotic fissured lesions lation. Distinction from idiopathic chilblain perniosis is not possible based
and ulcers are also sometimes present.3 Patients may develop chilblains many on histological features alone. The presence of lymphocytic vasculitis and
years after the typical discoid rash, or lesions may develop simultaneously. interface changes appears to be more common in chilblain lupus compared
Occasionally, chilblains are the sole manifestation.3 While the majority of with idiopathic chilblains, but these features are not reliable discriminators.9
cases are sporadic, familial disease with an autosomal dominant inheritance A positive lupus band test and the presence of antinuclear antibodies favor a
has also been reported.4–7 diagnosis of chilblain lupus erythematosus.
Pigmented purpuric dermatoses 273
Fig. 8.42
Fig. 8.41 Majocchi's disease: characteristic brown plaques on the backs of the knees in a
Chilblain lupus male. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
erythematosus: there is
subepidermal edema with
red cell extravasation and
a superficial perivascular
lymphocytic infiltrate.
Pigmented purpuric dermatoses including

Majocchi's disease, Schamberg's disease,
pigmented purpuric lichenoid dermatitis
of Gougerot and Blum and itching purpura
Clinical features
The term pigmented purpuric dermatoses (purpura simplex, chronic capil-
laritis) encompasses a number of clinical syndromes characterized by orange/
brown pigmentation (due to hemosiderin deposition likened to cayenne
pepper), interspersed with fine pinpoint purpura (due to extravasated red
blood cells).1–4 All are of unknown etiology. These disorders may show Fig. 8.43
overlapping clinical and histological features. Indeed, some authors no lon- Schamberg's disease: a localized area of capillaritis showing characteristic cayenne
ger consider their classification to have nosological value. In addition to pepper speckling over the lateral malleolus of a male. By courtesy of R.A. Marsden,
the disorders listed below, unusual clinical presentations include unilateral MD, St George's Hospital, London, UK.
disease, zosteriform distribution, and concomitant morphea in addition to
familial disease.5–9
• In Majocchi's disease, the lesions tend to be discrete and annular, vary
from one to several centimeters in diameter, and are associated with
telangiectases (Fig. 8.42).
• Schamberg's disease is characterized by purpura and petechiae with
conspicuous pigmentation; there is a marked preponderance of males and
presentation in childhood is unusual (Figs 8.43, 8.44).10 Lesions, usually
irregular in shape and occurring predominantly on the lower limbs, may
remain for 10 years or longer. In some cases, the findings may mimic
those of chronic venous insufficiency. The lesions are asymptomatic in
most cases. However, some patients complain of pruritus.
• In pigmented purpuric lichenoid dermatitis of Gougerot and Blum,
patients, predominantly males, develop lichenoid papules in addition to
purpuric lesions, most often on the legs.
• Itching purpura (pruriginous angiodermatitis) also shows a male
predominance and is associated with an acute onset of widely distributed
orange macules (Figs 8.45, 8.46). It commonly begins on the dorsal
surface of the feet or ankles, but soon spreads to affect the thighs,
buttocks, trunk, and arms. This variant is associated with a shorter Fig. 8.44
duration than the others, with most patients being free from lesions by Schamberg's disease: in this patient, the bilateral distribution over the malleoli mimics
1 month. The itching, which is of unknown etiology, is usually severe. the effects of venous stasis. By courtesy of R.A. Marsden, MD, St George's Hospital,
Similar appearances may be caused by drug sensitivity. London, UK.
Fig. 8.47
Fig. 8.45 Pigmented purpura: there is an upper dermal heavy perivascular lymphocytic infiltrate.
Itching purpura: these
small macules are widely
distributed over both legs.
By courtesy of J. Newton,
MD, St Thomas' Hospital,
London, UK.
Fig. 8.48
Pigmented purpura:
the infiltrate consists
of lymphocytes and
histiocytes. Note the red
cell extravasation.
Fig. 8.46
Itching purpura: close-up
view of a typical orange
macule. By courtesy of J. the later stages they may not be present when hemosiderin-laden macrophages
Newton, MD, St Thomas' become conspicuous (Fig. 8.49). An iron stain is useful to demonstrate
Hospital, London, UK. hemosiderin. Recently, cases of pigmented purpuric dermatosis associated
with granulomatous inflammation have been described and designated granu-
lomatous pigmented purpuric dermatoses.13,14 Some cases of granulomatous
Since lichen aureus has more distinctive features, it is discussed separately pigmented dermatosis appear to be associated with hyperlipedemia.15
(see below).
Histological features It should be emphasized that extravasated red blood cells and hemosid-
All variants show similar histopathological features. A perivascular lympho- erin associated with a lymphocytic capillaritis are non-specific findings.
cytic infiltrate is associated with reactive endothelial changes and extravasated The differential diagnosis is broad and includes other forms of perivascular
red blood cells (Figs 8.47, 8.48).11 The lymphocytes are predominantly of the lymphocytic infiltrates and lymphocytic capillaritis. Careful clinical cor-
T-helper subset.12 The density of the infiltrate is highly variable. The Gougerot- relation is necessary to establish a correct diagnosis. Progression of lesions
Blum variant is often associated with a dense lichenoid lymphocytic infiltrate. mimicking pigmented purpuric dermatoses to mycosis fungoides has been
Extravasated red blood cells are usually appreciated in early lesions, while in documented.16,17 However, this appears to be an uncommon event and
Lichen aureus 275
Fig. 8.49 Fig. 8.50

Pigmented purpura: there Lichen aureus: golden-
is abundant hemosiderin red-brown plaques on the
deposition as revealed ankle. By courtesy of M.
with the Perl Prussian blue Price, MD, St Thomas'
stain for iron. Hospital, London, UK.
it is more likely that these cases represent examples of purpuric cutane- fashion immediately below the epidermis (Figs 8.51, 8.52). In contrast
ous T-cell lymphoma from the beginning. The absence of epidermotropism to lichen planus, however, there is no evidence of basal cell hydropic
and cytological atypia favors pigmented purpuric dermatitis over a T-cell degeneration and cytoid bodies are not usually found. A Grenz zone is
lymphoproliferative disorder. However, in rare cases, distinction may be sometimes present, although the infiltrate may abut the overlying epi-
difficult or impossible and ancillary investigations such as immunohistologi- dermis. Lymphocytic exocytosis is sometimes present. Scattered within
cal and T-cell gene rearrangement studies may be indicated. Adding to this the infiltrate are increased numbers of blood vessels. Hemosiderin-laden
occasionally difficult distinction, cases of pigmented purpuric dermatoses macrophages are present in the deeper aspect of the infiltrate or in the
with clonal T-cell gene rearrangements have been reported.13,18 Therefore, it adjacent noninfiltrated dermis. Purpura is a variable feature and there is
appears that the results of gene rearrangement studies may not always reliably no evidence of frank vasculitis.
aid in this differential diagnosis. All information – clinical, histological, immu-
nohistological, and genetic – should be evaluated in context.
There may be some histological overlap with the Gougerot-Blum variant of
Lichen aureus pigmented purpuric lichenoid dermatitis but lichen aureus tends to be more
localized.
Clinical features
Lichen aureus (lichen purpuricus) is a rare variant of the pigmented purpu-
ric dermatoses. It may be differentiated from the other forms by virtue of
its distinctive clinical and histological features.1–4 It is, therefore, discussed
separately.
Lichen aureus shows a male predilection (2:1) and tends to affect the
younger age group, with a peak incidence in the fourth decade. Children
may occasionally be affected.3 Lesions are usually asymptomatic, although
pruritus is an occasional feature. The disease is characterized by discrete
or confluent lichenoid macules and papules, which may be golden yellow,
bronze, purple, or dark brown, and may resemble a bruise (Fig. 8.50).
Sometimes a purpuric element is evident. The lesions of lichen aureus are
characteristically very persistent, although occasionally spontaneous reso-
lution is a feature. They occur most often on the lower legs, but may affect
quite a wide variety of sites, including the arms, hands, trunk, thighs, and
vulva.5,6 Lesions are usually unilateral and limited to only one or two sites;
they consist of either solitary ovoid maculopapules 3–5 cm in diameter or
irregular plaques up to 20 cm across. Rarely, a zosteriform pattern has been
described.7
The epidermis is structurally normal. A dense lymphohistiocytic infil- Fig. 8.51
trate is present in the upper dermis, usually distributed in a bandlike Lichen aureus: there is a dense bandlike infiltrate in the upper dermis.
Fig. 8.52 Fig. 8.53

Lichen aureus: the infiltrate consists of lymphocytes and histiocytes. Note the marked Pruritic urticarial papules and plaques of pregnancy: there is focal spongiosis. Note
red cell extravasation. the perivascular upper dermal infiltrate.
Pruritic urticarial papules and plaques

of pregnancy
Clinical features
Pruritic and urticarial papules and plaques of pregnancy (PUPPP, also known
as polymorphic eruption of pregnancy, toxemic rash of pregnancy, toxic ery-
thema of pregnancy, late onset prurigo of pregnancy) is a common dermatosis
of uncertain etiology with an estimated incidence of 0.5%.1,2 The disorder is
most frequently seen in the primigravida.3,4 Characteristically, it presents late in
pregnancy, towards the end of the third trimester with an average time of onset
in the 36th week.3,4 Rarely, presentation during the postpartum period has been
documented.3–5 In a recent study, the male to female infant ratio in affected
patients was 2:1.6 In one large series, 76% of patients were primigravidas.3,4
As its name indicates, urticarial papules and plaques are associated with
vexatious pruritus. Patients frequently complain that pruritus interferes with
sleep.3 At onset, papules are often localized to the abdomen along lines of
stria distensae. This pattern is seen in approximately 50% of patients.1,3 Small
vesicles are occasionally present.3 With time, the papules spread to involve the
proximal limbs and torso and coalesce to form plaques.4 The distal extremi-
ties are rarely affected.4,7 Sparing of the face is a helpful diagnostic clinical
clue. Typically, the lesions resolve shortly after delivery. Importantly (see dif- Fig. 8.54
ferential diagnosis section below), PUPPP does not usually recur with subse- Pruritic urticarial papules
quent pregnancies. and plaques of pregnancy:
One group found PUPPP was associated with increased maternal weight high-power view showing
gain and increased newborn weight compared with a control population.8,9 spongiosis.
Some studies suggest a relationship between PUPPP and twin gestation with
two such reports documenting 10% and 16% of cases, respectively, associated
with twin gestations.3,8–10 These data have led some authors to postulate that biopsies had eosinophils in the infiltrate. However, other authors report con-
abdominal distension may play a role in the pathogenesis of PUPPP.8 Other trary experience, with most biopsies showing eosinophils. It is our experi-
reported association include hypertensive disorders and induction of labour.11 ence that most biopsies show at least rare eosinophils if multiple sections are
Rarely, congenital abnormalities have been noted in association with PUPPP examined.
but this may be due to small statistical sampling. In one report, one child had The lymphohistiocytic infiltrate is also variable in density, ranging from
hypoplastic dental enamel, while another developed congenital laryngomal- modest numbers of cells to a dense infiltrate with a tightly ‘cuffed’ perivas-
acia requiring surgical intervention.3 In this same series, another child was cular distribution.3 Mild papillary dermal edema is a common finding but
reported to have a ventriculoseptal defect. Most authors, however, believe that marked edema is rarely seen.3 The additional feature of spongiotic vesicula-
there is no direct association between PUPPP and congenital abnormalities. tion characterizes later lesions. Less common manifestations include eosino-
philic spongiosis, and rarely eosinophil-rich subepidermal blistering.
Early lesions (urticarial papules) of polymorphic eruption of pregnancy show Differential diagnosis
epidermal and upper dermal edema accompanied by a perivascular lympho- As can be deduced from the above histological description, the biopsy findings
histiocytic infiltrate with variable numbers of eosinophils (Figs 8.53–8.55). are non-specific. The main differential diagnosis includes urticaria, hypersen-
Often, the number of eosinophils is modest and in one series only 17% of sitivity reactions, and pemphigoid gestationis. Usually, clinical examination
Pregnancy prurigo 277
pregnancy suggested that there is significant clinical and histological overlap

between eczema of pregnancy, pruritic folliculitis of pregnancy and prurigo
of pregnancy and that they should be regarded as a single disease complex
termed ‘atopic eruption of pregnancy’.6
The histological features are not specific, comprising mild spongiosis,
lymphocytic exocytosis, and a superficial perivascular lymphohistiocytic
infiltrate with occasional eosinophils (Figs 8.56 and 8.57). Frequently, his-
tological features of excoriation are present. Immunofluorescence studies are
negative.
The histological features are non-specific and clinical correlation is necessary
to render a firm diagnosis. The diagnosis is perhaps best approached as one of
exclusion, and underlying etiologies should be sought. The major differential
diagnosis includes hypersensitivity reactions (drug eruption, insect bites, etc.)
with superimposed prurigo nodularis.
Fig. 8.55
Pruritic urticarial papules and plaques of pregnancy: the infiltrate consists of
lymphocytes, histiocytes, and eosinophils.
and history will allow distinction from hypersensitivity reactions, which

may show identical histological features. Urticaria can be distinguished by
the presence of neutrophils. In our experience, distinction between the pre-
bullous phase of pemphigoid gestationis and PUPPP is the most common rea-
son for which the clinician performs a biopsy. Distinction is important since
pemphigoid gestationis, but not PUPPP, may be associated with significant
fetal morbidity. The presence of a subepidermal vesicle or marked papillary
dermal edema favors pemphigoid gestationis; however, some early lesions
will lack these features. Furthermore, PUPPP is frequently associated with
mild papillary dermal edema. Immunofluorescence studies are often neces-
sary for definitive diagnosis. Pemphigoid gestationis is associated with base-
ment membrane staining for C3 and sometimes IgG. Most cases of PUPPP
show negative immunofluorescence results.12 However, it should be noted
that there have been a few purported cases of PUPPP in which weak C3 Fig. 8.56
Pregnancy prurigo: there is a superficial perivascular inflammatory cell infiltrate.
staining in a linear pattern along the basement membrane was reported.3 In
some laboratories, granular deposits along the basement membrane have also
been described in cases of PUPPP.3,13 However, PUPPP is not associated with
positive strong linear immunofluorescence staining along the basement mem-
brane – a result that would strongly favor pemphigoid gestationis.13 As men-
tioned above, in contrast to pemphigoid gestationis, PUPPP does not tend to
recur during subsequent pregnancies.
Pregnancy prurigo
Clinical features
Pregnancy prurigo (prurigo gravidarum, prurigo gestationis) affects 1 in
300 pregnancies, presenting as pruritic, erythematous, 0.5–1.0-cm papules
and nodules with a predilection for the extensor surfaces of the extremities
and the abdomen.1–8 Superimposed features of excoriation with scale-crust
may be seen. Lesions usually present during the third trimester but may
present at all stages of pregnancy.6 The condition usually disappears fol-
lowing delivery, but in some cases it persists into the puerperium. Blistering
is not a feature. Fetal and maternal health does not appear to be adversely
affected.5

The pathogenesis of pregnancy prurigo is unknown. It has been suggested
that the condition represents pruritus gravidarum in a background of Fig. 8.57
atopic dermatitis.1,5 Patients often have a history of atopy.5 Serum IgE may Pregnancy prurigo:
be elevated in patients regardless of whether or not there is a positive his- the infiltrate consists
tory of atopy.5 Of interest, eczematous dermatitis appears to be common in of lymphocytes with
pregnancy.5 Furthermore, a recent comprehensive analysis of dermatoses of occasional eosinophils.
Urticarial vasculitis
Clinical features
Urticarial vasculitis is an uncommon condition characterized clinically by
chronic urticaria and histologically by leukocytoclastic venulitis.1–3 In some
patients, urticarial vasculitis is associated with antibody–antigen complexes –
a type III hypersensitivity reaction.4,5 In many patients, however, no underly-
ing cause is discovered.
Patients may have, in addition to urticarial skin lesions, angioedema, arth-
ralgia, gastrointestinal symptoms, and evidence of renal involvement. The
spectrum of illness ranges from mild symptoms to a serious systemic illness,
for which treatment with corticosteroids is sometimes necessary.6
The disease shows a female predominance (2:1) and is most often seen in
the third, fourth or fifth decade. It is rare in children.7 The cutaneous lesions
are urticarial in appearance, but usually last 24–72 hours (Figs 8.58–8.60).8
Pruritus, a burning sensation, or pain, are common complaints. The fre-
quency of attacks varies from daily to monthly. The skin lesions are edem-
atous, raised, and erythematous, and are associated with nonblanchable
purpura.
Systemic manifestations/associations include joint pain, stiffness and swell- Fig. 8.59
ing, particularly of the hands, elbows, feet, ankles, and knees. Frank arthri- Urticarial vasculitis: in
this patient, there is an
tis is extremely rare but may be associated with the development of valvular
extensive urticarial plaque.
heart disease.9,10 Proteinuria and hematuria may be seen in some patients.
Many patients are hypocomplementemic.4,11 Rarely, renal biopsy reveals the MD, St Thomas' Hospital,
features of focal or diffuse proliferative glomerulonephritis. Crescentic glom- London, UK.
erulonephritis, and mesangial and membranous nephropathy have also been
documented.6,12–14 Abdominal pain associated with nausea, vomiting, and
diarrhea is a feature in some patients.
The erythrocyte sedimentation rate (ESR) is raised in many cases and in
about 50% of patients there is hypocomplementemia. The presence of the lat-
ter correlates with systemic involvement.6,15 There may also be depression of
the early classical pathway components C1q, C4, and C2. Patients with hypo-
complementemic urticarial vasculitis have a high prevalence of autoantibodies
to endothelial cells and antibodies against C1q are invariably present.16–18 The
term ‘Schnitzler's syndrome’ has been applied to patients with urticarial vas-
culitis and monoclonal IgM gammopathy.19–24 Hepatosplenomegaly, elevated
ESR, elevated white blood cell count, fever, and joint pain are characteristic
Fig. 8.60
Urticarial vasculitis:
note the bizarre annular
purpuric urticarial plaque.
London, UK.
features and renal insufficiency has also been documented.20–22,25 An underly-

ing lymphoproliferative disorder is present in a minor subset of patients.19
Importantly, urticarial vasculitis (especially the hypocomplementemic vari-
ant) is often associated with, or heralds the onset of, a variety of systemic dis-
eases, including SLE, arthritis, interstitial lung disease, pericarditis, systemic
Fig. 8.58
Urticarial vasculitis: note
sclerosis, mixed connective tissue disease, relapsing polychondritis, inflam-
the urticaria with a livid matory myositis, hepatitis, inflammatory bowel disease, serum sickness, pol-
hue. By courtesy of J. yarteritis nodosa and Wegener's granulomatosis, viral infections, Sjögren's
Newton, MD, St Thomas' syndrome, cryoglobulinemia, polycythemia rubra vera, adverse reaction to
Hospital, London, UK. drugs, and as a response to sunlight.6,15,26–44 In one study, more than 50% of
Urticarial vasculitis 279
patients had uveitis, scleritis, conjunctivitis or episcleritis.6 It appears that

patients with hypocomplementemia have more severe disease.26 Some authors
have postulated that hypocomplementemic urticarial vasculitis represents a
form of systemic lupus erythematosus.45 Others, however, have shown no
significant difference in the association with lupus in patients with normo-
complementemic compared with hypocomplementemic urticarial vasculitis.6
A diagnosis of urticarial vasculitis in any patient should initiate an evaluation
for underlying disease. Fortunately, urticarial vasculitis usually has a benign
outcome.6
Urticarial vasculitis has been documented in association with malig-
nancy.6,46–51 Given the rarity of this association, it may well be coincidental.
In urticarial vasculitis, vascular damage is superimposed on a background
of dermal edema and inflammation typical of urticaria. The vasculitis affects
the superficial vascular plexus. Extravasation of red blood cells is evidence
of vascular damage. The vasculitis shows features of leukocytoclastic vas-
culitis except that the histological features tend to be subtle and are easily
Fig. 8.63
Urticarial vasculitis: there is a heavy lymphocytic and eosinophil infiltrate. In this
example, there are conspicuous flame figures.
overlooked (Figs 8.61–8.63). Mild or focal fibrinoid changes associated with

few neutrophils and sparse karyorrhexis are typical. In our experience, the
vasculitis is usually low grade in nature. Others have shown that endothe-
lial necrosis is unusual.52 Nevertheless, more impressive necrotizing vasculitis
may sometimes be encountered (Fig. 8.64). Urticarial vasculitis appears to
represent a spectrum of disease ranging from urticaria with very mild vascular
injury to frank necrotizing vasculitis.53–55
Clinical correlation is necessary to distinguish urticarial vasculitis from
other forms of leukocytoclastic vasculitis. Although urticarial vasculitis
is often associated with subtle, low-grade vascular injury, this pattern
should not be relied upon in the distinction from other forms of vasculi-
tis. In short, the pathologist's role in diagnosis is to confirm the presence
of vasculitis.
Fig. 8.61
Urticarial vasculitis: in this example of an early lesion, there is a conspicuous
perivascular eosinophil infiltrate. There is no evidence of vessel wall damage.
Fig. 8.64
Urticarial vasculitis: this
Fig. 8.62 biopsy of a purpuric lesion
Urticarial vasculitis: in this field, there is marked edema accompanied by a mixed shows features of florid
lymphocytic and eosinophil infiltrate. vasculitis.

Tumor necrosis factor receptor-associated
The pathogenesis of this condition is unknown.
periodic syndrome (familiar Hibernian fever) Histologically, the eruption is characterized by a superficial and deep
lymphohistiocytic infiltrate accompanied by conspicuous eosinophils. The
Clinical features epidermis is hyperkeratotic and there is mild acanthosis frequently accom-
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare panied by spongiosis. Other manifestations include eosinophilic spon-
autosomal dominant condition with a predilection for individuals of Irish and giosis, bullous pemphigoid-like subepidermal blistering, and eosinophilic
Scottish descent.1–5 Other terms used to describe this disorder include familial panniculitis.
Hibernian fever, benign autosomal dominant familial periodic fever, and auto- Direct immunofluorescence may disclose perivascular deposits of C3 and
somal dominant periodic fever with amyloidosis. Patients usually present in IgM. Indirect immunofluorescence studies are negative.
infancy or early childhood with prolonged episodes of fever accompanied by (in The lymphocytes are of the CD3+ T-cell phenotype with a predominance
descending order of frequency) abdominal pain, cutaneous manifestations, myal- of CD4+ T-helper cells over CD8+ T-suppressor cells. B cells are absent.
gia, headache, arthralgia, and pleuritic chest pain.3 Rare associations include
central nervous system involvement due to a demyelinating disorder, IgA neph-
ropathy, and small vessel vasculitis with concomitant relapsing panniculitis.6–8 Viral exanthemata
Cutaneous manifestations include migratory asymptomatic, nonscaly
A variety of viral infections may present with cutaneous eruptions (Table 8.1).
erythematous macules and plaques, annular and serpiginous lesions measur-
Although some viruses are associated with an eruption with distinc-
ing up to 28 cm in diameter.2,3 The trunk and extremities are predominantly
tive clinical features, others are affiliated with a non-specific maculo-
affected with lesions presenting proximally and migrating distally.3 Patients
papular dermatosis. Exceptionally, exanthemata may represent a primary
may also develop conjunctivitis and periorbital edema.2 Amyloidosis is an
cutaneous infection. More commonly, the clinical features are a manifes-
occasional complication.9
tation of an immune response, such as an immune complex disease or a
cell-mediated hypersensitivity reaction, to an infection at an extracuta-
neous site.
TRAPS is due to a mutation of the TNFRSF1A gene which encodes the tumor Biopsy of a viral exanthem often shows a superficial perivascular lym-
necrosis factor receptor.3 The gene has been localized to chromosome 12p13.4 phocytic infiltrate. Some cases may show epidermal pathology such as inter-
More than 60 mutations have been identified in the TNFRSF1A gene so far face changes with dyskeratotic cells. The histological features are entirely
but the precise disease mechanism remains elusive.10 non-specific and distinction from hypersensitivity reactions (e.g., a drug erup-
Histologically, the skin lesions are characterized by dermal edema and a tion) is impossible without clinical (often including serological investigation)
superficial and deep perivascular and interstitial infiltrate of lymphocytes and correlation. Viruses that infect cutaneous sites may be visualized by light
a lesser number of macrophages.1–3 There is no evidence of vasculitis. Small microscopy including immunohistochemistry, or demonstrated by viral culture,
numbers of neutrophils or plasma cells may occasionally be present.3 immunological testing, PCR or DNA hybridization. Skin manifestations of
The infiltrate consists of CD3+ T lymphocytes and CD68+ macrophages. viral infections are described in detail in Chapter 18.
CD4+ T-helper and CD8+ T-suppressor forms are both represented. CD20+
B lymphocytes are not present.
Table 8.1
Viruses associated with cutaneous eruptions
Eosinophilic, polymorphic and pruritic
Cytomegalovirus
eruption associated with radiotherapy Enterovirus (coxsakievirus, echovirus)
Epstein-Barr virus
Clinical features Hepatitis B virus
Rueda and coworkers have recently documented a polymorphic cutaneous erup- Human immunodeficiency virus
tion which develops in females undergoing radiotherapy for cancer (eosinophilic, Paramyxovirus
Parvovirus
polymorphic, and pruritic eruption associated with radiotherapy, EPPER).1–6
Roseola (human herpesvirus-6)
Although a wide spectrum of tumors may be present, cervical squamous carci-
Rubella
noma is by far the most common. The cutaneous lesions are intensely pruritic and Rubeola (measles)
include excoriations, erythematous papules, vesicles, blisters, and panniculitis- Toga virus
like lesions. The extremities, particularly the legs, are predominantly affected.
Granulomatous, necrobiotic and Chapter
See
for references and
additional material
perforating dermatoses
9
Sarcoidosis 281 Necrobiotic xanthogranuloma 306 Granulomata in congenital
immunodeficiency syndromes 314
Granuloma annulare 288 Palisaded neutrophilic and granulomatous
dermatitis 308 Aluminum granuloma 315
Necrobiosis lipoidica 295
‘Metastatic’ Crohn's disease 309 Perforating disorders 316
Rheumatoid nodule 300
Granulomatous cheilitis 310 Reactive perforating collagenosis 316
Pathogenesis and histological features 301
Perforating folliculitis 318
Differential diagnosis 301 Acne agminata 310
Elastosis perforans serpiginosa 319
Elastolytic granulomata 302 Perioral dermatitis 310 Hyperkeratosis follicularis et parafollicularis in
Annular elastolytic giant cell granuloma 302 cutem penetrans 321
Demodicosis 311 Perforating pseudoxanthoma elasticum 322
Actinic granuloma (O'Brien) 302
Atypical facial necrobiosis lipoidica 304 Infective granulomata 311 Necrotizing infundibular crystalline
Granuloma multiforme 304
Foreign body granulomata 311 folliculitis 323
Rheumatic fever nodule 306
Granulomatous contact dermatitis 313 Chondrodermatitis nodularis chronica
helicis 324
Sarcoidosis
Clinical features
Sarcoidosis (Gr. sarkos, flesh; eidos, form), so-named because its histological
features were originally thought to resemble a sarcoma (Boeck), is a common
systemic disease of unknown etiology. It is characterized and defined by the
presence of noncaseating granulomata, usually (but not invariably) affecting
multiple organ systems.1–10 Manifestations are variable. Patients may present
with:
• an acute and usually self-limiting variant,
• a chronic form exclusively affecting the skin (up to between 20%
and 40% of patients with cutaneous sarcoidosis do not have systemic
involvement),
• a serious systemic chronic variant with widespread lesions, which affects
multiple systems, is associated with high morbidity, and may occasionally
be fatal.
Sarcoidosis is more commonly encountered in industrialized countries and
shows particularly high incidences in northern Europe (including the UK),
Fig. 9.1
the USA, and New Zealand, where as many as 20/100 000 of the population
Sarcoidosis: this patient presented with multiple plaques with raised margins
may be affected. It presents particularly in people in their third and fourth on the neck. From the collection of the late N.P. Smith, MD, the Institute of
decades and shows a female predominance.11 In the USA, sarcoidosis is com- Dermatology, London, UK.
mon among blacks and there is a similar tendency in the UK (Figs 9.1, 9.2).
An epidemiological study of sarcoidosis in the Detroit, Michigan, area found
that African-Americans living there had a 3.8 times greater risk of developing children and occurring mainly during teenage years presents with a multisys-
the disease compared with Caucasians.12 The disease is rare in Asians.13 First- temic disease similar to that seen in adults. Younger children under the age of
and second-degree relatives of patients with sarcoidosis seem to have a sig- 4 present with a cutaneous rash, arthritis, and uveitis.18 Infantile sarcoidosis
nificant risk of developing the disease compared to the normal population.14 should not be confused with Blau's syndrome. This disease is inherited in an
The disease is rare in children, presents mainly in teenagers and although the autosomal dominant fashion and is characterized by sarcoidal granulomata
manifestations are usually similar to those seen in adults, infants may present in the skin, uveal tract and joints but with no pulmonary involvement.19,20
with symptoms simulating juvenile rheumatoid arthritis (Fig. 9.3).15–17 Two Despite the similarities between both diseases, no genetic linkage has been
forms of sarcoidosis have been identified in children. A variant affecting older identified.
282 Granulomatous, necrobiotic and perforating dermatoses
form of sarcoidosis is associated with a good prognosis, with most patients

experiencing resolution within 6 months of onset of symptoms.25–27 In one
study, however, 16% of patients who presented with erythema nodosum
developed chronic disease.26
A not uncommon mode of presentation is the development of a wide-
spread, usually asymptomatic, maculopapular eruption. Individual lesions
are erythematous or violaceous, 3–6 mm in diameter, and most commonly
seen on the face (particularly in a periorbital distribution), the trunk, the
extensor aspects of the extremities, and the neck (Figs 9.4, 9.5). In this
variant the patient may also develop acute lymphadenopathy and uveitis, and
a chest X-ray examination can reveal features of early respiratory involve-
ment. Spontaneous resolution sometimes occurs. Occasionally, micropapular
lesions are seen, particularly on the face and limbs (Fig. 9.6). Rarely patients
develop sheets of pinhead-sized lichenoid papules on the trunk and limbs.
The onset is abrupt and lesions may appear in crops. Some patients develop
nodules and plaques, which may occur anywhere on the body, but most
often affect the face, extremities, buttocks, and shoulders (Figs 9.7–9.11).
Annular or serpiginous lesions are also encountered and sometimes there is a
prominent telangiectatic component (angiolupoid sarcoid) (Figs 9.12, 9.13).10
Fig. 9.2 Rarely, epidermal changes result in a psoriasiform or even ichthyosiform
Sarcoidosis: papules are present on both upper and lower lips. From the collection
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 9.4
Fig. 9.3 Sarcoidosis: widespread erythematous plaques on the upper arm, some with
Sarcoidosis: the condition
an annular appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital,
is rare in children.
London, UK.
There are widespread
micropapules on this
child’s face. By courtesy
of C.T.C. Kennedy, MD,
Bristol Royal Infirmary,
Bristol, UK.
Rarely, sarcoidosis presents in monozygotic twins.21 Coexistence with

common variable immune deficiency is also a rare occurrence.22
Cutaneous lesions occur in 20–35% of patients with systemic sarcoido-
sis and may be classified into non-specific (erythema nodosum) and spe-
cific (granulomatous) subtypes.10 Cutaneous sarcoidal granulomata appear
to be associated with a poorer prognosis and an increased incidence of pul-
monary fibrosis and uveitis. Chronic facial lesions have been shown to be
more commonly associated with involvement of the lungs, sinuses, and
eyes.23 Erythema nodosum occurs quite commonly in sarcoidosis, reported
incidences varying from 11% to 31%.24 There is a significant female pre-
dominance (3:1). Interestingly, erythema nodosum appears to be relatively
uncommon in both African-Americans and Caucasians in the USA. It pres-
ents as erythematous, tender, subcutaneous nodules, usually on the anterior
tibial regions. Erythema nodosum may be associated with pyrexia, polyarth- Fig. 9.5
ralgia (wrists, knees, and ankles), a very high erythrocyte sedimentation rate Sarcoidosis: characteristic mauve plaque on the malar area with an infiltrative
(ESR) and bilateral hilar lymphadenopathy (Lofgren's syndrome). This acute appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
Sarcoidosis 283
Fig. 9.6
Sarcoidosis: micropapular variant. Note the tiny lichenoid papules. By courtesy of Fig. 9.8
the Institute of Dermatology, London, UK. Sarcoidosis: erythematous
plaque adjacent to the
eye. From the collection
Fig. 9.7
Sarcoidosis: there is extensive facial involvement, a commonly affected site. From
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
appearance.28 An exceptional case mimicking lipodermatosclerosis has been

described.29 Chronic skin lesions are associated with pulmonary fibrosis, ocu-
lar, and bone involvement.
Most characteristic of sarcoidosis, however, is lupus pernio. This chronic Fig. 9.9
Sarcoidosis: the
violaceous plaque most often affects the nose, cheek, and ears, but lesions
extremities are commonly
also sometimes affect the fingers and knees (Fig. 9.14). It is a particularly dis-
affected. From the
figuring variant and resolution is especially complicated by marked scarring. collection of the late N.P.
Lupus pernio is often associated with lesions in the upper respiratory tract Smith, MD, the Institute of
and can be followed by nasal obstruction and septal perforation. Patients also Dermatology, London, UK.
have severe pulmonary fibrosis, bone cysts, and ocular lesions. This variant
has an insidious onset and is associated with a prolonged course and poor
prognosis.15 manifestation of the disease. Sarcoidosis has also been documented present-
Patients with sarcoidosis not uncommonly develop lesions in scar tis- ing in a tattoo in association with interferon-alpha (IFN-α) treatment for
sue30,31 and also in relation to trauma at the sites of desensitizing injections, chronic hepatitis C.40 Interestingly, sarcoidosis has also been reported rarely
tattoos, venipuncture, surgery, laser, cosmetic fillers, and BCG (Fig. 9.15).32–37 in patients receiving interferon and ribavirin for chronic hepatitis C,41,42 and
A single case attributed to copper-containing earrings has been described.38 in rare patients on interferon-alpha therapy for melanoma.43,44 Sarcoidosis in
Sarcoidal granulomata in association with foreign bodies do not necessarily patients with chronic hepatitis C may present concomitantly with the disease
imply a diagnosis of sarcoidosis. However, a small number of patients with and unrelated to medication, or more often triggered by treatment, mainly
sarcoidal granulomata in association with silica and tattoo pigment may have ribavirin and interferon-alpha.45
systemic sarcoidosis or the latter may develop subsequently.39 Awareness of Hypopigmented lesions may be seen in black patients.46 Unusual cuta-
this problem is important as such cutaneous granulomata may be the first neous manifestations include subcutaneous nodules, ichthyosiform lesions,
Fig. 9.10
Sarcoidosis: these grouped nodules are present on sun-damaged skin of the upper
chest. By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.12
Sarcoidosis: annular
lesions on the ankle. By
Fig. 9.11
Sarcoidosis: small nodules on the anterior aspect of the neck. By courtesy of R.A.
Marsden, MD, St George’s Hospital, London, UK.
erythroderma, scarring and nonscarring alopecia, lymphedema, nail dystro-

Fig. 9.13
phy in the absence of underlying bone changes, verrucous lesions, generalized
Sarcoidosis: close-up view of an annular lesion. Note the beaded appearance.
atrophy, leonine facies, palmar erythema, and leg ulcers with or without gran- By courtesy of the Institute of Dermatology, London, UK.
ulomatous vasculitis.47–61 Lesions of scarring alopecia may clinically mimic
discoid lupus erythematosus.62 Subcutaneous nodules are rare and present as
persistent, freely mobile, often painful lesions measuring 5–15 mm in diam- • Stage III: pulmonary infiltrates, but no lymphadenopathy,
eter. It has been suggested that subcutaneous lesions are more often associ- • Stage IV: irreversible fibrosis and bullae, cysts, emphysema.
ated with systemic disease.63 In a further study the subcutaneous involvement Stage I disease is frequently associated with spontaneous resolution; pro-
occurred at the beginning of the disease and the associated systemic disease gression to stage II disease is uncommon. Severe pulmonary involvement as
was not severe.64 Oral and genital involvement is rare but disease restricted to seen in stage III patients correlates with deep chronic plaque lesions and lupus
the vulva has been documented.65–67 Sarcoidosis has also been described pre- pernio. Patients have interstitial fibrosis and eventual cor pulmonale, which
senting as a testicular mass.68 may prove fatal.
Ninety percent of patients with sarcoidosis have pulmonary involvement.27 Systemic vasculitis involving small- to large-caliber vessels has been found
Bilateral hilar lymphadenopathy is the commonest intrathoracic manifesta- in some adults and children with sarcoidosis.69 This manifestation tends to be
tion of sarcoidosis and together with pulmonary involvement forms the most more common in African-American and Asian patients.69
frequent lesion. Intrathoracic manifestations in sarcoidosis are classified into Ocular lesions develop in about 20% of patients with sarcoidosis. Acute
five subgroups: 6,10 anterior uveitis is the most common manifestation; it is frequently bilateral
• Stage 0: normal chest X-ray, and shows a predilection for females. It correlates with a benign outcome and
• Stage I: bilateral hilar and/or paratracheal lymphadenopathy with no erythema nodosum. Chronic uveitis also affects the anterior chamber and if
pulmonary involvement, untreated may progress to glaucoma and blindness. Other lesions include
• Stage II: lymphadenopathy with pulmonary infiltrates, retinal vein perivasculitis, disc edema, and neovascularization. Conjunctival
Sarcoidosis 285
Peripheral lymphadenopathy develops in about 30% of patients. However,

histological examination of peripheral lymph nodes will reveal granulomata
in about 75% of patients with sarcoidosis. Although splenomegaly is only
present in 10–25% of patients, granulomata are present in about 50%
of cases. Splenic disease is usually asymptomatic, but patients may have
abdominal pain, hypersplenism and, very rarely, splenic rupture. Splenic
disease correlates positively with a high frequency of intrathoracic sarcoido-
sis. Liver function test abnormalities are quite common and about 20% of
patients have hepatomegaly; 60% of patients have hepatic granulomata on
histological examination.
Cardiac lesions are uncommon, but are of particular importance due to
the associated mortality.6 In a recent autopsy series, 50% of all deaths were
due to cardiac disease.72 This same study found that the clinician often does
not appreciate the presence of cardiac involvement – the antemortem diag-
nosis of cardiac lesions was made in only 29% of patients.72 Granulomata
may occur at any site, but appear to show a predilection for the conduction
system. Clinical manifestations include ventricular tachycardia, complete
heart block, congestive cardiac failure, pericardial effusion, and myocardial
infarction. Sarcoidal granulomata may affect small and large blood vessels, in
particular the pulmonary vasculature.
Fig. 9.14 Muscle involvement is usually asymptomatic. Histological examination of
Sarcoidosis: lupus pernio.
random muscle biopsies reveals granulomata in as many as 50% of patients.
The nose shows typical
Rare features include asymptomatic palpable nodules and a polymyositis-like
scaly violaceous swelling.
By courtesy of the syndrome.
Institute of Dermatology, Although a rare complication, patients with sarcoidosis appear to be more
London, UK. prone to develop cryptococcosis than other infections.73
Radiologically demonstrable bone lesions occur in about 15% of
patients. Early lesions consist of osteoporosis, cortical thinning, and mottled
rarefaction. Established lesions are cystic and are sometimes associated
with pathological fractures. The hands and feet are predominantly affected
(Fig. 9.16). Destruction of the nasal bones can result from direct infiltration
in patients with lupus pernio.
Hypercalcemia and, particularly, hypercalcuria are important complica-
tions of sarcoidosis. This is possibly due to increased intestinal absorption of
calcium and abnormal production of 1,25-dihydroxyvitamin D.74 It is more
often transitory, but in a small proportion of patients it is persistent and
sometimes complicated by the development of renal failure due to nephrocal-
cinosis. Granulomata are found on histological examination of the kidney in
up to 40% of patients.
Laboratory investigations reveal a wide variety of abnormalities of the
immune system (see below). Patients may demonstrate elevated levels of
serum angiotensin-converting enzyme (ACE). Unfortunately, this finding is
not specific for sarcoidosis, increased values also being found in patients with
diabetes mellitus, alcoholic liver disease, and leprosy. It is sometimes of value
Fig. 9.15
Sarcoidosis: tattoo
reaction. There are
multiple dome-shaped
nodules. By courtesy
of the Institute of
granulomata may be present in up to 30% of patients; therefore biopsy can

be a useful and relatively safe method of establishing the diagnosis. The lacri-
mal gland is also sometimes affected.
Neurological involvement occurs in 5–15% of patients with systemic sar-
coidosis. Clinical manifestations include facial nerve palsy, Guillain-Barré
syndrome, optic nerve disease, meningitis, seizure, and encephalopathy.6,70,71
In one study, neurosarcoidosis was the presenting symptom in 31% of
patients.70 The combination of uveitis, facial nerve palsy, fever, and swelling
of the parotid gland is known as uveoparotid fever (Heerfordt's syndrome).
This condition is often associated with central nervous system involvement. Fig. 9.16
Hypothalamic and pituitary lesions are rare and may manifest as diabetes Sarcoidosis: there is marked swelling of the distal interphalangeal joints. By courtesy
insipidus or panhypopituitarism. of R.A. Marsden, MD, St George’s Hospital, London, UK.
in monitoring the level of disease activity in patients known to have sarcoido- example, HLA-A1 and HLA-B8 are associated with arthritis, HLA-A1 is
sis. Patients may also display increased levels of serum and urinary lysozyme, also associated with uveitis, and HLA-B13 may be associated with a chronic
serum beta-2-microglobulin, and collagenase. refractory variant.10 Patients with HLA-DR17 have a better prognosis.106 One
The Kveim test was used in the past to aid in diagnosis. A homogenate of study has shown that patients with sarcoidosis have an increased frequency of
known sarcoid tissue is injected intradermally at a marked (India ink) site, and a glutamine residue at position 69 of the B1 chain of the HLA-DPB molecule
4–6 weeks later the injection site is biopsied. A positive result depends upon compared with a control population.107 This is particularly interesting since
the detection of an epithelioid cell granuloma. False-positive reactions may a similar polymorphism has been documented in patients with chronic beryl-
occur with other diseases including Crohn's disease, infection (mycobacterial, lium disease, a disorder also characterized by granulomata and which shares
fungal), berylliosis, silicosis, asbestosis, and lymphoma. The stimulatory some pathological features in common with sarcoidosis.
‘sarcoidal’ antigen of the Kveim reagent has not been identified.75 The Kveim Immunological investigations in patients with sarcoidosis have produced
test is almost never used nowadays because of difficulties in obtaining the an immense wealth of data, which reveal that there is clearly an associated
homogenate of sarcoid tissue. state of abnormal immunological hyperactivity. There are alterations of both
Although sarcoidosis is associated with a high morbidity, the mortality rate cell-mediated and humoral immunity. Despite great efforts to clarify the
is low, being of the order of 3–6%. Causes of death include cardiac involve- immunobiology of sarcoidosis, particularly with regard to the precise anti-
ment and respiratory or renal failure. The prognosis is better in females and gens that may facilitate the disease, we still do not have a clear understand-
appears to be improved in those with a positive purified protein derivative ing of the disease process. Sarcoidosis, at least in part, appears to be due
(PPD) skin test and normal serum immunoglobulin levels. The severity of dis- to a hyperactive T-helper cell proliferation with lymphokine production.108
ease is greater in blacks and Asians compared with Caucasians.76 Of interest, Increased T-helper (Th1, Th2) cells are present in the alveolar lung paren-
despite the very marked upset in immunological phenomena, patients do not chyma. Several studies have demonstrated selective activation of certain oli-
seem to have an associated greatly increased risk of opportunistic infections goclonal T-cell subsets.109–112 In one study, there was a correlation between
except as a consequence of therapy (e.g., corticosteroids). the particular oligoclonal T-cell subsets and disease activity.109 Th1 lympho-
The association between sarcoidosis and a number of systemic diseases cytes (T cells expressing interleukin (IL)-2 and IFN-γ) preferentially accumu-
is probably coincidental. Sarcoidosis has been documented in association late in pulmonary parenchyma and the alveolar space compared with Th2
with vitiligo, pernicious anemia, autoimmune thyroiditis, Graves' disease, lymphocytes (T cells expressing IL-4 and IL-5).113 Compared with T-cells in
chronic hepatitis, Addison's disease, Sjögren's syndrome, diabetes mellitus peripheral blood, T cells obtained by bronchoalveolar lavage show greater
and ulcerative colitis, lymphoma, human immunodeficiency virus (HIV) expression of IFN-γ and tumor necrosis factor alpha (TNF-α).106 Of interest,
infection, and primary biliary chirrosis.77–88 Interestingly, patients with patients with HLA-DR17 show a muted cytokine response, a finding that is
acquired immunodeficiency syndrome (AIDS) usually develop manifesta- perhaps related to the better prognosis observed in this subset of patients.107
tions of sarcoidosis after antiretroviral therapy is started. This phenome- T lymphocytes, in turn, stimulate B cells. Abnormalities of humoral
non is the result of the immune restoration syndrome.85,89 Associations with immunity include a non-specific polyclonal hypergammaglobulinemia and
cutaneous autoimmune disease include dermatitis herpetiformis and linear circulating immune complexes in acute forms of the disease, particularly in
IgA disease.90,91 A single case of trachyonychia associated with sarcoidosis association with erythema nodosum.
has been reported.92 The paramount puzzle in unraveling the pathogenesis of sarcoidosis is
identifying the initial event(s) that lead to the disease. Despite our increas-
Pathogenesis and histological features ing knowledge of the immunobiology of sarcoidosis, we seem no closer to
The pathogenesis of sarcoidosis is poorly understood. The demonstration of answering this key question.
familial clustering suggests hereditary susceptibility to sarcoidosis in at least Histologically, sarcoidosis is characterized by a dense, noncaseating
a subset of patients.14,93 granulomatous infiltrate in the dermis (Figs. 9.17, 9.18), which sometimes
Despite intensive studies, the etiology and pathogenesis of sarcoidosis extends into the subcutaneous fat. The granulomata are discrete and strik-
remains elusive.94,95 It is likely, however, that sarcoidosis represents a reaction ingly uniform in size and shape. They are composed of epithelioid histiocytes
pattern that may develop in a predisposed patient on exposure to one or more with abundant eosinophilic cytoplasm and oval or twisted vesicular nuclei
infective agents or other antigens. often containing a small central nucleolus (Fig. 9.19). Variable numbers of
The role of mycobacteria in the pathogenesis of sarcoidosis is a controver- Langhans giant cells are present and sometimes a scattering of lymphocytes
sial topic. Attempts at detection of mycobacterial DNA by polymerase chain is seen at the peripheral margin of the granuloma (Fig. 9.20). Discrete small
reaction (PCR) have produced conflicting results. While some authors have
failed to detect mycobacterial DNA, others have identified DNA of various
strains of tuberculous and nontuberculous mycobacteria.96–100 In one study,
although amplified mycobacterial DNA was detected by PCR in 38% of sar-
coidosis patients, mycobacterial DNA was also detected in tissue in 44% of
control patients.101 Furthermore, most studies published in the literature fail
to report more than 6% positivity for Mycobacterium tuberculosis DNA in
patients with sarcoidosis.102 In another interesting study, cell wall deficient
acid-fast bacteria (L forms) were cultured from the blood of 19 of 20 patients
with sarcoidosis but not from controls.103 In summary, these mixed results
between laboratories have not clarified the role of mycobacteria in the patho-
genesis of sarcoidosis. It seems, however, that mycobacteria may be of etio-
logical importance in at least a subset of cases.
Propionibacterium acnes DNA has also been identified in tissues of
patients with sarcoidosis, including involved lymph nodes.104,105 The signifi-
cance of this finding remains uncertain. Human herpesvirus 8 DNA has not
been demonstrated in tissues of patients with sarcoidosis.105
The occasional association with known autoimmune diseases, such as pro-
gressive systemic sclerosis and systemic lupus erythematosus (SLE), has inevi-
tably led to the proposal of an autoimmune pathogenesis. Although many
familial cases have been reported in the literature, no consistent pattern of Fig. 9.17
inheritance has emerged. The results of human leukocyte antigen (HLA) Sarcoidosis: the dermis is replaced by uniform circumscribed nests of non-
typing have shown associations with particular features of the disease; for caseating granulomata.
Sarcoidosis 287
central foci of fibrinoid necrosis are sometimes present but caseation necrosis
is rare (Fig. 9.21).114,115 Transepidermal elimination is sometimes seen.116
The epidermis is usually normal although occasional cases display acantho-
sis and sometimes the granulomata are focally lichenoid. A predominantly
lichenoid pattern may exceptionally be seen.117 Exceptional cases of sarcoido-
sis may display histologic findings that focally overlap with granuloma annu-
lare, palisading neutrophilic and granulomatous dermatitis, and interstitial
granulomatous dermatitis.118 Further histologic findings described include
elastophagocytosis, perineural granulomas resembling leprosy, mucin deposi-
tion, and an infiltrate rich in plasma cells.115
In some cutaneous lesions, inclusion bodies are present, although much
less frequently than in lymph nodes. The Schaumann body, a basophilic,
laminated, rounded, conchoidal structure composed of calcium carbonate, cal-
cium oxalate, phosphate, iron, and dolomite, is not specific for sarcoidosis and
is seen in a number of other granulomatous conditions including tuberculosis
and berylliosis (Fig. 9.22).119–121 The asteroid body is a small intracytoplasmic
eosinophilic star-shaped structure; it is not specific for sarcoidosis, being seen
also, for example, in tuberculosis, tuberculoid leprosy, berylliosis, and atypi-
cal facial necrobiosis. It is also commonly found in necrobiotic xanthogran-
Fig. 9.18 uloma.122 Initial studies suggested that the asteroid body was composed of
Sarcoidosis: note the paucity of lymphocytes and absence of necrosis.
collagen but more recent reports, using immunohistochemistry, suggest that
Fig. 9.19
Sarcoidosis: the epithelioid cells are composed of pink cytoplasm with a central oval Fig. 9.21
or sometimes twisted vesicular nucleus containing a small basophilic nucleolus. Sarcoidosis: occasionally small foci of ‘fibrinoid’ necrosis may be seen in the center
The granuloma also contains lymphocytes and occasional fibroblasts. of the granuloma, but cellular detail is not lost.
Fig. 9.20 Fig. 9.22

Sarcoidosis: in this example the granulomatous reaction is associated with abundant Sarcoidosis: in this lymph node biopsy specimen, fragmented, laminated
foreign material. Schaumann bodies are seen. They are very rarely a feature of cutaneous sarcoidosis.
it is a product of the microtubular system.123,124 The presence of foreign mate- Other documented associations of granuloma annulare include morphea,
rial in sarcoidal granulomata does not exclude the diagnosis of sarcoidosis. In chronic hepatitis C infection, autoimmune thyroiditis, secondary hyperpara-
fact, polarizable material has been found in up to 5% of cases.125–127 thyroidism, sarcoidosis, Plummer's disease, myelodysplastic syndrome, met-
It has been shown that the gli-1 oncogene is consistently and abnormally astatic carcinoma, and a bee sting.25–33 Granuloma annulare has also been
expressed in the cells forming the granulomata not only in sarcoidosis but described after vaccination for tetanus and diphtheria, hepatitis B and tuber-
also in granuloma annulare and necrobiosis lipoidica. This observation raises culosis (BCG), and after mesotherapy.34–38 It may also develop in the scars
the possibility of trials using inhibitors of gli-1 signaling to treat this group of of herpes zoster.39–42 It is important to highlight that most patients with the
granulomatous disorders.128 condition heal after variable periods of time, and long follow-up has not
The visceral lesions are characterized by an identical histology of nonca- revealed consistent associations with any systemic diseases.43 A further study
seating granulomata, which may be accompanied by significant scarring, for has found no consistent relationship between malignant neoplasms and gran-
example in the lung, where advanced cases are characterized by interstitial uloma annulare.44 However, it has been suggested that elderly patients with
fibrosis and sometimes honeycomb lung formation. In the liver, granulomata lesions that do not have typical features of granuloma annulare but display
are most commonly found in the portal tracts or in relation to central veins. microscopic findings resembling granuloma annulare should be investigated
Splenic lesions are randomly distributed and are not usually associated with for an underlying malignancy, especially lymphoma.44
significant fibrosis. Granuloma annulare has developed during treatment with allopurinol,
amlodipine, daclizumab, and antitumor necrosis factor.45–48 Interferon-alpha
has been associated with generalized interstitial granuloma annulare.49 It is
Differential diagnosis most likely, however, that granuloma annulare-like eruptions secondary to drug
Sarcoidosis must be approached as a diagnosis of exclusion and has to be administration often represent interstitial granulomatous drug eruptions.
distinguished from the numerous conditions that may be associated with a
noncaseating granulomatous histology, including some forms of tuberculo- Localized granuloma annulare
sis, tuberculoid leprosy, berylliosis, fungal infections, Crohn's disease, and
The localized variant is the commonest type. It usually presents in the first
foreign body granulomatous reactions.129 Therefore, the use of special stains,
three decades and is associated with a female preponderance (2.25:1). Lesions
including the Ziehl-Neelsen preparation for mycobacteria and the periodic
consist of one or several papules, which may be skin-colored, red or viola-
acid-Schiff (PAS) and methenamine silver reactions for fungi, is mandatory
ceous, and are typically distributed to form an annular or arcuate lesion 1–5
before diagnosing sarcoidosis. Depending on the clinical context, culture
cm in diameter (Figs 9.23–9.27). About 50% of patients have solitary lesions.
may also be required to exclude an infective etiology. Tuberculoid leprosy
The acral sites are most commonly affected, in particular the knuckles and
is characterized by nerve involvement, a feature that is usually absent in
dorsum of the fingers. In a small proportion of patients, lesions are present
sarcoidosis.
on both the upper and lower limbs, and occasionally the trunk is affected.
Some of the granulomata seen in a variety of primary immunodeficiency
Lesions on the palms are exceptional.50 Facial involvement appears to be
syndromes closely mimic those found in sarcoidosis and histological distinc-
uncommon.51,52 In a reported case, lesions were restricted to the area involved
tion may be impossible. A study comparing granulomata in sarcoidosis to
by a Becker's nevus.53 Although lesions may be persistent, approximately 50%
those seen in primary immunodefiencies found a much lower rate of CD4+/
of patients can anticipate resolution by about 2 years from onset. However,
CD8+ cells in the former as opposed to the latter.130
recurrences are, unfortunately, quite common. Patients in which the disease
Labial and gingival involvement may be histologically mistaken for
arises earlier in life appear to have earlier resolution of lesions.54 Interestingly,
Crohn's disease and granulomatous cheilitis (Miescher). It is worth noting
on occasion lesions regress spontaneously after biopsy.55 In one case, spon-
that in rare cases oral involvement in Crohn's disease may precede systemic
taneous resolution resulted in mid-dermal elastolysis.56 Rarely, granuloma
manifestations by several years. Metastatic Crohn's disease may be difficult
annulare has been reported in families and in monozygotic twins.57 A case has
to distinguish from sarcoidosis. The former often show nonsuppurative gran-
been documented in which the lesions recurred seasonally with sun-exposed
ulomata in a diffuse pattern and surrounded by a thin cuff of lymphocytes.
areas.58 There has only been a single case report of cutaneous granuloma
Further frequent findings include the presence of numerous eosinophils and
annulare with similar lesions in an intra-abdominal location.59 In one case,
ulceration, findings not often seen in sarcoidosis.131
granuloma annulare was the first sign of adult T-cell leukemia/lymphoma and
Granulomatous lesions that have been described in exogenous ochronosis
appear to be related to sarcoidosis.132 However, similar lesions have also been
described as showing changes mimicking actinic granuloma.133
Granuloma annulare
Clinical features
Granuloma annulare is a common, usually asymptomatic, dermatosis of
unknown etiology.1,2 It may be divided into six clinical subsets:
• localized,
• generalized,
• perforating,
• subcutaneous,
• papular,
• linear.
Unusual clinical variants include pustular follicular lesions and presenta-
tion with patches.3,4 A single case presenting as contact dermatitis has been
reported.5 Granuloma annulare (often with widespread disseminated lesions)
has been described in patients with HIV infection and sometimes may be the
presenting sign.6–18 Granuloma annulare, mainly the generalized variant (see Fig. 9.23
below), has also been reported in association with both Hodgkin's and non- Localized granuloma annulare: a typical annular lesion over the knuckle. Stretching
Hodgkin's lymphoma.19–22 Exceptionally, anterior uveitis and concomitant of the skin reveals a translucent beaded margin. By courtesy of R.A. Marsden, MD,
skin lesions have been described.23,24 St George’s Hospital, London, UK.
Granuloma annulare 289
Fig. 9.24 Fig. 9.27

Localized granuloma annulare: in this patient multiple lesions are present on the feet. Localized granuloma annulare: in this patient there is a large plaque on the ankle
From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. with a hint of central clearing. By courtesy of the Institute of Dermatology,
London, UK.
in a further patient it was associated with angioimmunoblastic T-cell lym-

phoma.60,61 Very rarely, acral, localized granuloma annulare may present as
an acute and painful eruption.62
Generalized granuloma annulare

Generalized lesions occur in approximately 15% of patients with granuloma
annulare.2,63 As with the localized form, there is an increased incidence in
females; however, the median age differs the majority of cases occurring in
patients in the fourth to seventh decades, with the rest appearing during the
first decade. Patients with generalized granuloma annulare have an increased
incidence of HLA-Bw35.64 Generalized granuloma annulare is defined as
lesions occurring on at least the trunk and either upper or lower extremities,
or both.2 Most lesions are papules, which may be distributed in an annular
pattern, but maculopapules and nodules also occur. They vary in hue from
flesh-colored or red, to tan, brown or yellow. Numbers vary from several
dozen to hundreds (Figs 9.28 to 9.30). A single patient has been documented
with generalized disease accompanied by marked swelling of the hands and
Fig. 9.25 another patient developed the disease following erythema multiforme.65,66
Localized granuloma annulare: this arm lesion shows a characteristic beaded margin. Lesions may be asymptomatic or pruritic.2 As with the localized form, the
From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 9.26 Fig. 9.28

Localized granuloma annulare: close-up view of annular lesions. By courtesy of the Generalized granuloma annulare: innumerable papules are present on this patient’s
Institute of Dermatology, London, UK. arms. By courtesy of J. Williams, MD, Brigham and Women’s Hospital, Boston, USA.
Fig. 9.29 Fig. 9.31

Generalized granuloma annulare: there are widespread papules and plaques. Perforating granuloma annulare: the extremities are most often affected. Necrotic
By courtesy of the Institute of Dermatology, London, UK. debris and crust can be seen. From the collection of the late N.P. Smith, MD, the
the extremities, often the dorsum of the hands (Fig. 9.31). Presentation of
lesions on the ears has exceptionally been described, as has a generalized vari-
ant.80–82 It may affect both children and adults, and both localized and gener-
alized forms exist. Spontaneous resolution sometimes occurs within months
or years of onset. An exceptional case of perforating granuloma annulare
which developed following tattooing has been reported.83
Subcutaneous (deep) granuloma annulare

The subcutaneous variant is synonymous with the pseudorheumatoid nod-
ule of childhood and deep granuloma annulare.84–87 Lesions may present
de novo or arise in association with typical cutaneous papules. It occurs
in childhood, often affecting the underlying periosteum and involving pre-
dominantly the lower legs (particularly the tibia), feet, buttocks, hands,
and head.88 Lesions may also present on the penis or eyelid.89,90 An excep-
tional case of numerous lesions limited to the scalp of a child which
regressed spontaneously has been reported.91 A further patient presented
Fig. 9.30 with a periorbital subperiostal lesion and in another patient the lesion was
Generalized granuloma
congenital.92,93 In one study of 47 patients, the mean age was 4.3 years.88
annulare: in this patient
In some instances, there is a past history of trauma. By definition, such
numerous annular lesions
are present. From the children do not have rheumatoid arthritis or rheumatic fever. The lesion
collection of the late usually regresses after several years. However, recurrences appear in 19%
N.P. Smith, MD, the of patients.88
London, UK. Papular granuloma annulare
Papular granuloma annulare presents as flesh-colored or hypopigmented,
disease is persistent, but some patients experience resolution within 4 years. 1–3-mm diameter papules on the dorsal aspect of the hands, usually in male
Anetoderma has been exceptionally reported as a complication of general- children. Occasional lesions may be umbilicated or generalized (Figs 9.32,
ized granuloma annulare.67 A remarkable association with giant cell arteri- 9.33).94
tis, gastrointestinal stromal tumor, and other internal malignancies including
ovarian and gastric cancer has been reported.68–70 Tuberculous lymphaden- Linear granuloma annulare
its was an association in one case.71 In two instances, the condition was the The linear variant is very rare and may have a bilateral distribution.95,96
initial manifestation of chronic myelomonocytic leukemia.72 An association Rarely, it may follow Blaschko's lines.97 This variant overlaps and may in
with lymphoma, including Hodgkin's disease, has also been described.73 some cases be the same as the condition described as interstitial granuloma-
A patient with hepatitis B developed generalized granuloma annulare, and viral tous dermatitis.
DNA was detected in the skin lesions by PCR.74 A further case presented in a
photosensitive distribution and healed with scarring and milia formation.75 Pathogenesis and histological features
The cause of granuloma annulare is unknown. The original concept that it
Perforating granuloma annulare represented a tuberculid has long since been discounted. Although it has been
Perforating granuloma annulare is distinguished by the presence of tran- reported at the site of previous herpes zoster infection and verruca vulgaris,
sepidermal elimination of necrobiotic collagen.10,18,76–79 Clinically, the lesion it is unlikely that an infectious pathogenesis exists. Borrelia has been dem-
presents as a group of papules with an umbilicated crust usually located on onstrated by focus-floating microscopy in a number of biopsies of patients
Fig. 9.32 Fig. 9.34

Papular granuloma annulare: widespread papules are present on this patient’s back Granuloma annulare: view through the edge of a necrobiotic focus. In the center a
and shoulders. By courtesy of the Institute of Dermatology, London, UK. small blood vessel shows fibrinoid necrosis with occlusion. This is an uncommon
finding.
• the predominance of T-helper inducer cells in the infiltrate,

• the histopathological resemblance of the infiltrate to that of conditions of
known delayed hypersensitivity pathogenesis, including sarcoidosis and
tuberculosis.104
It has been suggested that Th1 lymphocytes expressing interferon-gamma
induce a delayed hypersensitivity reaction leading to macrophages becoming
aggressive effector cells that express tumor necrosis factor-alpha and matrix
metalloproteinases.105 If tumor necrosis factor alpha plays a role in the induc-
tion of the disease, then agents that block this cytokine may be useful in
treating the condition. Although some patients respond to these agents other
do not and the reason for this is not clear. Monozygotic twins with general-
ized granuloma annulare and the 8.1 ancestral haplotype, a genotype that
leads to increased production of tumor necrosis alpha, have responded well
to adalimumab.106
Patients with granuloma annulare may have raised serum migration
inhibition factor activity.87 Defective neutrophil migration has also been
reported.107,108 Other proposed pathogenetic mechanisms include collagen
damage by macrophage lysosomal hydrolytic enzymes as the initial event,
Fig. 9.33 or a primary disorder of collagen leading to an allergic or nonallergic tissue
Papular granuloma annulare: numerous small, scaly papules are present. reaction. The increased incidences of diabetes mellitus and HLA-B8 may
By courtesy of the Institute of Dermatology, London, UK. also be of pathogenetic significance (compare with necrobiosis lipoidica).109
In a study of a group of pediatric patients with multiple lesions of granu-
loma annulare it was found that they had significantly lower serum insulin
with granuloma annulare raising the possibility of a pathogenetic role for values than the control group and showed mild impairment of glucose tol-
the organism in some cases of the disease.98 However, a study based on PCR erance.110 However, these children, often had a family history of diabetes
found no association between granuloma annulare and Borrelia infection.99 mellitus.
There is a wide variety of currently possible pathogenetic mechanisms, most Although there are reports of generalized granuloma being associated with
of which have some merit, but none of which satisfactorily clarifies the pre- sunlight, this appears to be of doubtful significance.2
cise mechanism by which the lesions of granuloma annulare develop.100 It has been shown that the glioma-associated oncogene homologue gli-1,
Particularly popular are an immune complex vasculitic process and a cell- a member of the vertebrate zinc finger transcription factor genes of the gli
mediated delayed hypersensitivity reaction. Evidence in favor of the former superfamily is highly expressed in a number of granulomatous disorders
has been the detection, by direct immunofluorescence, of immunoreactants including granuloma annulare.111 The relevance of this in the pathogene-
(IgM and complement) in blood vessel walls in some patients.100 Elevated lev- sis of granuloma annulare is not clear but it raises the possibility of using
els of circulating immune complexes have also been recorded.101 The histology inhibitors of gli-1 signaling in the treatment of granulomatous noninfectious
may reveal features suggestive of a vasculitic process, including endothelial diseases.
swelling, vessel wall thickening (due to the deposition of PAS-positive mate- The most characteristic histological lesion seen in granuloma annulare is
rial), vascular occlusion, and necrosis (Fig. 9.34).102 All of the latter changes the palisading granuloma (Figs 9.35–9.38). This consists of a central core of
may, of course, develop as a consequence of the inflammatory process rather degenerate (necrobiotic) collagen, surrounded by an often radially arranged
than cause it. A recent study of serial sections of 38 biopsies in 35 patients infiltrate of lymphocytes, histiocytes, and fibroblasts. Elastic tissue may be
found no evidence of a vasculitic process in any of the cases.103 absent within these foci and there can be phagocytosis of elastic fibers by
In favor of a cell-mediated delayed hypersensitivity reaction are: giant cells at the periphery of the granuloma (Fig. 9.39).112 However, altered
• the finding of activated T-lymphocytes in lesions of granuloma annulare elastic fibers are not a constant finding. Solar elastosis is not a feature of
on electron microscopic examination, granuloma annulare. In some lesions the altered collagen has a somewhat
Fig. 9.37
Fig. 9.35 Localized granuloma
Localized granuloma annulare: the characteristic appearance of a well-circumscribed annulare: this lesion is
palisading granuloma consisting of a necrobiotic center surrounded by a cellular from the palm of the
infiltrate. hand, an uncommonly
affected site. There is a
sharply delineated focus
of necrobiosis in the deep
reticular dermis.
Fig. 9.36
Localized granuloma annulare: the collagen is fragmented and in part granular. Note
the peripheral palisade of histiocytes, occasional lymphocytes, and fibroblasts.
Fig. 9.38
basophilic appearance due to the presence of acid mucopolysaccharides, but Localized granuloma annulare: the necrobiosis is advanced, presenting as eosinophilic
granular debris. The histiocytic palisade is well established.
more commonly there is eosinophilia, due in part to fibrin deposition (Fig.
9.40). Heparin sulfate is an important component of the mucin in granuloma
annulare but not of other cutaneous diseases associated with mucin deposi-
tion (Fig. 9.41).113 cases when the collagen changes are inconspicuous and should, therefore,
Occasionally, sparse karyorrhectic debris is present in the center of the encourage examination of additional sections to detect more typical features
lesion and sometimes the necrobiotic foci contain lipid droplets. More (Fig. 9.45).
often, however, the collagenous degeneration is not organized into a nod- An almost inevitable feature of granuloma annulare is the presence of a
ular pattern, but affects isolated fibers in a random pattern, an appear- perivascular chronic inflammatory cell infiltrate, both within the lesion and
ance often best appreciated on low-power examination (Fig. 9.42).114 In in the adjacent tissue. Well-formed sarcoidal granulomata with associated
this so-called diffuse or interstitial form of granuloma annulare, affected giant cells are seen in some cases. Significant numbers of eosinophils may be
fibers, which are swollen and intensely eosinophilic, alternate with appar- encountered.115 In one study, eosinophils were present in 66% of biopsies, of
ently normal fibers to give a rather disorganized appearance (Figs. 9.43, which 14% showed more than 10 eosinophils per high-power field.115 Plasma
9.44). Necrobiosis is minimal or absent. Characteristically, the collagen cells are rare and this is useful in the differential diagnosis with necrobiosis
fibers are separated by mucin, which stains positively with Alcian blue at lipoidica (see below). Neutrophils are a rare finding and when present, par-
pH 2.5. Histiocytes are often seen infiltrating around and between affected ticularly in association with changes of vasculitis, it is likely that there is an
fibers, and this feature may be a helpful clue to the diagnosis in early association with systemic disease.116
Fig. 9.39 Fig. 9.42

Localized granuloma annulare: there is loss of elastic tissue within the granuloma. Diffuse granuloma annulare: the collagen bundles are arranged haphazardly. Note
Elastic-van Gieson. the circumferential lymphocytic infiltrate.
Fig. 9.40 Fig. 9.43

Localized granuloma annulare: the red-staining material in the center of the Diffuse granuloma annulare: individual fibers are swollen and intensely eosinophilic.
granuloma is fibrin. Martius scarlet blue. The apparent separation of the fibers is due to increased mucin.
Fig. 9.41 Fig. 9.44

Localized granuloma annulare: in this example there is abundant mucin in the Diffuse granuloma annulare: higher-power view showing the dense interstitial
center of the necrobiotic focus. Alcian blue stain. histiocytic infiltrate.
Fig. 9.45 Fig. 9.47

Diffuse granuloma annulare: high-power view. Perforating granuloma annulare: close-up view showing the dermal perforation and
transepidermal elimination of collagenous debris.
Fig. 9.46
Perforating granuloma annulare: scanning view showing widespread typical Fig. 9.48
granuloma annulare (in the upper-right quadrant degenerate collagen is undergoing Subcutaneous granuloma annulare: within the subcutaneous fat and involving the
transepidermal elimination). fascia is a massive necrobiotic nodule.
Although the relationship with Borrelia infection is debatable, it has been

suggested that formation of pseudorosettes in granuloma annulare may sug-
gest infection with the organism.117
In perforating granuloma annulare the necrobiotic debris is present in
close proximity to the epidermis and may be seen to be engulfed by the latter
to form a perforating channel by which the necrotic material is extruded to
the surface (Figs. 9.46, 9.47). If serial sections are performed, the perforation
is often shown to occur through a hair follicle.
The subcutaneous lesions are much larger than the superficial ones
(Figs. 9.48, 9.49) and are frequently composed of multiple nodules. There is
usually massive necrobiosis and abundant mucin; on occasions, lipid droplets
are evident. Mucin, however, may be minimal or not apparent and if fibrin
deposition is present, distinction from rheumatoid nodule is impossible.
A dense rim of lymphocytes, histiocytes, and fibroblasts surrounds the necro-
biotic center. Multinucleate giant cells are common and eosinophils are often
present. The latter appear to be more common in this variant than in ordinary
granuloma annulare. Fibrosis of the surrounding tissue may be marked. In
up to 25% of cases of subcutaneous granuloma annulare, changes of classic
granuloma annulare may be seen in the dermis.118 Fig. 9.49
Papular and linear variants show histological features similar to those Subcutaneous granuloma annulare: note the intensely eosinophilic necrobiosis and
described for typical granuloma annulare. surrounding fibrosis.
Granuloma annulare must be distinguished from necrobiosis lipoidica, Necrobiosis lipoidica
rheumatoid nodule, actinic granuloma, and granuloma multiforme. Points of
distinction are summarized in Table 9.1. Clinical features
Granuloma annulare-like lesions with the added features of vasculitis and Necrobiosis lipoidica is a disease of unknown etiology which shows a strong
a significant component of acute inflammatory cells may be encountered in association with diabetes mellitus.1–6 Although the affiliation is likely to
the setting of systemic disease.116,119 This pattern of disease is discussed in have pathogenic implications, the precise mechanism by which the lesions
detail in the section on palisaded neutrophilic and granulomatous dermatitis of necrobiosis lipoidica develop is, nevertheless, unknown and the nature
and related disorders. of the relationship between the two diseases is unclear. Therefore, although
Granuloma annulare-like drug eruptions have been reported. The presence the diagnosis of diabetes is most often established before the onset of the
of associated interface changes favors a drug eruption.10,120 skin lesions, on occasion, typical plaques may precede the apparent onset
Very rarely, scleromyxedema may focally mimic interstitial granuloma of diabetes mellitus by several years. The course of the cutaneous disease
annulare histologically.121 However, the changes simulating granuloma annu- does not appear to be related to the hyperglycemia, and treatment of diabetes
lare are focal, and elsewhere in the biopsy there are more typical features of does not affect the outcome of the cutaneous lesions. In one study, proteinu-
scleromyxedema including fibrosis and increase in fibroblasts. ria, retinopathy, and smoking were more common in patients with necro-
Occasionally, infection by Mycobacterium marinum may mimic intersti- biosis lipoidica compared with patients with diabetes but no skin disease.7
tial granuloma annulare. The microscopic features may be so similar that the Interestingly, however, only a minority of patients with necrobiosis lipoidica
diagnosis can only be made by special stains and culture.122 has diabetes mellitus. It has been shown that 11% of patients with necrobio-
Although epithelioid sarcoma, with its associated geographic necrosis, sis lipoidica have diabetes mellitus and a further 11% develop the disease or
may bear a superficial resemblance at low-power examination to granuloma altered glucose tolerance on follow-up.8
annulare, the degree of nuclear atypia and pleomorphism in the former con- Necrobiosis lipoidica may develop in both juvenile (type I) and maturity-onset
dition should afford their distinction in the majority of cases. In addition, (type II) diabetes. Interestingly, the condition improves in diabetic patients
epithelioid sarcoma often shows perineural tumor infiltration. It should be after pancreatic transplant.9 Necrobiosis lipoidica has been documented in
noted, however, that mitotic activity may be encountered in granuloma annu- patients with endocrine disorders other than diabetes such as hypo- and
lare.123 In difficult cases, keratin, epithelial membrane and, in up to 60% of hyperthyroidism, and also in association with inflammatory bowel disease
cases, CD34 antigen immunoreactivity in epithelioid sarcoma should assist in and vasculitis.10 One nondiabetic patient with necrobiosis lipoidica and
this differential diagnosis. ataxia telangiectasia has been reported.11 Exceptionally, necrobiosis lipoidica
Rare cases of mycosis fungoides may be associated with a tissue reac- and granuloma annulare have presented simultaneously.12,13 The disease has
tion resembling granuloma annulare.124,125 The presence of interstitial also been documented in association with sarcoidosis.14,15
lymphocytes with nuclear atypia and epidermotropism, a feature not seen Necrobiosis lipoidica shows a marked female preponderance (3.3:1) and,
in granuloma annulare, should resolve this differential diagnosis. However, although a wide age range may be affected, patients present most often in the
in difficult cases, immunophenotyping and gene rearrangement studies may fourth decade (those associated with diabetes mellitus) or fifth decade (those
be required. not associated with diabetes mellitus). The condition is rare in childhood
Table 9.1
Differential diagnosis of palisading granulomata and variants
Granuloma Subcutaneous Necrobiosis Rheumatoid Actinic Granuloma

annulare (GA) GA Perforating GA lipoidica (NL) Atypical NL nodule granuloma multiforme
Epidermis Normal Normal Transepidermal Normal or Normal Normal Normal or Normal
elimination atrophic or atrophic
acanthotic
Location of Superficial Deep dermis Superficial Deep dermis Upper and Deep dermis Upper and Upper and mid
lesion dermis and subcutis dermis and subcutis mid dermis and subcutis mid dermis dermis
Necrobiosis Circumscribed Massive sharp Circumscribed Diffuse and Rarely Massive Absent Focal
or ill defined border marked present sharp margin
Mucin Common Abundant Common Variable Absent Common Absent Present
Lipid Occasional Variable Variable Common Absent Variable Absent Absent
Fibrosis Absent Marked Absent Common; may Absent Common Usually Slight
be marked absent
Loss of elastica Yes Yes Yes Yes Yes Yes Very marked Yes
Vascular Common Variable Minimal Common Absent Variable Absent Absent
thickening
Capillary Absent Common Absent Variable Absent Common Absent Absent
hyperplasia
Giant cells Relatively few Common Relatively few Common Common Relatively Abundant; Common
few contain elastica
Asteroid bodies Absent Absent Absent Absent Present Absent Not Absent
uncommon
Palisading of Common Common Common Variable Absent Common Infrequent Inconspicuous
histiocytes degree in
Reprinted from Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 3:217–230; Copyright Elsevier 1980, with permission from the American Academy of Dermatology, Inc.
and is often associated with diabetes mellitus. It also appears to be related to

underlying renal and retinal disease.16–20 Familial cases may also occur, with
or without, diabetes.21–23 A case of monozygotic twins with diabetes mellitus
type 2 and necrobiosis lipoidica has been reported.24
The characteristic lesion, sometimes referred to as a sclerodermatous
plaque, is round or oval, circumscribed, and often has a slightly elevated
rim. It is typically a few millimeters to several centimeters in diameter.
Newly acquired lesions are often red-brown in color, but with progression
the center of the lesion becomes yellowish and the peripheral border may
acquire a violaceous hue. Larger plaques are usually irregular and more
variably shaped. Scaling and telangiectasia may become evident. Ulceration
appears to be relatively frequent and has been reported in up to 13% of
patients.25–27 Perforating necrobiosis lipoidica is very rare and may be seen
very exceptionally in children.28,29 In perforating cases, the clinical appear-
ance may consist of a focal scaly depression or comedone-like lesions.
Atypical forms may also be found: patients sometimes manifest papules
and nodular lesions, and occasionally plaques resembling granuloma annu-
lare are seen. (It should be noted, however, that rarely these two conditions
appear to coexist.)12,30 Clinical presentations with papulonecrotic and nod-
uloulcerative lesions mimicking gummata or erythema induratum have been Fig. 9.51
documented, albeit exceptionally.25 The lesions may be solitary or multiple, Necrobiosis lipoidica:
often symmetrical, and show a predilection for the lower extremities, in typical lesion with an
erythematous border.
particular the pretibial area (Figs 9.50–9.53). They can also occur on the
arms, hands, fingers, abdomen, nipples, and back; rarely the face or scalp
late N.P. Smith, MD, the
is affected, in which case diabetes is seldom present.31 Generalized lesions Institute of Dermatology,
may exceptionally occur.32 London, UK.
It is doubtful whether the so-called atypical necrobiosis lipoidica of the
face and scalp represents a variant of necrobiosis lipoidica. The name was
chosen because of the coexistence of typical lesions of necrobiosis lipoid-
ica on the shins of one of the patients in the original series. However, most
patients do not present with classic lesions of necrobiosis lipoidica elsewhere
and the microscopic findings do not resemble the latter entity.33
Involvement of the penis with lesions resembling chronic balanitis has been
described.34–36 Rarely, lesions are associated with Koebner's phenomenon.37–39
Necrobiotic and silicotic granulomata developing within phlebectomy scars
have also been reported.40
The disease tends to chronicity. It is of interest that necrobiosis lipoid-
ica has been reported to be associated with cutaneous hypo- or complete
anesthesia in both diabetic and nondiabetic patients.41,42 One study found
Fig. 9.52
Necrobiosis lipoidica: lesion on shin showing atrophy and telangiectasia.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
loss of nerves within lesions and, based on this finding, the authors pos-
tulated that destruction of nerves might explain the sensory loss that is
observed in some patients.42,43 Hypohidrosis and partial alopecia have also
been reported.44
Rarely, squamous carcinoma may arise in longstanding lesions.45–49
One such case developed in association with perforating necrobiosis
lipoidica.50
Fig. 9.50
Necrobiosis lipoidica: Pathogenesis and histological features
characteristic, bilateral,
symmetrical lesions.
The precise pathogenesis of necrobiosis lipoidica is unknown. Of primary
From the collection of the importance is the temporal relationship between collagen degeneration and
late N.P. Smith, MD, the the inflammatory infiltrate.51 The close association of necrobiosis lipoidica
Institute of Dermatology, and diabetes mellitus suggests a causal relationship, but the exact mechanism
London, UK. is uncertain. In the past, some 60% of patients with necrobiosis lipoidica were
Gli-1, the glioma-associated oncogene homologue, has been found to be

expressed in a number of granulomatous skin disorders including necrobiosis
lipoidica.64 The explanation for this is not clear but it suggests that inhibitors
of gli-1 may be used in the treatment of the disease.
Recently, spirochetal microorganisms, likely to be Borrelia, have been
identified in lesions of necrobiosis lipoidica in patients from central Europe.65
The significance of this finding is unclear.
The histopathological features are variable, depending to some extent on
the presence or absence of coexistent diabetes mellitus.66,67 The palisading
granuloma with necrobiosis is more typical of the diabetes-related variant,
whereas a granulomatous sarcoidal type of reaction is more often a feature
of nondiabetes-related necrobiosis. Nevertheless, there is very considerable
overlap and in the majority of cases one cannot predict, on histological
grounds alone, which cases are, and which are not, diabetes-related.
The epidermal changes are usually inconspicuous or absent. There may,
however, be acanthosis or atrophy, and hyperkeratosis is not uncommon.
The hallmark of necrobiosis lipoidica is the palisading necrobiotic granu-
loma. Large, often confluent areas of necrobiosis are present, usually centered
in the lower dermis, although the superficial dermis and subcutaneous fat may
Fig. 9.53 also be affected (Figs 9.54–9.56). When the subcutaneous fat is involved,
Necrobiosis lipoidica: the changes are seen mainly in the septa. The foci of necrobiosis consist of
chronic lesion with
ulceration and crusting.
London, UK.
reported as having coexistent diabetes mellitus.2,4,52,53 However, its reported

prevalence in diabetes is only of the order of 3/1000.51 Furthermore, a recent
study has found that only a minority of patients with necrobiosis lipoidica
have diabetes.8
It has been suggested that the lesions develop as a consequence of diabetic
microangiopathy: the vessel walls in lesions of necrobiosis lipoidica are typi-
cally thickened by a diastase-resistant PAS-positive material. This does not
explain the development of necrobiosis lipoidica in nondiabetic patients or
the absence of the disease in patients with established microvascular lesions.
An association with venous insufficiency and hypercholesterolemia has been
suggested in a very small group of patients.54 The significance of this finding is
therefore unclear. Study of microcirculation by Doppler flowmetry and oxygen
partial pressure in necrobiosis lipoidica lesions in nondiabetics has demon-
strated an altered microcirculation.55 Low oxygen and high carbon dioxide
pressures, presumably reflecting ischemia, characterize necrobiotic plaques.56
Such vascular changes, although possibly causal, could equally well develop as
a consequence of the necrobiotic changes. Aberrant platelet aggregation may
also play a role in pathogenesis. Platelet survival times are markedly reduced
in patients with necrobiosis lipoidica.57 Whether this is of pathogenic impor-
tance is uncertain.
Autoantibodies against cytoskeleton proteins have been observed in sera
from patients with necrobiosis lipoidica. These autoantibodies (IgG anti-
troponin, antidesmin, antikeratin, anti-insulin, antitrinitrophenol, and IgA
and IgM antikeratin) were found to be elevated in patients with necrobiosis
lipoidica compared with diabetic patients without evidence of necrobiosis
lipoidica.58 What role, if any, these autoantibodies play in the pathogen-
esis of necrobiosis lipoidica is unclear. Synthesis of collagen by fibroblasts
cultured from lesions is decreased compared with fibroblasts from normal
skin.59
Also of uncertain significance is the reported detection, by immunofluo-
rescence, of immunoreactants (IgM and C3) in blood vessel walls in some
cases of necrobiosis lipoidica.60,61 Epidermal dendritic S-100-positive cells are
increased in number.62 Whether this reflects an immunological aspect to the
development of necrobiosis lipoidica has yet to be determined.
Glut-1 (the human erythrocyte glucose transporter) is expressed by the
fibroblasts in areas of sclerotic collagen from biopsies of patients with necro-
biosis lipoidica.63 This raises the possibility of an altered transport of glucose Fig. 9.54
in the affected areas contributing to the histopathological features seen in this Necrobiosis lipoidica: the epidermis is unaffected; there is extensive necrobiosis in
disease. the reticular dermis. A heavy chronic inflammatory cell infiltrate is present.
e osinophilic, swollen or degenerate collagen, often appearing hyalinized with

a surrounding infiltrate of variable numbers of lymphocytes and histiocytes
(Fig. 9.57). Aggregates of lymphoid cells, with or without germinal center
formation, are frequently found.68 Plasma cells are almost invariably present.
In a single case, the plasma cell infiltrate was mononclonal, and further
investigations revealed an underlying monoclonal gammopathy.69 The necro-
biotic foci sometimes contain mucin. Palisading is variable, being more con-
spicuous in those instances associated with a heavy inflammatory cell infiltrate.
The areas of necrobiosis are associated with loss of elastic tissue (Fig. 9.58).
Usually, epithelioid histiocytes and giant cells are evident and sometimes there
are well-formed granulomata resembling the sarcoidal type of necrobiotic his-
tological reaction (see below) (Fig. 9.59). Very rarely, asteroid bodies are iden-
tified.70 Lipid droplets, best seen with oil red O or Sudan IV staining on frozen
tissue, are almost invariably present in the necrobiotic foci. Usually, a mild to
moderate perivascular lymphocytic infiltrate is seen in the adjacent dermis.
Cholesterol clefts are rare and only exceptionally may be prominent.71,72
A careful search often reveals vascular changes in necrobiosis lipoidica. These
consist of blood vessel wall thickening, with intimal proliferation and narrow-
ing of the lumen. Occasionally thrombi are noted. Sometimes increased num-
Fig. 9.55 bers of vessels are a feature. The vascular changes are more obvious in patients
Necrobiosis lipoidica: the lesion extends down to the subcutaneous fat.
Fig. 9.56 Fig. 9.58

Necrobiosis lipoidica: high-power view of Figure 9.54. Necrobiosis lipoidica: note the complete absence of elastic tissue. Elastic-van
Gieson.
Fig. 9.57 Fig. 9.59

Necrobiosis lipoidica: the degenerate collagen is surrounded by a palisade of Necrobiosis lipoidica: there is a granulomatous infiltrate with conspicuous
histiocytes, lymphocytes, and fibroblasts. multinucleate giant cells.
with associated diabetes mellitus or other systemic disease. These changes are
particularly severe in those cases where necrobiosis is very marked. One study
also showed that neutrophilic and granulomatous vasculopathies correlated
with systemic disease.73 In addition, telangiectatic superficial venules are a com-
mon feature. Cases with necrobiosis-like features and significant vasculitis and
neutrophilic infiltrates in the setting of systemic disease are discussed in detail
in the section on palisaded neutrophilic and granulomatous dermatitis associ-
ated with systemic disease. In lesions with anesthesia, S-100 shows destruction
of nerve fibers in the areas of necrobiosis.42,43
In the diffuse variant there is very widespread necrobiosis with a mini-
mal inflammatory cell response; such cases are usually associated with dia-
betes (Fig. 9.60). Sometimes linear infiltrates of histiocytes between collagen
fibers are a feature, as in granuloma annulare. Lipomembranous fat necrosis
is noted in occasional cases.74
In the sarcoidal type of necrobiosis lipoidica, which is more often noted
with the nondiabetes mellitus-associated variant, the appearances are those
of naked epithelioid cell granulomata, particularly in the lower dermis
(Fig. 9.61). Langhans and foreign body giant cells are usually conspicuous
and a lymphocytic and plasma cell infiltrate may be evident (Fig. 9.62).
Necrobiosis is usually minimal; multiple levels may have to be examined Fig. 9.61
Necrobiosis lipoidica (granulomatous variant): well-defined noncaseating granulomata
before its presence is confirmed (Fig. 9.63). The sarcoidal type of necrobiosis
replace the reticular dermis. Necrobiosis is present to the left of center.
lipoidica in patients without diabetes mellitus has in the past been described as
Miescher's granuloma.
Perforating necrobiosis lipoidica is associated with transepidermal
elimination of necrobiotic collagen and also degenerated elastotic material
(Figs 9.64–9.66).71,75,76
Necrobiosis lipoidica must be distinguished from granuloma annulare, rheu-
matoid nodule, actinic granuloma, and granuloma multiforme. Points of
distinction are summarized in Table 9.1. The presence of massive necrobio-
sis associated with numerous cholesterol clefts, bizarre multinucleated giant
cells, and Touton-type giant cells distinguishes necrobiotic xanthogranu-
loma from necrobiosis lipoidica. As noted above, prominent cholesterol cleft
formation, which is a feature that usually suggests necrobiotic xanthogranu-
loma, may rarely be seen in necrobiosis lipoidica.66,67 Small punch biopsies
may not be adequate for definitive evaluation and sampling bias may be
misleading. Clinical correlation should be taken into consideration before
making a final diagnosis.
Fig. 9.62
Necrobiosis lipoidica (granulomatous variant): the naked granulomata are very
reminiscent of sarcoidosis. Note the multinucleate giant cells.
Fig. 9.60
Necrobiosis lipoidica
(diffuse variant): a
broad band of confluent Fig. 9.63
necrobiosis has destroyed Necrobiosis lipoidica (granulomatous variant): higher-power view of the necrobiotic
the entire reticular dermis. focus seen in Figure 9.61.
Fig. 9.64
Perforating necrobiosis lipoidica: there is widespread hyperkeratosis and crusting.
A perforating channel is seen on the right side of the picture. Fig. 9.66
Perforating necrobiosis:
the dermis immediately
beneath the site of
perforation shows severe
necrobiotic change.
Fig. 9.65
Perforating necrobiosis: Fig. 9.67
close-up view of the Rheumatoid nodules: lesions on the knuckles are commonly seen in rheumatoid
perforating channel. arthritis. By courtesy of Dr J.C. Pascual, MD, Alicante, Spain.
from several millimeters to 5 cm in diameter. Numbers may vary from one to
over a hundred. Ulceration sometimes occurs. Intrapulmonary rheumatoid
Rheumatoid nodule nodules have been exceptionally associated with leflunomide in a patient with
rheumatoid arthritis.7 A case of large cavitary pulmonary lesions in a patient
Clinical features with HIV has been reported.8
Rheumatoid nodules are subcutaneous lesions that develop at sites of trauma Rheumatoid nodules are more commonly found in patients with severe
or at pressure points in approximately 30% of adults with rheumatoid arthri- rheumatoid arthritis and are associated with a high titer of rheumatoid fac-
tis.1–3 They are most commonly found on the extensor aspect of the forearms tor, joint erosions, and an increased incidence of rheumatoid vasculitis.9
and elbows (particularly the olecranon process), the feet, knees, knuckles, They are not, however, specific for rheumatoid arthritis, being found in
buttocks, scalp, and back (Figs 9.67, 9.68).4 They have also been described approximately 5–7% of patients with SLE (although in this condition they
involving a wide variety of other sites, including the abdominal wall, heart tend to be localized about the hands) and occasionally in seronegative anky-
(pericardium, myocardium, and valves), larynx, lungs, pleura, splenic cap- losing spondylitis.10,11 Clinically similar lesions have also been reported in
sule, peritoneum, mesenterium, eye, bridge of nose, pinna, ischial tuberosity, patients with scleroderma. Presentation of multiple rheumatoid nodules on
thyrohyoid membrane, and Achilles tendon.5,6 Lesions are often fixed to the the fingers in association with little or no arthritis has been described as
underlying periosteum or deep fascia. They present as firm, asymptomatic, rheumatoid nodulosis.12–14 This, however, can be associated with destruc-
dome-shaped masses in the subcutaneous fat or deeper tissues and measure tive arthritis.15 A similar name (cutaneous nodulosis) has been given to the
Rheumatoid nodule 301
Fig. 9.68 Fig. 9.69

Rheumatoid nodule: close-up view. By courtesy of Dr J.C. Pascual, MD, Alicante, Rheumatoid nodule: there is massive necrobiosis with adjacent scarring and a
Spain. dense lymphocytic infiltrate. Rheumatoid nodules characteristically occur in the soft
tissues.
development of multiple small nodules at different sites during methotrexate

therapy for rheumatoid arthritis.16 Etanercept has been linked to the excep-
tional development of extensive pulmonary nodulosis while infliximab and
the aromatase inhibitor letrozole are associated with accelerated cutaneous
nodulosis.17–19

Although these lesions develop at sites of pressure and trauma (implying
pathogenetic significance), there is some evidence in support of an immune
complex-mediated pathogenesis, as both IgG and IgM have been detected
by immunofluorescence in the walls of blood vessels adjacent to rheumatoid
nodules.20 Similarly, both rheumatoid factor and complement have been dem-
onstrated within the substance of rheumatoid nodules. Localization of IgM
rheumatoid factor and terminal complement complexes C5b-9 has been dem-
onstrated on the luminal surface of endothelial cells in rheumatoid nodules.21
C4d has been shown in association with palisading macrophages and in areas
of fibrinoid necrosis, further supporting the role of complement activation in
the pathogenesis of the lesions.22 Proinflammatory cytokines and cell adhe-
sion molecules (TNF-α, IL-1β, IL-Ra RNA, E-selectin) have been shown in
rheumatoid nodules and are likely to play a role in mediating injury.23 The Fig. 9.70
Rheumatoid nodule: in this example, tendon can be seen on the right side of the
expression of cytokines in the rheumatoid nodule is very similar to that in
field.
the synovial lining in rheumatoid joints and suggests that the pathogenesis of
both is very similar and driven by Th1 lymphocytes.24 The cytokines involved
include IFN-γ, IL-1beta, TNF-α, IL-12, IL-18, IL-15, and IL-10.23 Although
massive central necrosis is predominant, apoptosis has been demonstrated
throughout the nodule.25 In some cases of deep granuloma annulare the histological changes are similar
Rheumatoid nodules are typically located in the subcutaneous fat or to rheumatoid nodule. Deep granuloma annulare (‘pseudorheumatoid nod-
soft tissues although they may extend into the deeper reticular dermis. This ule’) tends to have more mucin deposition and less fibrin than typical rheu-
is in contrast to the more superficial location of both granuloma annu- matoid nodules.28 Therefore, the latter are referred to as ‘red’ granulomas
lare and necrobiosis lipoidica. They are multinodular and associated with and the former as ‘blue’ granulomas.29 However, some rheumatoid nodules
very extensive necrobiosis (Figs 9.69, 9.70). Fibrin deposition is often seen do contain mucin. Clinicopathological and serological correlation is advised
in the center of the nodule.26 Immunoglobulin, lipid, glycosaminoglycans, before establishing a definitive diagnosis.
and nucleoproteins may also be present. Old lesions are sometimes associ- Compared to rheumatoid fever nodule, rheumatoid arthritis nodules tend
ated with cyst formation due to liquefactive degeneration of the contents of to be better circumscribed and surrounded by a well-defined palisade of his-
the nodules. A well-developed palisade of histiocytes and occasional giant tiocytes. In addition, the fine fibrinoid strands that form the center of a rheu-
cells characteristically surrounds necrobiotic foci and fibrinoid material matic fever nodule contrast with the more dense sheet-like areas of necrobio-
(Fig. 9.71). Asteroid inclusions are not a feature. The outer layer is com- sis and fibrin deposition in the rheumatoid arthritis nodule.
posed of vascular granulation tissue, and in older lesions marked fibrosis Patients combining the features of severe rheumatoid arthritis with pali-
is a frequent accompaniment. An inflammatory cell infiltrate of lympho- sading granulomata accompanied by a neutrophilic infiltrate and leukocyto-
cytes, plasma cells, and eosinophils is often present. Leukocytoclastic vas- clastic vasculitis have been described.9 These lesions are discussed under the
culitis has occasionally been reported to affect the blood vessels in and rubric of palisaded neutrophilic and granulomatous dermatitis with vasculi-
around early nodules. A rare case with perforation of the epidermis has tis. In short, lesions showing these features may be associated with a number
been documented.27 of systemic diseases, including rheumatoid arthritis.
Annular elastolytic giant cell granuloma

Clinical features
The term ‘annular elastolytic giant cell granuloma’ has been used to describe
not only cases of actinic granuloma but also lesions in which destruction of
elastic fibers occurs in the absence of solar elastosis.6 In fact, some cases pres-
ent at sites with little sun exposure and the disease may also occur in chil-
dren.7 Thus, although the terms actinic granuloma and elastolytic giant cell
granuloma have been used interchangeably in the literature, the latter term
should be reserved for elastolytic granulomata occurring in skin without solar
elastosis.8
Lesions usually present on the trunk and neck and rarely on proximal limbs.
They vary in size but tend to be large. Despite the name annular, some cases
present with papules or reticular erythema.9 In those that are annular there is
an advancing raised border which may be papular. Rarely, lesions are general-
ized.10 Spontaneous resolution is rare.9 A reported case describes a lesion that
developed at the site of an old burn scar and spread after trauma.11
Elastolytic granulomata have rarely been described in association with
Fig. 9.71 adult T-cell leukemia lymphoma, primary cutaneous CD4-positive small/
Rheumatoid nodule: the necrobiotic connective tissue is surrounded by a well- medium-sized pleomorphic T-cell lymphoma, acute myelogenous leukemia,
developed histiocytic palisade. and monoclonal gammopathy.12–14 Elastolytic granulomata have also been
documented in internal organs.15 The latter, however, probably represents
sarcoidosis with prominent elastolysis.

Elastic fibers become altered through an unknown mechanism and appear
to induce factor XIIIa-positive cells and CD68-positive macrophages to form
granulomata.16
Histological features may be identical to those of actinic granuloma (see
below) except for the absence of solar elastosis. Ideally, in annular lesions the
biopsy should be a wedge including the center, the advancing edge, and nor-
mal skin for comparison purposes. This is not always possible, particularly
in lesions that do not have an annular configuration. The center of the lesion
is completely devoid of elastic fibers and there is usually no inflammation.
The loss of elastic fibers appears to be irreversible.17 In the advancing margin
there is a granulomatous reaction with fragmentation and phagocytosis of
elastic fibers. In one case, histology showed features of mid-dermal elastolysis
leading the authors to suggest that annular elastolytic giant cell granuloma
may possibly represent a prodromal or inflammatory stage of the disease.18
Fig. 9.72 Many granulomatous reactions, including infections, often display elas-
Rheumatoid nodule: the palisading histiocytes may sometimes show mitotic tophagocytosis. However, in these conditions the change is mild and focal.
figures which may lead the unwary to consider epithelioid sarcoma. In granuloma annulare, there is usually very little or no elastophagocytosis,
while in annular elastolytic giant cell granuloma there is no necrobiosis or
palisading granuloma.19
Although epithelioid sarcoma, with its associated geographic necrosis,
may bear a superficial resemblance at low power to rheumatoid nodule, the Actinic granuloma (O’Brien)
degree of nuclear atypia and pleomorphism in the former should allow easy
distinction between these conditions (Fig. 9.72). However, in difficult cases, Clinical features
keratin and epithelial membrane antigen immunoreactivity in epithelioid
Actinic granuloma develops on the sun-damaged skin of the neck, face, upper
sarcoma should assist in the differential diagnosis.
chest or arms of middle-aged patients.1–5 It may also affect the conjunc-
tiva, and a single case affecting the upper lip has been reported.6–9 A further
Elastolytic granulomata case presented as alopecia.10 The incidence is equal in men and women, and
individuals with blond hair and freckled skin are predisposed, particularly
This is a controversial group of diseases, the prototype of which is the actinic those living in sunny climates. An association with the longstanding use of
granuloma. Other entities that probably belong to this group include atypical sunbeds and with doxycycline phototoxicity has also been described.11,12
facial necrobiosis lipoidica and granuloma multiforme (see below). It has been Lesions present as one or more skin-colored or pink papules, which
suggested that all these conditions represent examples of granuloma annulare enlarge to form annular or arcuate plaques up to 1 cm in diameter. The edge
occurring in different clinical settings.1–4 However, the clinicopathological of the lesion is somewhat raised, forming a border 0.2–0.5 cm in width.
features are distinctive and the pathological process clearly relates to the pri- These annular plaques enlarge slowly and the center may gradually clear to
mary destruction of elastic fibers by a granulomatous infiltrate. In granuloma appear relatively normal or slightly atrophic with variable depigmentation.
annulare, as in diseases such as sarcoidosis, destruction of elastic fibers does Lesions are asymptomatic and there is no evidence of anesthesia. They do not
not always occur and when it does, it tends to occur focally, developing as a develop on nonsun-damaged skin. Spontaneous resolution may take place
secondary phenomenon.5 after months or years.
Elastolytic granulomata 303
Bilateral periocular actinic granulomata have been documented in a patient

with renal failure.13 Other rare associations include relapsing polychondritis,
cutaneous amyloidosis, and giant molluscum contagiosum.14–16

The pathogenesis of actinic granuloma is poorly understood. It has been sug-
gested that the antigenic stimulus for the formation of granulomata in both
actinic granuloma and temporal arteritis is actinically degenerated elastic
tissue.17,18 Interestingly, phototesting in a single case failed to reproduce the
lesions of actinic granuloma.19
The features are best appreciated by examination of a radial biopsy
through the edge of a lesion and including uninvolved skin.20,21 The epidermis
may be normal or atrophic. The peripheral unaffected skin shows gross solar
(actinic) elastosis (Figs 9.73–9.75). Within the rim of the lesion there is a for-
eign body giant cell reaction in association with, and engulfing, fragmented
elastotic material (elastoclasis) (Figs. 9.76, 9.77).20,21 The granulomatous
reaction is centered in the zone of solar elastosis and, accordingly, tends to be
confined to the superficial dermis.22 The giant cells may contain asteroid bod-
ies. There is an accompanying chronic inflammatory cell infiltrate composed
Fig. 9.75
of histiocytes, lymphocytes, and plasma cells. Necrobiosis is not a feature Actinic granuloma: the granulomatous infiltrate is associated with degenerate
elastic fibers.
Fig. 9.73 Fig. 9.76

Actinic granuloma: a granulomatous reaction is present the superficial dermis Actinic granuloma: elastotic material is seen in the cytoplasm of the giant cell in the
surrounding an ill-defined necrobiotic process. Solar elastosis is evident. centre of the field.
Fig. 9.74
Actinic granuloma: in addition to solar elastosis, this example also shows interface Fig. 9.77
change with conspicuous cytoid bodies. Actinic granuloma: high-power view of basophilic degenerate elastic fibers.
of this condition. Palisading of histiocytes is either absent or minimal and,

if present, is related to the elastotic debris. Dermal mucin does not appear
to be increased.22 Fibroblasts are scant and fibrosis is minimal. In the actinic
granuloma, blood vessels appear normal. Within the central zone the collagen
appears relatively normal, although it is more obviously horizontally aligned
and may appear more closely packed than normal. Slight scarring is present
in the central area where elastic tissue is absent.22
The facial location, presence of elastophagocytosis, and absence of necro-
biosis aid in distinguishing actinic granuloma from other granulomatous
lesions. The absence of dermal mucin, necrobiosis, and palisading granu-
loma and the presence of marked elastoclasis and mild scarring help to distin-
guish actinic granuloma from granuloma annulare, the disorder that it most
resembles.14,23
Atypical facial necrobiosis lipoidica

This variant of necrobiosis lipoidica deserves separate mention because of its Atypical facial necrobiosis lipoidica: a dense granulomatous infiltrate occupies the
dermis.
unusual clinical features and distinctive histology.1–5 Atypical facial necro-
biosis lipoidica, which predominantly affects females (9:1), usually develops
in the absence of diabetes mellitus, and manifests most often in the fourth
decade. Patients present with one or more annular, nonscaling plaques on the
upper face and scalp, which typically have slightly raised, relatively uniform
borders and measure 1–5 cm in diameter (Fig. 9.78). Although early lesions
are erythematous with a brown border, older lesions are characterized by cen-
tral depigmentation. Atrophy, however, is minimal or absent. Patients may,
in addition, show involvement of other sites, including the arms, hands, and
trunk. Very rarely, patients have concomitant typical necrobiosis lipoidica on
the shins. It is for this reason that the name was originally coined. We now
believe, however, that the condition probably has no relationship whatsoever
to necrobiosis lipoidica. It is much more likely that it represents a variant of
an annular elastolytic granuloma.
The condition is characterized by a dense granulomatous infiltrate, with con-
spicuous giant cells, involving the dermis (Figs 9.79, 9.80). The infiltrate has
a rather irregular distribution, being dispersed between individual collagen
bundles. Occasional circumscribed granulomata may sometimes be a feature.
Asteroid bodies are often found in the cytoplasm of giant cells. Typically,
there is loss of elastic tissue in the areas of granulomatous inflammation.
Fig. 9.80
Atypical facial necrobiosis lipoidica: close-up view of the granulomata. Note the
conspicuous giant cells.
Rarely, ill-defined foci of necrobiosis are noted (Fig. 9.81), but well-defined
palisading granulomata are not present. In cases with coexistent necrobiosis
lipoidica, biopsies from the affected areas on the shins show the typical histo-
logical features of this condition.
In contrast to actinic granuloma with which this condition is often confused,
the surrounding skin does not show evidence of significant solar elastosis and
elastoclasis.
Granuloma multiforme
Clinical features
This dermatosis of unknown etiology is of particular importance because clin-
ically it can be confused with leprosy; however, it is not associated with cuta-
Fig. 9.78 neous anesthesia.1,2 Granuloma multiforme, which shows a marked female
Atypical facial necrobiosis lipoidica: atrophic plaque on forehead with a well-defined predominance, is seen most often in Central Africa, especially eastern Nigeria.
edge. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, It has also been documented in the Congo, Uganda, India, and Tunisia.3–6
London, UK. The disease is very common in some villages. It particularly affects patients
Elastolytic granulomata 305
Fig. 9.81 Fig. 9.83

Atypical facial necrobiosis lipoidica: an ill-defined focus of necrobiosis is present. Granuloma multiforme: there are multiple large irregular plaques. By courtesy of the
over 40 years of age. Lesions, which tend to chronicity, are found on the
upper and exposed parts of the body. They commence as small, flesh-colored,
indurated, pruritic papulonodules, 1–8 mm in diameter and raised 1–3 mm
above the skin surface, which extend peripherally and coalesce to form annu-
lar lesions and plaques (Figs 9.82, 9.83). Very large lesions become irregular
and develop scalloped or gyrate borders. Central healing may be associated
with residual hypopigmentation.
The epidermis is normal. Situated within the dermis is an ill-defined, irregu-
lar, necrobiotic lesion (Fig. 9.84).7 In general, this affects individual collagen
fibers, producing a rather haphazard picture of abnormal fibers interspersed
with unaffected ones and associated with a histiocytic infiltrate (Fig. 9.85).
Only rarely is a well-defined palisading granuloma seen. In addition to his-
tiocytes, giant cells are commonly found and the tissues show a perivascular
lymphocytic infiltrate with variable numbers of plasma cells and eosinophils.
Fig. 9.84
Granuloma multiforme: there is extensive necrobiosis.
Fig. 9.82
Granuloma multiforme:
typical annular lesions
with raised borders in a
child. By courtesy of R.A.
Marsden, St George’s Fig. 9.85
Hospital, London, UK. Granuloma multiforme: necrobiosis is seen in the center.
and granulomatous dermatitis. Other systemic diseases, including con-

nective tissue disease, infection, vasculitis, neoplasia, and inflammatory
bowel disease, may be associated with lesions with similar histology. The
reader is referred to this section for a more detailed discussion of this
group of disorders. In short, a diagnosis of rheumatic fever nodule should
only be made in the setting of confirmed rheumatic fever. In the absence
of such history, a careful search for other underlying systemic diseases is
necessary.
Rheumatoid arthritis nodules tend to be better circumscribed and sur-
rounded by well-defined palisade of histiocytes. In addition, the fine fibrinoid
strands that form the center of a rheumatic fever nodule contrast with the
more dense sheetlike areas of necrobiosis in the rheumatoid arthritis nodule.
Necrobiotic xanthogranuloma
Clinical features
Necrobiotic xanthogranuloma (necrobiotic xanthogranuloma with parapro-
Fig. 9.86 teinemia) is an extremely rare condition of unknown etiology.1–3 It occurs
Granuloma multiforme: note the complete loss of elastic tissue. Elastic-van Gieson. equally in men and in women, in the late middle aged and elderly (average
age at presentation is 56 years). The disease is characterized by the develop-
ment of nodules and plaques, which show a predilection for the face, neck,
trunk and, less commonly, proximal limbs. The facial lesions are charac-
The giant cells do not contain asteroid bodies. Perineural involvement is not teristically periorbital (most often infraorbital) in distribution and consist
a feature.1 The adjacent vasculature is normal. Loss of elastic tissue is typical of papules that progress to nodules, and plaques that may form irregular
in relation to the inflammatory infiltrate and healed areas are characterized ulcers (Fig. 9.87). Although periorbital involvement is fairly constant, in
by absence of elastic tissue and mild superficial scarring (Fig 9.86).1 some patients this feature is absent.4,5 Scarring and telangiectasia are com-
mon. Lesions are sharply demarcated and have a distinctive xanthomatous
Differential diagnosis appearance. Ocular complications are common and include episcleritis,
The exact nosological position of granuloma multiforme is unknown. It is keratitis, proptosis, uveitis, and iritis.6 Some patients report pain but this is
probably a clinicopathological variant of elastolytic granuloma. An associa- not a usual feature.2
tion with sun exposure has been suggested.8 The granulomata do not show The lesions on the trunk and limbs are irregular, well-demarcated, bright
a perineural distribution, thus helping to distinguish granuloma multiforme yellow, dermal and subcutaneous plaques measuring up to 25 cm across
from leprosy. Nevertheless, since infection must be excluded before giving a (Fig. 9.88). They may be complicated by ulceration, hemorrhage, scarring,
definitive diagnosis, stains for organisms (especially mycobacteria and fungi) central atrophy, and telangiectases, and typically have a peripheral inflam-
must be performed to exclude this possibility. Culture should also be per- matory border. Violaceous and flesh-colored nodules are sometimes pres-
formed when clinically appropriate. ent, particularly over the trunk. Unusual presentations include a solitary
nodular lesion mimicking a tumor and, exceptionally, the absence of skin
involvement.7,8 A lesion presenting at the site of a blepharoplasty scar and a
Rheumatic fever nodule further lesion presenting in the scar of a burn have been reported.9,10
Involvement of myocardium, lung, larynx, kidneys, salivary gland,
Clinical features and skeletal muscle has been documented.11–16 Patients may have arthritis,
Fortunately, effective antimicrobial therapy has relegated rheumatic fever to chronic obstructive pulmonary disease, neuropathy or hypertension.2 Other
a rare pediatric infection. As a consequence, complications of rheumatic fever
are only rarely encountered in dermatology practice. In older studies, approx-
imately one-third of patients with rheumatic fever develop papules that had a
tendency to occur over bony prominence of the knee, elbows, fingers, ankles,
spine, scalp, and rarely at other sites.1–3 Most patients had multiple nodules.
In one report, the number of nodules ranged from 1 to 108.1 Lesions per-
sisted from days to several months. Interestingly, in a more recent study of
44 patients with rheumatic fever, only one had a single subcutaneous nodule.4
Biopsy shows central gossamer fibrin associated with variable numbers of
neutrophils, lymphocytes, plasma cells, and karyorrhexis. The lesions are
often not well circumscribed and histiocytes surround the lesion, forming a
poorly defined palisade.
The histological features of the rheumatic fever nodule are not pathog-
nomonic. Clinical correlation is required to establish a definite diagnosis.
The rheumatic fever nodule can be classified under the rubric of ‘palisaded
neutrophilic and granulomatous dermatitis associated with systemic dis-
ease’. Rheumatic fever nodule is discussed separately, however, because of Fig. 9.87
its historic interest and its longstanding recognition as a distinct clinical Necrobiotic xanthogranuloma: indurated yellow plaques are present around both
entity. The differential diagnosis is therefore that of palisaded neutrophilic eyes and on the eyelids. By courtesy of the Institute of Dermatology, London, UK.
Necrobiotic xanthogranuloma 307
Fig. 9.88 Fig. 9.89

Necrobiotic xanthogranuloma: there are multiple yellow plaques around the shoulders Necrobiotic xanthogranuloma: there is a dense infiltrate extending throughout the
and overlying the clavicles. By courtesy of the Institute of Dermatology, London, UK. dermis into the subcutaneous fat.
reported cases include one associated with Graves' disease, another with
linear morphea, one with scleroderma and one with lichen sclerosus.2,17–19 In
another patient there was an association with syncitial giant cell hepatitis.20
Nodular transformation of the liver is a feature noted in rare patients.14,21
Laboratory investigations reveal anemia, leucopenia, and a raised ESR.
Most patients with necrobiotic xanthogranuloma have an associated mono-
clonal paraproteinemia, usually IgG kappa type. Few present with a lambda
paraprotein and an exceptional case has been documented with two mono-
clonal paraproteins. Some patients have multiple myeloma or B-cell lym-
phoma.22–26 A case with associated Hodgkin's lymphoma has also been
reported.27 Diabetes mellitus is sometimes present and occasionally hyper-
lipidemia. Other associations that may be encountered include low serum
complement levels and cryoglobulinemia.

The pathogenesis of necrobiotic xanthogranuloma is unknown. The plasma
cells in the infiltrate are consistently polyclonal, supporting a reactive pro-
cess.3 Direct immunofluorescence has shown IgM, C3, and fibrinogen deposi-
Fig. 9.90
tion in blood vessel walls.6 It has more recently been suggested that activation
Necrobiotic xanthogranuloma: there is extensive necrobiosis and a dense histiocytic
of monocytes is responsible for the intracellular accumulation of lipoprotein- infiltrate with conspicuous giant cells.
derived lipids and the hypocholesterolemia.28 Focus-floating microscopy of
six cases demonstrated the presence of Borrelia.29 The significance of this
finding is unclear.
Necrobiotic xanthogranuloma has a very distinctive histological appear-
ance.6,26 Large areas of marked necrobiosis alternate with foci of xanthogran-
ulomatous infiltration throughout the reticular dermis with extension into
the subcutaneous fat (Fig. 9.89).4 Exceptionally, necrobiosis is absent.30
Involvement of the subcutaneous fat is predominantly in a septal distribution
and can mimic panniculitis.31 The necrobiotic collagen appears as amorphous
eosinophilic debris (Fig. 9.90). The granulomatous infiltrate is composed of
epithelioid and foamy histiocytes in addition to conspicuous giant cells, many
of which are of the Touton type (Figs 9.91, 9.92). Foreign body giant cells
are also present. Lymphocytes and plasma cells are often prominent and for-
mation of germinal centers is sometimes seen. A characteristic feature is the
presence of large and bizarre angulated giant cells with considerable numbers
of nuclei irregularly grouped together within copious eosinophilic cytoplasm
in the tissue immediately adjacent to foci of necrobiosis (Fig. 9.93). Asteroid
bodies, which are often found in the cytoplasm of giant cells, have been sug-
gested as a useful diagnostic finding.32 Frozen sections and oil red O staining
for fat may reveal focal lipid droplets. Cholesterol clefts and lipid vacuoles
are sometimes seen within the foci of necrobiosis and xanthogranulomatous Fig. 9.91
inflammation (Fig. 9.94). In rare cases, however, lipid deposition and giant Necrobiotic xanthogranuloma: in this field, there are conspicuous xanthomatized
cells are inconspicuous.33 The granulomatous and necrobiotic process may histiocytes.
affect muscular arteries. Staining for elastic fibers reveals their absence in the
necrobiotic areas; Alcian blue staining may reveal small amounts of inter-
stitial mucin. As with most necrobiotic disorders, transepidermal elimina-
tion of necrobiotic collagen is sometimes a feature.34 A case with prominent
elastophagocytosis has been described.35The lungs and heart may show giant
cells, granulomata, necrobiosis or a combination of these features in patients
with systemic disease.12
The clinical and histological features are distinctive: the presence of massive
necrobiosis associated with numerous cholesterol clefts, bizarre multinucle-
ated giant cells, and Touton-type giant cells distinguishes necrobiotic xan-
thogranuloma from necrobiosis lipoidica and other necrobiotic dermatoses.
It should, however, be noted that prominent cholesterol cleft formation may
rarely be seen in necrobiosis lipoidica.36 Small punch biopsies may not be ade-
quate for definitive evaluation and sampling bias may be misleading. Clinical
correlation should be taken into consideration before making a definitive
diagnosis.
Fig. 9.92
Necrobiotic xanthogranuloma: Touton giant cells are sometimes prominent.
Palisaded neutrophilic and granulomatous
dermatitis
Clinical features
Palisaded neutrophilic and granulomatous dermatitis (interstitial granu-
lomatous dermatitis) is a term that has been applied to a reaction pattern
of necrobiotic and granulomatous inflammation encountered in the setting
of systemic disease.1 Other terms that have been applied to similar, overlap-
ping and, in some cases, probably identical lesions, include interstitial granu-
lomatous dermatitis with arthritis, rheumatoid papules, superficial ulcerating
rheumatoid necrobiosis, cutaneous extravascular necrotizing granuloma, and
Churg-Strauss granuloma.1–6 Myriad underlying systemic diseases have been
purported to be associated with these lesions including rheumatoid arthri-
tis, lupus erythematosus, systemic sclerosis, Sjögren's syndrome, thyroiditis,
Raynaud's syndrome, hepatitis, inflammatory bowel disease, lymphoprolif-
erative disorders, myelodysplastic syndrome, vasculitis (Wegener's granulo-
matosis, Churg-Strauss syndrome, Takayasu's arteritis, periarteritis nodosa),
hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, mixed
cryoglobulinemia, drug reactions (especially sulfonamides), carcinoma, diabe-
tes, and infections (streptococcal, HIV, Epstein-Barr virus, parvovirus).1–4,7–12
Fig. 9.93 In most cases an underlying systemic disease is found, and it is rare that an
Necrobiotic xanthogranuloma: angulated giant cells with darkly staining nuclei are underlying disease is not detected.13
commonly present. The lesions are mainly located on the extremities and less commonly the
trunk in an adult.1 Children are seldom affected.14,15 The disease is character-
ized by papules and nodules, which are often arranged in a linear pattern.
These linear lesions may be confluent and have been described as linear bands
or cords with a ‘ropelike’ consistency (the so-called rope sign). Plaques have
also been described.6

The pathogenesis of palisaded neutrophilic and granulomatous dermatitis
most likely depends on the associated/underlying disease. In a number of
cases autoantibodies, particularly anti-DNA in type, are found.16 It has been
suggested that the disease is mediated by immune complexes.17 Direct immu-
nofluorescence studies have demonstrated fibrin and IgM in the vasculature
of some patients.1
A variety of histological patterns have been described. These patterns may
be seen in the same or different biopsies from the same patient, emphasizing
the fact that they are not separate diseases.18 Some biopsies resemble the inter-
stitial variant of granuloma annulare without a well-defined palisade, loosely
organized histiocytes, and variable numbers of neutrophils with nuclear dust.
Fibrin is also seen. In fact, some would label these lesions as falling within the
spectrum of granuloma annulare.4 However, mucin deposition is not as marked
Fig. 9.94 as seen in granuloma annulare and the changes are more ill defined. In other
Necrobiotic xanthogranuloma: cholesterol clefts are a characteristic feature. samples, palisaded histiocytes surround individual collagen bundles and in
‘Metastatic’ Crohn’s disease 309
‘Metastatic’ Crohn’s disease

Clinical features
Patients with Crohn's disease may present with cutaneous and oral lesions,
the most frequent of which are aphthous stomatitis, pyoderma gangrenosum,
and erythema nodosum.1 Metastatic cutaneous lesions in Crohn's disease are
rare and defined as the presence of sterile granulomatous lesions that occur
at sites not contiguous with the gastrointestinal tract. They predominantly
involve the skin of the lower limbs, genitalia, perineum, perianal region, and
lips. One review of the literature showed that approximately 50% of patients
with cutaneous Crohn's disease have involvement of the lower extremi-
ties.2 Most affected patients are adults but lesions may rarely be seen in chil-
dren.3 The lesions present as single or multiple papules, plaques, nodules,
and ulcers.2–12 Vulval tumor-like masses, vulval or penile swelling, and herpes
virus-like lesions have occasionally been described.10,13,14 Penile lesions may
sometimes occur.15 Colostomy site involvement has also been documented.
One patient has been reported as presenting with an erysipelas-like erup-
tion involving the lip and nasolabial region and a further patient presented
Fig. 9.95
with involvement of the nipple.5,16 In some patients, mucocutaneous lesions
Palisaded neutrophilic and granulomatous dermatitis: an interstitial inflammatory
cell infiltrate is present in the center of the field, mimicking diffuse granuloma
precede evidence of bowel involvement.7,17,18 Of uncertain significance is the
annulare. finding that cutaneous Crohn's disease seems to be highly associated with
involvement of the large bowel.13 The duration of lesions is variable, typically
lasting from months to years.

The pathogenesis of mucocutaneous Crohn's disease is not understood.
Histologically, lesions are usually manifest as ill-defined, noncaseating,
and nonsuppurative granulomata present in the superficial (often papil-
lary) dermis; however, granulomata may also involve the deep dermis and
even subcutaneous adipose tissue.19,20 The granulomata are surrounded by
a small cuff of lymphocytes.20 In addition, there is a superficial and deep,
perivascular, mixed inflammatory cell infiltrate. The granulomata resemble
those seen in the bowel. Necrobiotic collagen has been described in a num-
ber of cases.19 Lymphocytes and plasma cells are also commonly present and
eosinophils can be prominent.20 Ulceration of the epidermis may be seen.20
Recently, the histological features of metastatic Crohn's disease have been
expanded to include the findings of significant necrobiosis with leukocyto-
clasis, and vasculitis (see palisaded neutrophilic and granulomatous derma-
titis, above).19,21
Fig. 9.96 Since the histological features of cutaneous Crohn's disease are non-specific,
Palisaded neutrophilic and granulomatous dermatitis: close-up view showing a definitive diagnosis requires clinical confirmation of the presence of asso-
necrobiosis, histiocytes, and neutrophils associated with karyorrhexis. ciated bowel disease. Therefore, endoscopy, evaluation of gastrointestinal
biopsies, and review of clinical findings all play a role in confirmation of this
diagnosis. Sarcoidosis may be indistinguishable from metastatic Crohn's dis-
the background there is a neutrophilic infiltrate with karyorrhexis (Figs 9.95, ease; however, the granulomata of the former tend to be more discrete and
9.96). In late stages, fibrosis may be seen. The various changes described are compact. Eosinophils may be prominent in metastastic Crohn's disease and
more likely to represent the evolution of the lesions. Variable numbers of eosino- are rare in sarcoidosis.20 Mycobacterial infection is also an important differ-
phils may be noted and, when present, appear to occur mostly in patients with ential diagnosis; therefore liberal use of special stains for microorganisms is
a peripheral eosinophilia. Frank leukocytoclastic vasculitis is present in some essential. Culture should be performed as deemed clinically appropriate.
cases.18 A few cases may resemble necrobiosis lipoidica.4 As noted above, cutaneous granulomata may precede evidence of bowel
involvement.7,16,17 Therefore, patients with granulomatous skin disease of
Differential diagnosis uncertain etiology should be followed up carefully for evidence of bowel
From the above discussion it can be seen that a number of different terms disease.
have been proposed to describe lesions resembling granuloma annulare or Granulomatous cheilitis may also show identical histological features.
rarely necrobiosis lipoidica but with the added features of acute and eosino- Studies have documented patients presenting with granulomatous cheili-
philic inflammation, karyorrhexis and neutrophils with leukocytoclasia and tis who subsequently developed clinical manifestations or pathological evi-
rarely with leukocytoclastic vasculitis. Some authors include these changes dence (without gastrointestinal symptoms) of Crohn's disease.20,22–27 One
within the spectrum of granuloma annulare and necrobiosis lipoidica.4 The group study described a patient in whom granulomatous cheilitis antedated
precise terminology preferred by the dermatopathologist is probably not development of Crohn's disease by 7 years.28 It appears, therefore, that some
important. More significant than any nosological nuances is issuing a report patients with granulomatous cheilitis are at risk for development of Crohn's
that alerts the clinician to the possibility that the patient may have underly- disease and require gastrointestinal evaluation and careful clinical follow-up.
ing systemic disease and that, when such lesions are encountered, appropriate Similarly, vulval Crohn's disease precedes development of bowel involvement
clinical evaluation is necessary.10 in 25% of cases.13
Granulomatous cheilitis
Granulomatous cheilitis (cheilitis granulomatosa, Meischer's cheilitis, orofa-
cial granulomatosis) is discussed elsewhere.
Acne agminata
Clinical features
Acne agminata (lupus miliaris disseminatus faciei, acnitis, papular tuberculid) is
a rare condition originally thought to be a form of tuberculid but an association
with tuberculosis has since been excluded.1–4 Some authors consider this disease
to be synonymous with granulomatous rosacea. However, the distinctive clini-
cal presentation, and the absence of typical rosacea in patients affected by the
disease, argue against this. Recently, a new name has been suggested for the dis-
ease: facial idiopathic granulomata with regressive evolution (FIGURE).5
Clinical presentation is characterized by fairly monomorphous yellowish-
brown papules typically involving the central face with predilection for peri-
ocular areas (Fig. 9.97). The disease is limited to the eyelids in rare cases.6 Fig. 9.98
Involvement of axillae or upper limbs is an exceptional finding.7–9 There is Acne agminata: there are multiple caseating granulomata.
no sex predilection and the age range is wide although most cases occur in
young to middle-aged adults.10 An exceptional case during pregnancy has
been documented.11 Response to conventional treatment for rosacea is often
ineffective but lesions tend to regress spontaneously over a period of months
or even years, leaving mild scarring.12

As suggested by some synonyms, infection by mycobacteria has been favored
by certain authors as a potential etiological factor. This theory is no longer ten-
able due to the absence of past or present systemic tuberculosis and the constant
failure of isolation of bacilli. In a study from Israel, mycobacterial DNA was
not detected by PCR.1 It has been suggested that the development of lesions is
due to an unusual granulomatous reaction to ruptured hair follicles.13
The histological features vary with the stage of evolution and may be
entirely non-specific.14 A biopsy from a well-established lesion shows a central
area of well-defined caseous necrosis surrounded by multinucleate giant cells
and epithelioid cells (sometimes indistinguishable from tuberculous infection)
(Figs 9.98 and 9.99). Serial sections often reveal a relationship of the necrosis
Fig. 9.99
Acne agminata: close-up view. The condition is not a tuberculid. Special stains and
culture for tubercle bacilli are invariably negative.
to a destroyed hair follicle. Special stains may demonstrate a ring of elastic

fibers in the center of the necrotic focus, possibly representing the isthmus of
the hair follicle. The granulomata are not usually related to Demodex follicu-
lorum as is often the case in granulomatous rosacea. Focal vasculitis is only
exceptionally seen.
The diagnosis is fairly easy in the presence of granulomata surrounding an
area of caseation necrosis since the latter is not usually a feature of either
granulomatous rosacea or perioral dermatitis. In biopsies showing only focal
granulomatous inflammation, establishing the diagnosis may require very
careful clinicopathological correlation.
Fig. 9.97
Acne agminata: note the Perioral dermatitis
characteristic distribution
of papules on the cheek Clinical features
and around the eyes.
From the collection of the Perioral dermatitis (perioral granulomatous dermatitis, periorificial derma-
late N.P. Smith, MD, the titis) is a common dermatosis that may represent a variant of rosacea.1–6
Institute of Dermatology, It is discussed in this section since it can, on occasion, be associated with
London, UK. granulomatous histology. Patients are usually young women but the condition
Foreign body granulomata 311
a predilection for the face. Their pathogenetic role in skin diseases has
always been controversial and they are often regarded as innocent bystand-
ers. However, it does seem that in a small number of cases, particularly in
immunocompromised patients, they have an important role in causation of
disease.1–4 The mites do not appear to be a primary factor in the develop-
ment of rosacea although they may play a part in the granulomatous form
of the disease. Traditionally, three facial forms of involvement have been
described: pityriasis folliculorum, rosacea-like demodicosis, and demodi-
cosis gravis. Skin eruptions attributed to the mites, however, have variable
manifestations and include a rosacea-like eruption, a perioral dermatitis-
like eruption, chronic blepharitis, follicular plugging and erythema and a
disseminated form in immunocompromised patients.1–12 Localized pustules
and even abscesses have also been reported.13 An unusual case of a patient
with demodicosis presenting as a facial plaque after ophthalmic herpes
zoster has been described. In a further case, the disease mimicked favus
in a child.14 Adults are mainly affected but cases in children have been
reported.9–11,15

Fig. 9.100
Perioral dermatitis: erythema and papules in a characteristic distribution. From the The pathogenetic link between the mites and cutaneous disease is a matter of
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. controversy. In cases where there seems to be a clear link, the density of mites
is very high.4
Histologically, the findings combine suppurative and granulomatous
changes. Dilated hair follicles with multiple mites are seen and there is forma-
can occur in children.1,7 Presentation in identical twins is exceptional but has tion of neutrophilic pustules. This is associated with a variable, perifollicular
been documented.8 A granulomatous variant of perioral dermatitis has been mononuclear cell infiltrate composed of lymphocytes and plasma cells. When
described in children.9–11 It tends to be more common in Afro-Caribbean the hair follicle ruptures, focal granulomata are seen and often contain frag-
children and has been labeled facial Afro-Caribbean childhood eruption ments of the mites.
(FACE).9 Typically, perioral dermatitis consists of erythematous papules and
pustules with a characteristic distribution on the chin and nasolabial folds
(Fig. 9.100). Involvement of the inner cheeks, the skin around the nose, Infective granulomata
forehead or periocular area is unusual. Based on the fact that some cases
show perinasal and periocular involvement, the name periorificial dermatitis Infections, particularly fungal and mycobacterial, are often associated with
has been suggested.12 Extrafacial and generalized involvement has also been granulomatous inflammation. Conversely, the vast majority of routine
documented.13 The clinical appearances may mimic acne but comedones are biopsies showing granulomatous inflammation are not due to an infection.
absent.14 However, when faced with a specimen showing granulomatous inflamma-
tion, the pathologist must maintain a low threshold for performing stains
Pathogenesis and histological features for organisms and for issuing recommendations for microbiology culture.
The pathogenesis of perioral dermatitis is not clearly understood but If such an approach is not taken, the vast majority of infectious causes of
the condition seems to be etiologically linked in some cases to the use of granulomatous inflammation will be misdiagnosed. In addition, although
potent topical steroids, the application of cosmetics, certain toothpastes, pathologists tend to associate certain patterns of granulomatous inflam-
epoxy diacrylates in dental composite resins, contraceptive pills, and some mation with infection by specific organisms (e.g., caseating granulomatous
moisturizing creams.15–23 In rare patients, the disease appears during preg- inflammation and Mycobacterium tuberculosis), it should be remembered
nancy and may flare up before the menstrual period.23 Even inhaled cor- that the same organism can cause several different patterns of granuloma-
ticosteroids have triggered perioral dermatitis.24 Physical sunscreens with tous inflammation (e.g., Mycobacterium leprae). Similarly, mixed suppu-
high sun protection factor have also been blamed for causing the disease rative and granulomatous inflammation may result from both atypical
in children.25 Multiple dental fillings with a mercury-containing amal- mycobacteria and deep fungal infections. A practical corollary to this is
gam induced perioral dermatitis in a girl and in a further case the disease that the pathologist should order several special stains to evaluate for a
appears to have been triggered by orthognathic surgery.26,27 An association variety of organisms rather than relying on a single stain for the most likely
has also been reported in renal transplant patients on systemic steroids and culprit.
azathioprine.28 Specific infectious causes of granulomatous inflammation are discussed in
Biopsy shows mild acanthosis, focal spongiosis, and hyperkeratosis with detail in Chapter 18.
parakeratosis and a mild perivascular and periadnexal lymphohistiocytic
infiltrate. The appearances are almost indistinguishable from those found in
rosacea.29 Ruptured hair follicles with microabscess formation are occasion- Foreign body granulomata
ally seen. Sometimes granulomata with sarcoidal features are present.30 Giant
A wide variety of substances when present within the dermis may result in
cells have also been documented, in which case distinction from sarcoidosis
a foreign body giant cell reaction and can mimic primary granulomatous
may be difficult.1,31 In most cases, clinical correlation resolves any diagnostic
disorders. These are summarized in Table 9.2 and examples are shown in
difficulties.
Figures 9.101–9.108. Therefore, when examining specimens with granu-
lomatous inflammation of uncertain etiology, all sections should be exam-
Demodicosis ined with polarized light to exclude foreign material. Most foreign body
granulomatous reactions occur as a result of external foreign matter, particu-
There are two species of Demodex that live in a symbiotic relationship larly suture material. It can also occur as a result of injury from sea urchin
in human hair follicles. The mites are D. folliculorum and D. brevis. spines, particularly on acral sites.1–4 The granulomata formed are often for-
The former is mainly found in the infundibulum of the hairs and the lat- eign body and sarcoidal, but other types of granulomata including necrobi-
ter in the sebaceous glands. They are ubiquitous in the skin but there is otic, suppurative, and tuberculoid have been described.4 Interestingly, a study
Table 9.2
Important causes of foreign body granulomata
Endogenous Exogenous
Keratin Silica Graphite Cactus spine
Hair shaft Beryllium Paraffin Vegetable oil
Ruptured cyst Zirconium Shrapnel Mineral oil
contents
Released lipids Talc Sutures Food particles
Urate crystals Silicone Arthropods Wood splinters
Tattoo pigment Sea urchin spine
Fig. 9.103
Foreign body granuloma:
this free hair shaft has
been partially engulfed by
foreign body giant cells.
Fig. 9.101
Foreign body granuloma: there is a florid granulomatous reaction to shrapnel.
Fig. 9.104
Foreign body granuloma: high-power view
found Mycobacterium marinum DNA using PCR in a number of sea urchin

granulomata raising the possibility that the organism may be involved in the
pathogenesis of the disease.5 Foreign body granulomatous reactions second-
ary to internal foreign bodies are mainly secondary to hair shafts within the
dermis after folliculitis or to fragments of keratin as a result of ruptured epi-
dermoid or trichilemmal cysts. Another source of foreign body granuloma-
tous r eaction to internal material is gout.
The pathologist should be particularly aware that beryllium and zir-
conium may be associated with granulomata that mimic sarcoidosis, the
so-called sarcoidal ‘naked’ granuloma. It is especially important to think
Fig. 9.102 of these agents as rare possible causes of granulomata since neither is vis-
Tattoo site: foreign body ible with routine or polarization microscopy. Beryllium was once used in the
and sarcoidal responses manufacture of fluorescent light bulbs. Following exposure to beryllium,
may occasionally be seen patients may develop either systemic berylliosis or have cutaneous involve-
in tattoo reaction. ment only. Pulmonary lesions follow inhalation.5 Skin involvement, in the
Granulomatous contact dermatitis 313
Fig. 9.105
Suture granuloma: suture fragments are present; note the multinucleate giant cells.
Fig. 9.107
Bioplastique and silicone
granuloma: note sclerosis
and cystic spaces.
Fig. 9.106
Suture granuloma: when viewed with polarized light, suture fragments show
birefringence.
Fig. 9.108
form of papules, follows direct inoculation.6 Diagnosis of chronic beryllium
Bioplastique and silicone granuloma: note silicone spaces resembling lipoblasts in
disease is based on demonstration of a cell-mediated response to beryllium by the left of the field. On the right there are irregular cystic space containing foreign
patch testing.6 Diagnosis may also be established by laser microprobe mass material.
spectrometry.6,7
Zirconium was once added to antiperspirants.8 Patients developed pap-
ules at sites where the substance was used and interstitial lung disease also
occurred.9 More recently, elephantiasis following nodal involvement has Granulomatous contact dermatitis
been described in patients with beryllium and zirconium exposure from min-
eral-rich soil (podoconiosis).10 Diagnosis may be made using spectrographic Clinical features
analysis.6,7,11 There are rare reports of a granulomatous reaction to metals, mainly pal-
Foreign body granulomata following esthetic microimplants are relatively ladium and less commonly gold and a titanium alloy, particularly at the
uncommon nowadays, as the material used is greatly improved. Silicone gran- site of ear piercing but also in relation to piercing at other body sites.1–8
ulomata are sometimes found and occasionally one encounters foreign body Granulomata induced by titanium have also been reported after implanta-
granulomata to cosmetic microimplants such as Dermalive (hyaluronic acid tion of a titanium-containing pacemaker.9 Areas of swelling, induration, or
and acrylic hydrogel), artecoll (PMMA-microspheres), bioplastique (polym- red papules and/or nodules develop at the site of piercing and this may occur
ethylsiloxane), and bioalcamid.12,13 Foreign body granulomata to iron oxide shortly after or weeks and even months after the patient starts wearing ear-
after permanent p igmentation of the eyebrows have also been reported.14 rings. Most cases have been reported in adults but similar lesions may be
A metastatic silicone granuloma mimicking acne agminata and associated seen in children.10
with the sicca complex has been reported in a silicone breast implant A granulomatous contact dermatitis to propolis has also been
patient.15 described.11

The pathogenesis is likely to be a delayed hypersensitivity reaction to the
metal. This is proven by the fact that patients usually have a positive patch
test to palladium or less frequently gold. A positive reaction to zinc has also
been found.
Throughout the dermis and sometimes extending into the subcutis, there
is a prominent, diffuse granulomatous inflammatory cell infiltrate. This
comprises epithelioid histiocytes and scattered giant cells surrounded by
lymphocytes and sometimes plasma cells are present. Necrosis is not usually
seen. In a case report of a reaction to titanium alloy (containing titanium,
aluminium, and vanadium) brown-black particles were demonstrated his-
tologically within the cytoplasm of macrophages.8 In another example trig-
gered by gold earrings, intracytoplasmic crystalline inclusions were found
within macrophages.6
Differential Diagnosis
The differential diagnosis from sarcoidosis and other granulomatous pro-
cesses may be difficult. The clinical history of piercing and the sites affected
are useful in achieving a correct diagnosis. Fig. 9.110
Tuberculoid granulomata in agammaglobulinemia: high-power view
Granulomata in congenital
immunodeficiency syndromes
A number of inherited immune deficiency diseases may on occasion present
with noninfectious granulomata involving different organs including the
skin.1–4 These diseases include combined immune deficiency, chronic granu-
lomatous disease, ataxia telangiectasia, common variable immunodeficiency,
and X-linked infantile hypogammaglobulinemia (Figs 9.109–9.112).
In combined immune deficiency, cutaneous tuberculoid and necrobiotic
granulomata may occur and in a single instance perineural invasion was
identified, closely mimicking tuberculoid leprosy.5,6 Cutaneous granulomata
in chronic granulomatous disease may show caseation necrosis without a
detectable trigger and can also be associated with foreign bodies.7,8 In ataxia
telangiectasia, patients present with either necrobiotic or tuberculoid gran-
ulomata.9–11 In common variable immunodeficiency, tuberculoid, sarcoidal,
and caseating granulomata have been documented.12–14 In X-linked infan-
tile hypogammaglobulinemia, caseating granulomata have been reported.15
An unusual perforating neutrophilic and granulomatous dermatitis has been
reported in a patient with agammaglobulinemia.16 It is important to highlight
the fact that affected patients have an immune deficiency; therefore, every
Fig. 9.111
effort should be made to rule out an infectious process with special stains Necrotizing granuloma in agammaglobulinemia: there is very extensive dermal
and cultures. necrosis with a surrounding granulomatous infiltrate.
Fig. 9.109
Tuberculoid granulomata in agammaglobulinemia: there is a diffuse granulomatous Fig. 9.112
infiltrate throughout the dermis. Necrotizing granuloma in agammaglobulinemia: high power view.
Aluminum granuloma 315
Aluminum granuloma
Clinical features
Aluminum granuloma refers to the persistent, sometimes painful, subcutaneous
nodules that develop at the sites of vaccination or hyposensitization with agents
containing aluminum hydroxide as an absorbing agent (Fig. 9.113).1–5 If a vac-
cine is erroneously applied intradermally, lesions may occur within the dermis.6
The term granuloma is a misnomer as lesions do not usually consist of granu-
lomatous inflammation. The lesions develop after a few weeks or years after the
injections and are thought to be secondary to a hypersensitivity reaction to alu-
minum hydroxide. Often, patients have positive patch tests to aluminum hydrox-
ide. The most common vaccine associated with this reaction is tetanus toxoid
but any vaccine containing aluminum hydroxide as an absorbent may induce the
reaction, including hepatitis A and C and human papillomavirus vaccines.7
Intramuscular vaccines induce a condition described as macrophagic myo-
fasciitis. This condition has been described both in children and adults.8,9

The occurrence of the nodules appears to be the result of a delayed hypersen- Aluminum granuloma: there is a dense inflammatory cell infiltrate within the
subcutaneous fat.
sitivity reaction to aluminum.
Four histological patterns, which can overlap, may be found:10
• A predominantly lobular panniculitis with fairly non-specific findings
including focal inflammation consisting of lymphocytes, histiocytes,
and plasma cells with fat necrosis. Loose subcutaneous collections of
histiocytes with a slightly granular, bluish cytoplasm are always found
but their number varies and the change may be subtle.
• A prominent subcutaneous, predominantly mononuclear, inflammatory
cell infiltrate with eosinophils and focal formation of germinal centers
often mimicking a marginal zone lymphoma (Figs 9.114–9.116). Plasma
cells are often prominent. Careful examination reveals scattered grouped
histiocytes with bluish granular cytoplasm.
• A deep granuloma annulare-like infiltrate with numerous histiocytes
surrounding an area of necrobiosis (Figs 9.117, 9.118). All the
histiocytes show a characteristic bluish granular cytoplasm.
• A pattern with hyaline necrosis of the subcutaneous lobule mimicking
lupus profundus. This is associated with lymphocytes, and plasma cells
and germinal centers may also be seen. Careful examination reveals the
presence of typical histiocytes with bluish granular cytoplasm.
A case with numerous mast cells and associated with urticaria has been
described.11
The material within the histiocytes represents aluminum. Confirmation of Fig. 9.115
the presence of aluminum can be done histochemically with the use of azurin Aluminum granuloma: the infiltrate consists of lymphocytes, histiocytes and plasma
stain or by energy dispersive X-ray microanalysis. cells.
Fig. 9.113 Fig. 9.116

Aluminum granuloma: multiple depressed nodules with scarring are evident. From Aluminum granuloma: the histiocytes have markedly granular cytoplasm due to the
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. presence of aluminum.
disease in the same biopsy.33 Drugs including sirolimus and indinavir have
also been associated with the disease.34,35 The inherited cases are not associ-
ated with any systemic disorder. Reactive perforating collagenosis has also
been reported in a patient with HIV/AIDS in association with end-stage renal
failure.36 Perforating collagenosis is seen in approximately 10% of patients
with renal failure.1,2,37 Patients may develop lesions either before or after dial-
ysis treatment.2 In most cases, underlying diabetes mellitus is also present.1,2,37
Affected individuals suffer generalized pruritus and crusting papules. A single
case with a zosteriform distribution has also been documented.38
Following mild trauma, such as a scratch or insect bite, patients develop
flesh-colored papules 1–2 mm in diameter. These enlarge, become umbili-
cated and, over the course of about 4 weeks, grow to reach a diameter of
some 5–10 mm (Figs 9.119–9.121). Rarely, giant lesions are observed.39 The
umbilicated area contains keratinous debris, which is dark brown, hard, and
leathery. It is also very densely adherent, and bleeding results if detachment is
attempted. This is followed by regression. The papules flatten, and by 6–8 weeks
Fig. 9.117
Aluminum granuloma: in this example there is a palisading granuloma surrounding
a necrobiotic nodule.
Fig. 9.119
Reactive perforating collagenosis: there are multiple pink papules, some showing
central umbilication with crusting. By courtesy of D. McGibbon, MD, St Thomas’
Fig. 9.118
Aluminum granuloma: the histiocytes have finely granular cytoplasm.
Perforating disorders
Reactive perforating collagenosis
Clinical features
This is a very rare disorder of uncertain etiology in which patients are predis-
posed to develop an unusual skin reaction to mild trauma, causing damaged
collagen to be extruded through the epidermis.1–4 Although sporadic cases do
occur, in many instances reactive perforating collagenosis appears to be an
inherited condition, autosomal recessive and dominant variants having been
described.5–8 Reactive perforating collagenosis has been documented in asso-
ciation with the Treacher Collins syndrome.9 The disease shows an equal sex
incidence, most cases presenting in childhood, although lesions tend to per-
sist into adult life. In familial cases the expression of the disease is variable
and can sometimes be mild and subtle.10 Lesions may be precipitated by sun Fig. 9.120
Reactive perforating
exposure.10 An acquired variant occurring in adulthood and associated with
collagenosis: an example
IgA nephropathy, diabetes mellitus, chronic renal failure, hydronephrosis, on the cheek of a young
lung fibrosis, herpes zoster infection, cytomegalovirus, scabies, lymphoma, boy. By courtesy of E.
leukemia, and carcinoma (including papillary thyroid carcinoma and hepato- Young, MD, Wycombe
cellular carcinoma) has been described.11–32 In a single patient with Mikulicz's General Hospital, High
disease, the condition showed histologic features of IgG4-related sclerosing Wycombe, UK.
Perforating disorders 317
Fig. 9.121 Fig. 9.123

Reactive perforating collagenosis: close-up view. By courtesy of E. Young, MD, Reactive perforating collagenosis: irregular, swollen collagen fibers have penetrated
Wycombe General Hospital, High Wycombe, UK. the epidermis.
from onset all that remain are residual scars or hypopigmented areas. It is of
interest that lesions develop only after mild superficial trauma, deep penetrat-
ing wounds healing normally. A positive Koebner phenomenon is character-
istic and lesions may be induced by gentle needle scratching. Lesions tend
to be rather polymorphic: as old lesions heal, new ones develop. They are
distributed primarily on the upper and lower extremities and face, although
the trunk may be affected.40,41 Rarely, the palms and soles may be involved.
Mucosal involvement has also been described in one patient.42 The severity of
this condition seems to increase in cold weather, whereas there is a reduction
in the number of lesions in summer. Exceptionally, secondary bacterial infec-
tion within the lesions may occur.43

The pathogenesis of reactive perforating collagenosis has not been eluci-
dated.44 Transepidermal elimination of type IV collagen has been demon-
strated but the mechanism that triggers the process is not clear.45
A broadened dermal ridge containing degenerate, basophilic collagen char-
acterizes early, nonumbilicated lesions. The overlying epithelium is atrophic
and centrally is composed of a thin layer of parakeratotic material. At the lat-
eral margins there is typically acanthosis. In the fully established umbilicated
lesion the central plug is composed of parakeratotic debris, degenerate collagen,
and inflammatory cells (Figs 9.122, 9.123).46 The epidermis deep to the plug
Fig. 9.124
collagenosis: close-up
view of collagen fibers
within the epidermis.
is markedly thinned and is traversed focally by vertically orientated collagen

fibers (Figs 9.124, 9.125). Elastic fibers are not present within the extruded
connective tissue debris. On either side of the cup-shaped deformity, the epider-
mis is acanthotic and hyperkeratotic. A lymphohistiocytic infiltrate is present
in the superficial dermis. The histological appearances in reactive perforating
collagenosis and acquired perforating collagenosis are identical. Distinction
between these disorders requires clinical correlation (Figs 9.126, 9.127).
Changes identical to those seen in reactive perforating collagenosis may be
seen following trauma in ‘normal’ patients without stigmata of the disease.
Not uncommonly, biopsies of patients with prurigo nodularis/lichen simplex
chronicus (but who do not meet clinical criteria for reactive perforating
Fig. 9.122 collagenosis) show transepidermal elimination of collagen in a pattern simi-
Reactive perforating collagenosis: this is a transverse section through the center of lar to that seen in perforating collagenosis. Table 9.3 highlights points of
a lesion. Note the crust overlying multiple points of incipient perforation. distinction among the perforating disorders.
Fig. 9.125 Fig. 9.127

Reactive perforating collagenosis: transepidermal elimination is seen to better Reactive perforating collagenosis: higher-power view.
advantage with this Masson’s trichrome stain.
Perforating folliculitis
Clinical features
Perforating folliculitis is a not uncommon, usually asymptomatic, derma-
tosis of unknown etiology that superficially resembles Kyrle's disease.1–3
It shows a female predominance (2:1) and, although a wide range of age
groups may be affected, the majority of patients present in the third decade.
The disease is characterized by the development of discrete, erythematous
follicular papules, 2–8 mm in diameter, each containing a small central white
keratotic core. Lesions most often affect the extremities, with a predilection
for the hairy portions of the arms, forearms, and thighs. The buttocks may
also be involved (Figs 9.128, 9.129). Koebnerization is not usually a feature.
Duration of the rash is variable, ranging from several months to years and
remissions and exacerbation may punctuate the course. Some patients present
with features of more than one perforating disease (i.e., perforating folliculitis
and elastosis perforans serpiginosa).4
Perforating folliculitis is associated with renal failure in some patients.5–7
It has also been reported in the setting of HIV infection and recently was
Fig. 9.126 described in two dialysis patients with markedly elevated serum silicon
Reactive perforating collagenosis: this example developed in a patient with chronic levels.8,9 Primary sclerosing cholangitis may rarely be associated with
renal failure. perforating folliculitis.10,11 A number of medications have been associated with
perforating folliculitis including sorafenib, infliximab, and etanercept.12,13
Table 9.3
Differential diagnosis of perforating disorders
Kyrle’s disease collagenosis Elastosis perforans serpiginosa Perforating folliculitis
Age of patient Average 30 years (20–60) Childhood Second decade Third decade
Sex distribution ♂=♀ ♂=♀ 4 ♂=♀ 2 ♀=♂
Site Extensor lower extremities; upper Upper and lower Side and back of neck; upper Hair-bearing portions of
extremities; head, neck and trunk extremities; face extremities; face; lower extremities arms, forearms, thighs
Koebner phenomenon Occasionally positive Positive Occasionally positive Negative
Associated diseases Diabetes mellitus; renal failure; None; (acquired variant Down’s syndrome; Ehlers-Danlos None
hepatic insufficiency; congestive renal failure) syndrome; osteogenesis imperfecta;
cardiac failure pseudoxanthoma elasticum
Mode of inheritance ? autosomal recessive
? autosomal dominant
Histology Transepidermal elimination of Transepidermal Transepidermal elimination of Intrafollicular
degenerate parakeratin and elimination of collagen abnormal elastic tissue curled- up hair;
inflammatory debris transepidermal limination
of degenerate connective
tissue
The subsequent exposure of the follicular contents to the underlying dermis

results in necrosis of connective tissue and subsequent transepidermal
elimination.
The histopathological features of perforating folliculitis are those of a
widely dilated hair follicle containing ortho- and parakeratotic keratin, baso-
philic necrotic debris, connective tissue elements, and degenerate inflam-
matory cells (Fig. 9.130).2 A curled-up hair is sometimes found within the
keratinous plug or extruded into the perifollicular dermis. Typically, the
infundibular follicular epithelium is disrupted at single or multiple foci.
The underlying degenerate dermis, including collagen and elastic fibers, may
be seen to impinge upon the perforated follicle. The adjacent epidermis often
shows pseudoepitheliomatous hyperplasia. A foreign body giant cell reaction
is sometimes found within the superficial dermis.
Perforating folliculitis is differentiated from Kyrle's disease by uniform fol-
licular involvement associated with infundibular epithelial perforation (com-
pared with perforation at the base of the lesion in Kyrle's disease) and the
presence of tortuous hairs. Although elastic fibers may be found within
the dilated follicle, they are neither abnormal in appearance nor increased
Fig. 9.128
in quantity as seen in elastosis perforans serpiginosa. Table 9.3 highlights
Perforating folliculitis:
discrete scaly lesions on points of distinction among the perforating disorders. Keratosis pilaris is
the buttocks and thighs. associated with keratotic plugs that tend to be folliculocentric, but perfora-
By courtesy of K. Green, tion and inflammation are not features.
MD, Lister Hospital,
Stevenage, UK.
Elastosis perforans serpiginosa
Clinical features
Elastosis perforans serpiginosa (L. serpere, to creep) is a rare dermatosis asso-
ciated with transepidermal elimination of abnormal elastic tissue.1–3 It shows
a male predominance (4:1) and presents most often in the second decade.
A case with simultaneous onset in two sisters has been reported.4 Another
unusual case has been documented in an individual with a 47 XYY karyotype
and unilateral atrophoderma of Pasini and Pierini.5
The primary lesion is a 2–5-mm flesh-colored or red keratotic papule
containing an adherent plug, removal of which is associated with bleeding.
Classically, the papules are arranged in an arcuate or serpiginous pattern,
although sometimes they are randomly distributed (Fig. 9.131). Most often
the lesions are confined to one site, with the back and sides of the neck being
most frequently affected. Symmetrical involvement is very rare.6 Other sites
include the upper extremities, face, lower extremities, and abdomen, in
decreasing order of frequency. The penis is very rarely involved.7 In those cases
where multiple sites are involved, symmetrical distribution is characteristic.
Fig. 9.129
Perforating folliculitis:
close-up view. By courtesy
of K. Green, MD, Lister
Hospital, Stevenage, UK.

Although the exact etiology is unknown, the frequent finding of a distorted,
curled hair within the dilated follicle, often associated with disruption of
the epithelium, and the occasional presence of hair fragments within the
adjacent dermis suggest that mechanical disruption of follicular epithelium
by hair may be the cause of this condition. The lesions of perforating fol-
liculitis occur most commonly on the extensor aspects of the extremities,
suggesting that trauma may be implicated. It has been proposed that, as Fig. 9.130
with Kyrle's disease, chronic friction leads to abnormal keratinization of Perforating folliculitis: this field shows a dilated hair follicle containing keratinous
the follicular epithelium, which eventually results in follicular perforation. and basophilic debris. A hair shaft is visible.
abnormality of copper metabolism associated with reduced numbers of

elastic fibers in arterial walls. It may be, therefore, that penicillamine
locally depletes the dermis of copper, resulting in abnormally formed elastic
tissue and the subsequent development of elastosis p erforans serpiginosa.
In the established lesion there is a marked increase in elastic tissue in
both the reticular and papillary dermis (Fig. 9.132). The vertically ori-
entated fibers of the latter are thicker than normal and can be seen to
penetrate the epidermis. A section through the center of the lesion shows
characteristic transepithelial perforating canals, which may be transepi-
dermal, parafollicular or transfollicular in location and straight, wavy
or screwlike in configuration (Figs 9.133, 9.134). The canal contents
consist of a basophilic mass comprising degenerate epithelial cells, inflam-
matory debris, and numerous elastic fibers (Fig. 9.135). The superficial
plug is composed predominantly of keratinous material and basophilic
debris. Sometimes elastic fibers are identified in the stratum corneum. The
epithelium on either side of the perforating canal is acanthotic and may
Fig. 9.131
Elastosis perforans
serpiginosa: typical scaly
serpiginous eruption on
the elbow. By courtesy
of M.M. Black, MD,
St Thomas’ Hospital,
London, UK.
Rarely, lesions are widely disseminated. The eruption is usually asymptomatic,

although mild pruritus is sometimes a feature. Koebnerization is occasionally
noted.
Although elastosis perforans serpiginosa may occur as an isolated phenom-
enon, in quite a high proportion of cases it develops in association with other
conditions including Down's syndrome, Ehlers-Danlos syndrome, osteogen-
esis imperfecta, Marfan's syndrome, pseudoxanthoma elasticum, cutis laxa,
acrogeria, the Rothmund-Thomson syndrome and Moya Moya disease.8–17
Rarely, elastosis perforans serpiginosa may develop as a complication of pen-
Fig. 9.132
icillamine therapy for Wilson's disease and cystinuria.9,18–23 In patients treated Elastosis perforans serpiginosa: the epidermis is markedly thickened. Multiple
with penicillamine it may be associated with pseudoxanthoma elasticum and perforating channels containing basophilic debris are present.
cutis laxa.24,25 It has also been described in a patient with juvenile rheumatoid
arthritis.9

The pathogenesis of elastosis perforans serpiginosa is not entirely under-
stood. The documentation of familial cases suggests that a genetic component
plays a role in a subset of patients.26 The common association of elastosis
perforans serpiginosa with a variety of connective tissue disorders raises the
possibility of an elastic tissue defect as being of pathogenetic significance.
Histochemical and enzyme studies have confirmed that it is the elastic tissue
that is undergoing transepidermal elimination: electron microscopic studies
have shown that the elastic fibers are increased in size and have a convoluted
and branched pattern.27 It appears that these abnormal fibers have an irritant
effect, resulting in epidermal proliferation and their eventual engulfment by
the epidermis. Following epidermal growth with consequent upward migra-
tion, the abnormal elastic tissue is expelled via perforating canals. Recently,
it has been demonstrated that the 67 kD elastin receptor is present in the
keratinocytes associated with the elimination of elastic material in elastosis
perforans serpiginosa.28,29 This expression varies with the stage of the disease
and suggests that the elastin-keratinocyte interaction plays an important role
in the transepidermal elimination of elastin.28,29
It is of particular interest that this condition has been described follow- Fig. 9.133
Elastosis perforans
ing the use of the copper chelating agent penicillamine.9,18,19 Tissue copper
serpiginosa: this picture is
deficiency is known to be associated with damage to the elastica of arter- taken through the center
ies in experimental animals. The Blotchy mouse, which develops fusiform of a characteristic tortuous
aortic aneurysms, has a copper metabolism defect that includes reduced perforating canal. Note the
activity of the copper-dependent enzyme lysyl oxidase which is essential degenerate elastic tissue
for cross-linking the elastin molecules. In Menkes' syndrome, there is an at the base of the lesion.
Hyperkeratosis follicularis et parafollicularis

in cutem penetrans
Clinical features
Hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle's dis-
ease) is a very rare dermatosis of unknown etiology.1–4 It has an equal inci-
dence in men and women and an age of onset ranging from 20 to 60 years,
with an average of 30 years. The disorder is characterized by a widespread,
asymptomatic, and typically bilateral eruption of 1–8-mm papules, each con-
taining a central cone-shaped keratotic plug. Although lesions are located
most often on the extensor aspect of the lower extremities, they may also
affect the upper extremities, head, neck, and trunk (Figs 9.136, 9.137). They
may or may not be related to hair follicles. The mucous membranes, palms,
and soles are characteristically spared. Ocular changes have been documented
in a single kindred with the disease.5 In a further patient, there was involve-
ment of the conjunctiva and oral mucosa.6 Lesions may coalesce into plaques
and, occasionally, a Koebner-like appearance is present. There is no evidence
to suggest that Kyrle's disease has a genetic etiology. However, the disease
exceptionally can be seen in siblings and families.5,7,8 It is sometimes asso-
ciated with diabetes mellitus, renal failure, hepatic insufficiency, and con-
gestive cardiac failure.9,10 It is unclear whether Kyrle's disease is a distinct
Fig. 9.134 entity. Some cases clearly overlap with a perforating folliculitis and reports
Elastosis perforans of examples in patients with diabetes and renal failure may actually represent
serpiginosa: high-power examples of the latter condition. An overlap with Flegel's disease has also
view. been described.11

The precise pathogenesis of Kyrle's disease is unknown; however, it has been
suggested that the lesions develop as a consequence of rapid and abnormal
keratinization, which proceeds at a faster rate than epidermal proliferation,
with consequent premature and abnormal differentiation of all the epidermal
layers. In most instances, this is complicated by dissolution of the epidermal
basement membrane region, with extrusion of keratinous debris into the der-
mis and subsequent development of a foreign body granulomatous reaction.
Following this, the epithelium adjacent to the site of the breach proliferates
downwards and, by fusion medially, eventually walls off the inflamma-
tory debris. Subsequent epidermal proliferation deep to the debris results in
Fig. 9.135
Elastosis perforans serpiginosa: the elastic fibers stain strongly with elastic-van Gieson in
the superficial dermis, but less strongly as the fibers undergo transepidermal elimination.
manifest pseudoepitheliomatous hyperplasia. Commonly, a foreign body

giant cell reaction is present in the superficial dermis and occasionally elas-
tophagocytosis is evident.
In the penicillamine-induced variant the elastic fibers characteristically have
an irregular, serrated, saw-toothed border.7 Ultrastructurally, this gives the lateral
borders of the affected elastic fibers a ‘lumpy bumpy’ appearance.5
Although elastic fibers may be found within the dilated follicle in perforat-
ing folliculitis, they are neither abnormal in appearance nor increased in Fig. 9.136
Kyrle’s disease: multiple
quantity as seen in elastosis perforans serpiginosa. Keratosis pilaris is associ-
umbilicated lesions are
ated with keratotic plugs that tend to be folliculocentric but perforation and present on the thigh. The
inflammation are not features. Kyrle's disease is differentiated from elastosis largest contains a keratin
perforans serpiginosa by perforation of a keratin plug at the base of the lesion plug. By courtesy of M.M.
associated with curled hairs in the former. Table 9.3 summarizes the points of Black, MD, St Thomas’
distinction among the perforating disorders. Hospital, London, UK.
Fig. 9.137 Fig. 9.139

Kyrle’s disease: multiple keratotic lesions are present on the dorsum of the foot. Kyrle’s disease: this lesion shows a flask-shaped epidermal invagination containing
By courtesy of the Institute of Dermatology, London, UK. parakeratotic debris. In the lower-left corner of the lesion is a laminated focus of
basophilic degenerate material.
eventual transepidermal elimination. Transepidermal elimination or perfora-

tion, it seems, is of secondary rather than primary importance in this disorder.
From this description, it follows that in early lesions there may be no evidence
of an epidermal breach.
In a single case, reported regression of the lesions was seen after treatment
with clindamycin, raising the possibility of a bacterial agent in the etiology
of the disease. However, there is very little additional evidence to suggest that
the process may be triggered by bacteria.12
The histological features of an established lesion consist of a keratotic
plug filling an epidermal invagination.13–15 The keratinous plug shows parak-
eratosis and contains basophilic cellular debris (Figs 9.138, 9.139). Elastic
tissue is absent. The epithelium deep to the plug shows parakeratosis, which
extends to the point of epidermal disruption (Figs 9.140–9.143). Where the
keratinous debris is in contact with the dermis there is often a granuloma-
tous infiltrate. In more advance cases, downward epidermal proliferation and
encirclement results in incorporation of the basophilic keratotic debris into
the lower reaches of the epidermis and hence subsequent elimination. A lym-
phohistiocytic infiltrate is often seen around the epidermal downgrowth and
the superficial blood vessels. An exceptional case with acantholytic dyskera- Fig. 9.140
Kyrle’s disease: a
tosis mimicking Darier's disease has been described.16
somewhat earlier lesion
in which perforation
has not yet occurred.
Note the thinning of the
epidermis basally. Where
parakeratosis is evident
there is absence of the
granular cell layer.
Kyrle's disease must be distinguished from reactive perforating collagenosis
and elastosis perforans serpiginosa. In the former, collagen bundles may be
seen entering the lesion from the dermis; in the latter, the basophilic material
is elastic tissue. Kyrle's disease must also be distinguished from perforating
folliculitis (see above). Table 9.3 highlights points of distinction in the differ-
ential diagnosis of perforating disorders.
Perforating pseudoxanthoma elasticum

Pseudoxanthoma elasticum (Grönblad-Strandberg syndrome) is an inherited
Fig. 9.138 generalized degenerative disease of elastic tissue of which there are autosomal
Kyrle’s disease: scanning view through the center of an established lesion showing dominant and autosomal recessive variants. The disease is briefly discussed in
the keratin plug. this section since a perforating variant is recognized.
Necrotizing infundibular crystalline folliculitis 323
Perforating pseudoxanthoma elasticum is seen predominantly in multipa-

rous, obese, middle-aged and frequently hypertensive black women who present
with isolated abdominal, periumbilical involvement.1–6 Whether this represents
a forme fruste or a distinct entity is not yet known (so-called acquired pseudox-
anthoma elasticum). In some cases, however, transepidermal elimination is seen
in patients with systemic manifestations (Fig. 9.144).7 The perforating variant
may be associated with renal failure.6
The perforating subtype is characterized by transepidermal elimination of
the degenerate elastic tissue.7,8
Necrotizing infundibular crystalline

folliculitis
Clinical features
Only three cases of this distinctive entity have been reported. The first
two cases were described as a perforating disorder under the rubric tran-
sepidermal elimination of urate-like crystals but it has more recently been
Fig. 9.141 suggested that it represents a form of folliculitis.1,2 Two patients were male
Kyrle’s disease: this high-power view shows parakeratosis of the residual epithelium. with involvement of the back and the third patient was a female with a rash
on the face and a previous history of acne vulgaris. They all presented with
multiple umbilicated papules with waxy keratinous material in the center.
The lesions were asymptomatic and transient, and resolved spontaneously
without any treatment.

Although the material within the umbilicated craters resembles urate crystals
(monosodium urate monohydrate), none of the patients had evidence of gout
or hyperuricemia.
Histology is characteristic and consists of a crater full of eosinophilic
filamentous material surrounded by an amorphous matrix and bulging
into the dermis (Figs 9.145, 9.146). Focally, the filaments are distributed
in a parallel fashion mimicking urate crystals. The crystals are negatively
birefringent. Although in the first two cases a relationship with the hair
follicles was not described, in the most recent case partially destroyed hair fol-
licles were demonstrated. The residual infundibular portion of the hair folli
cles showed vacuolar and filamentous degeneration. By electron microscopy,
the filamentous material appears to represent tonofilaments.
Fig. 9.142
Kyrle’s disease: in this example there is incipient perforation.
Fig. 9.144
Fig. 9.143 Perforating pseudoxanthoma elasticum: multiple small crusted lesions are seen in a
Kyrle’s disease: high-power view showing liquefactive degeneration of the background of typical yellow papules. By courtesy of the Institute of Dermatology,
basal layer. London, UK.
Fig. 9.147
Chondrodermatitis
Fig. 9.145 nodularis: this presents
Necrotizing infundibular crystalline folliculitis: note a crater like area containing as a crusted lesion on the
filamentous material. helix and may be clinically
misdiagnosed as an
epithelial neoplasm.
By courtesy of R.A.
Marsden, MD, St George’s
A further study described an association with systemic vascular diseases and

connective tissue diseases including lupus erythematosus and rheumatoid
arthritis in a group of younger patients, with a predilection for females.9

The etiology is multifactorial, but trauma is likely to be of primary importance.
The exposed position of the ear, together with a known history of solar or physi-
cal trauma, appears important as many patients have outdoor jobs and evidence
of solar damage elsewhere. Of historic interest, in the past there appeared to be
a high frequency of cases in telephonists and nuns (wearing a wimple), again
supporting the role of physical trauma to the ear. Other factors including cold,
anatomical aberrations of the ear (such as a poor vascular supply), and senile
degeneration of the cartilage may play a role in development.3 Recently, it has
Fig. 9.146 been suggested that the process is due to arteriolar narrowing in the perichondrial
Necrotizing infundibular crystalline folliculitis: filamentous material mimicking urate region of the pinna.10 It is most unlikely, however, that the cartilaginous changes
crystals. described below are anything other than secondary. An exceptional case described
the simultaneous occurrence of the disease in middle-aged monozygotic twins.11
The pathogenetic mechanism of chondrodermatitis nodularis has been
Chondrodermatitis nodularis chronica interpreted as representing the process of transepidermal elimination.3 This
phenomenon occurs when a disturbance in the dermis initiates an epidermal
helicis response. Foreign material in the dermis may elicit one of three responses:
• If the material is inert, there is no response.
Clinical features • If the material is an irritant, either a superficial abscess or necrosis will
Chondrodermatitis nodularis chronica helicis presents as a small, usually soli- develop.
tary, painful dome-shaped nodule on the helix of the ear, most commonly in • The material (in this case degenerate collagen) may be eliminated by a
males over 40 years of age (mean age 60 years) and develops as a consequence gradual process of transepidermal elimination.
of chronic trauma (Fig. 9.147).1–3 Bilateral involvement is very rare.4 The Ulceration, although usual, may not be seen in early lesions.3,6 The epithe-
process is less common in women, when it is usually located on the antihe- lium on either side of the ulcer is hyperplastic and shows features of lichen
lix. Cases in children are exceptional.5 The pain is typically severe enough to simplex chronicus (Figs 9.148, 9.149). Pseudoepitheliomatous hyperplasia
wake the patient at night if the affected ear touches the pillow. In the majority is occasionally evident.6,12 Lesions have sometimes been shown to be related
of patients, symptoms are present for 2–3 years.3 to the follicular infundibulum.6 The crateriform ulcer contains keratinous
On close examination, a firm crust with a small erosion or tiny channel and epidermal debris superimposed on a focus of fibrinoid necrosis of the
underneath usually covers the nodule. Lesions measure 3–15 mm in diameter.6 underlying dermal collagen (Fig. 9.150). The base and radial edges of the
After surgical treatment there is a recurrence rate of 20%. Chondrodermatitis is lesion contain granulation tissue and a variable chronic inflammatory cell
frequently mistaken for squamous cell or basal cell carcinoma, but the clinical infiltrate, comprising lymphocytes, histiocytes, and occasional plasma cells
history and auricular location should allow the diagnosis to be made without (Fig. 9.151). Vascular thromboses and hair shaft fragments are sometimes
difficulty. Nevertheless, histological confirmation is advisable. An association evident.6 Nerve hyperplasia may be found and it has been suggested that this
with systemic sclerosis and childhood dermatomyositis has been reported.7,8 may explain the pain experienced by pressure.13
Chondrodermatitis nodularis chronica helicis 325
Fig. 9.150
Fig. 9.148 Chondrodermatitis nodularis: note the fibrin and intensely eosinophilic degenerate
Chondrodermatitis nodularis: this is a section through the center of the lesion cartilage.
showing ulceration. The adjacent epithelium is hyperkeratotic, parakeratotic, and
acanthotic. There is chronically inflamed granulation tissue at the base of the lesion.
Cartilage is evident in the center field.
Fig. 9.151
Fig. 9.149 Chondrodermatitis nodularis: high-power view of granulation tissue and
Chondrodermatitis nodularis: there is abundant granulation tissue at the base and inflammation.
adjacent to the ulcer.
It is thought that the pathogenetic process at advanced stages of this dis- Differential diagnosis
ease represents the transepidermal or, occasionally, transfollicular elimination
of damaged collagen.3,14 There are often degenerative changes present in Punch biopsies, which show the characteristic layering of fibrin, granula-
the underlying cartilage, including hyalinization, tinctorial changes, and tion tissue, and degenerating cartilage, are diagnostic and distinctive. Often,
perichondritis. Occasionally, degenerate and fragmented cartilage may also superficial shave biopsies sample only fibrin and granulation tissue without
be seen undergoing transepidermal elimination. The adjacent dermis often cartilage. Nevertheless, if the clinical setting is appropriate, the diagnosis can
shows marked solar elastosis.3 still be suggested.
Inflammatory diseases of the
10
Chapter
subcutaneous fat
See
for references and
additional material
Erythema nodosum 327 Crystal-storing histiocytosis 346 Familial partial lipodystrophy (Dunnigan
Erythema nodosum-like lesions in Behçet’s Gouty panniculitis 346 variant) 354
disease 332 Familial partial lipodystrophy (Köbberling
Nodular vasculitis 346 variant) 354
Weber-Christian disease 332 Familial partial lipodystrophy associated with
Subcutaneous sarcoidosis 349
α1-Antitrypsin deficiency-associated mandibuloacral dysplasia 355
Neutrophilic lobular panniculitis associated
panniculitis 333 Acquired lipodystrophy 355
with rheumatoid arthritis 349
Factitial and traumatic panniculitis 334 Acquired generalized lipodystrophy 355
Eosinophilic panniculitis 350 Acquired partial lipodystrophy 355
Cold panniculitis 337
Infective panniculitis 350 Localized lipoatrophy 356
Cytophagic histiocytic panniculitis 337 Lipoatrophic panniculitis 356
Acute infectious id panniculitis –panniculitic
Subcutaneous Whipple’s disease 339 bacterid 352 Lipophagic panniculitis of
childhood 357
Pancreatic panniculitis 339 Sclerosing panniculitis 352 Connective tissue panniculitis 357
Subcutaneous fat necrosis of the Membranous fat necrosis 353 Lupus erythematosus profundus 358
newborn 340 Scleroderma panniculitis 361
LIPODYSTROPHY 354 Dermatomyositis panniculitis 361
Sclerema neonatorum 343 Postirradiation pseudosclerodermatous
Familial lipodystrophy 354
panniculitis 361
Cutaneous oxalosis 343 Congenital generalized lipodystrophy
(Berardinelli-Seip syndrome) 354
Calciphylaxis 344
Inflammatory diseases of the subcutaneous fat are a source of considerable

confusion and often cause diagnostic difficulty to clinicians and pathologists
alike. This stems in part from the use of classifications and clinical descrip-
tions based upon time-honored but outdated literature.1–4 Inadequate biopsy
specimens are also a source of considerable difficulty, particularly the punch
biopsy specimen, which often yields no subcutaneous fat at all. Similarly,
histological subdivision into diseases that affect the lobule and those that
affect the septa is to some extent artifactual and sometimes unrewarding since
most disorders affect both.2,3,5 There is also a somewhat monotonous clinical
presentation, with most patients complaining of deep-seated, variably tender
or painful nodules, often affecting the lower extremities.
The subcutaneous fat has a limited repertoire of responses to noxious
stimuli. Fat necrosis is a common manifestation of many forms of pannicu-
litis and as a consequence there is often considerable histological overlap.
Although there are many variants of fat necrosis – including enzymatic, crys-
talline, suppurative, hyalinizing and microcystic – lipophagic fat necrosis is
the subtype most commonly encountered and is often a secondary feature
in many forms of panniculitis (Fig. 10.1). This is characterized by a lobular
infiltrate of histiocytes, xanthomatized cells, and foreign body giant cells,
frequently accompanied by granulomata (Fig. 10.2).
It is important to remember that the subcutaneous fat may be involved
in a secondary manner, for example, in the vasculitides, the deep cutaneous Fig. 10.1
fungal infections, by metastatic tumor, and following surgery or radiotherapy Lipophagic fat necrosis: numerous xanthomatized histiocytes have engulfed free
(Figs 10.3, 10.4). In this chapter the panniculitides are classified, where lipid following fat necrosis.
possible, on an etiological basis (Table 10.1).
Erythema nodosum 327
Table 10.1
Classification of panniculitis
• Erythema nodosum
– subacute nodular migratory panniculitis/erythema nodosum migrans
• Erythema induratum
– nodular vasculitis
• Panniculitis associated with connective tissue disease
– lupus panniculitis
– morphea profunda/scleroderma/eosinophilic fasciitis
– dermatomyositis
– connective tissue panniculitis
• Lipoatrophy
– localized (involutional; inflammatory, e.g. lipophagic panniculitis/
granulomatous lipoatrophy)
– lipodystrophy
• Factitial or traumatic panniculitis
– injection-induced (steroids, insulin, narcotics, other drugs)
– sclerosing lipogranuloma
– blunt trauma
• Cold panniculitis
– popsicle panniculitis
– equestrian panniculitis
Fig. 10.2 • Panniculitis of newborn or infants
Lipophagic fat necrosis: in this field xanthomatized multinucleated foreign body – sclerema neonatorum
giant cells are present. Such an infiltrate is a common manifestation of many forms – subcutaneous fat necrosis of the newborn
of panniculitis and merely reflects the presence of fat necrosis. • Drug-induced
– direct (local) effect, e.g. due to injection
– systemic effect or reaction
– poststeroid panniculitis
– lobular panniculitis secondary to ciprofloxacin
– Panniculitis associated with α1-antitrypsin deficiency
• Calcifying panniculitis
– renal failure
– parathyroid disease
• Pancreatic panniculitis
• Gouty panniculitis
• Panniculitis with cytophagic histiocytes
– cytophagic histiocytic panniculitis
– malignant histiocytosis
– sinus histiocytosis with lymphadenopathy
– T-cell lymphoma
• Eosinophilic panniculitis
– parasitic infection
– Well’s syndrome
– incidental finding of eosinophils in other forms of panniculitis
• Lipomembranous panniculitis
• Non-infectious subcutaneous granulomatous disease
– granuloma annulare, necrobiotic xanthogranuloma, rheumatoid
Fig. 10.3 nodule, sarcoidosis
‘Malignant’ panniculitis: this patient had a known history of bronchial small cell
• Infectious panniculitis
carcinoma and presented with a subcutaneous nodule on the chest wall.
• Subcutaneous Whipple’s disease
• Hemorrhagic panniculitis secondary to atheromatous emboli
• Vasculitis involving the panniculus
• Periarteritis nodosa
Reproduced with permission from Peters, M.S. and Daniel Su, W.P. (1992). Panniculitis.
Dermatologic Clinics, 10, 37–57.
There is considerable histological overlap in the various types of panniculitis

and one must take into account all the clinical information before attempting to
reach a definitive diagnosis. In patients in whom the diagnosis of panniculitis is
suspected, a deep surgical incisional biopsy is essential (Fig. 10.5). The punch
biopsy has no role whatsoever in the diagnosis of panniculitis.
Erythema nodosum
Clinical features
Erythema nodosum represents the commonest form of nodular panniculitis
Fig. 10.4 and is the prototype of septal panniculitis.1,2 It is, of course, a clinical syndrome
‘Malignant’ panniculitis: high-power view showing basophilic tumor cells with rather than a specific disease in its own right, representing a complex of
hyperchromatic nuclei. Note the crush artifact. symptoms and signs with multiple and very variable etiologies.3,4 It typically
328 Inflammatory diseases of the subcutaneous fat
Fig. 10.5
Panniculitis: a deep surgical biopsy is essential in all cases where panniculitis is
suspected. Fig. 10.7
Erythema nodosum:
the lesions are raised
and erythematous. By
Fig. 10.6
Erythema nodosum:
typical erythematous
nodule on the shins of a
young woman. From the
Smith, MD, the Institute of
Fig. 10.8
Erythema nodosum: in
affects young adults and shows a marked predilection for women (as high as this patient the lesions
9:1 in some series). Children are only rarely affected.5 Patients present with are healing and show a
characteristic bruiselike
a sudden onset of bright red, warm, tender nodules; these typically affect
appearance. By courtesy
the anterior and lateral aspects of the lower legs, but the arms, face, calves, of the Institute of
and trunk are occasionally involved (Figs 10.6, 10.7).6,7 Involvement of the Dermatology, London, UK.
soles of the feet is rare although it appears to be more often encountered
in children.8,9 The lesions are usually multiple, bilateral, symmetrically dis-
tributed, elevated above the skin surface, and measure 1–15 cm in diameter.7 and the development of new nodules at the periphery.10–13 The lesions,
Ulceration and scarring are not features. Subsequently, the erythema fades to which may persist for months or years, are usually associated with only
a bluish or livid hue and then to a yellow discoloration, reminiscent of a bruise mild symptoms.10 Recurrences are sometimes encountered. Scarring
(Fig. 10.8). The duration of the illness is 3–6 weeks. Patients sometimes also is not a feature. This variant is typically asymmetrical, unilateral,
have pyrexia, malaise, and vague aches and pains in the joints. Laboratory and distributed solely on the leg. It also shows a marked female
findings may include a raised erythrocyte sedimentation rate (ESR), leukocy- predominance (approximately 9:1), but tends to affect an older age group
tosis, and mild anemia.3 than classic erythema nodosum (mean age 50 years).11
Two clinical variants have been described. • Chronic erythema nodosum, a somewhat controversial entity, is
• Erythema nodosum migrans (subacute nodular migratory panniculitis, characterized by the presence of nodules over a course of months or even
migratory panniculitis) is similar to classic erythema nodosum, but the years.14 Otherwise, the clinical features appear indistinguishable from the
lesions appear to migrate due to central clearing of established lesions more typical condition.

The etiology and pathogenesis of erythema nodosum are unknown. Despite
the very occasional finding of immunoreactants (IgM or IgG, and C3) in the
blood vessel walls, an immune complex-mediated vasculitis is not consid-
ered likely.6 It is probable that erythema nodosum represents a non-specific
hypersensitivity reaction that involves delayed hypersensitivity mechanisms
in addition to a type 3 component.
There are many known associations. Although some are certainly of sig-
nificance in the etiology of this dermatosis, many are probably coincidental
(Table 10.2).15–28 In the earlier part of the twentieth century, tuberculo-
sis was noted in up to 90% of adult patients with erythema nodosum, but
this is now found in less than 1% of cases. Today, the more frequent asso-
ciations include streptococcal infections, sarcoidosis, ulcerative colitis and
Crohn's disease, Sweet's syndrome, Behçet's disease, menstruation, preg-
nancy, estrogens and the oral contraceptive, cat scratch disease and various
drug treatments (e.g., bromides, antibiotics, and sulfonamides). Other infec-
tious conditions that have been described in association with erythema nodo-
sum include cytomegalovirus, Epstein-Barr virus, parvovirus b19, Yersinia,
Mycoplasma, Chlamydia, Brucella, Bartonella, Rickettsia, Helicobacter Fig. 10.9
pylori, hepatitis B, atypical mycobacterial infections (e.g., swimming pool Erythema nodosum: this example shows the classical appearance of septal inflammation
granuloma), Salmonella, Shigella, meningococcal septicemia, Q fever, lep- with spread into the immediately adjacent lobule, giving rise to a lacelike appearance.
tospirosis, syphilis, human immunodeficiency virus (HIV), kerion, histo-
plasmosis, blastomycosis, amebiasis, ascaris, Chlamidophila pneumonia,
and giardiasis.15,25–27,29–49 Additional drugs that have been implicated in the
development of erythema nodosum include isotretinoin, interleukin (IL)-2,
minocycline, thalidomide, echinacea, gold salts, hepatitis B vaccine, all-trans-
retinoic acid, capecitabine, azathioprine, aromatase inhibitors, cabergoline,
and lidocaine.16,50–62 Erythema nodosum has also been reported following
a variety of malignancies including Hodgkin's lymphoma, myelodysplastic
syndrome, hairy cell leukemia, acute myeloid leukemia, acute myelomono-
cytic leukemia, diffuse large B-cell lymphoma, hypernephroma, non small cell
lung carcinoma, pheochromocytoma, carcinoid tumor, hepatocellular carci-
noma, carcinomas of the colon, pancreas and uterine cervix, and after radio-
therapy.63–79 In 20–30% of patients no obvious cause is identified (idiopathic
erythema nodosum).2 Erythema nodosum in renal transplant recipients can
be related to infections, malignancies, drugs, inflammatory bowel disease or
autoimmune diseases.80
Erythema nodosum migrans seems to be particularly related to pregnancy,
the oral contraceptive, streptococcal infection, and thyroid disease.10–12 Many
cases, however, have no obvious associated predisposing factors or conditions.
Histologically, erythema nodosum represents the prototype of septal pan-
niculitis. It is characterized by a combination of features, including vascular Fig. 10.10
change, septal inflammation, hemorrhage, and a variable degree of acute Erythema nodosum: in the acute phase, venulitis is very occasionally present
or chronic panniculitis (Fig. 10.9). Although it is often said that erythema although many sections or levels must be examined before its presence is detected.
nodosum characteristically affects the septal component of the panniculus,
it should be noted that there is not infrequently involvement of the lobule,
in part or in whole, particularly if older lesions are biopsied. In the past,
cases of the latter might have been diagnosed as Weber-Christian disease.
Frank vasculitis is only very exceptionally encountered. When present, it
involves the small veins, and very occasionally medium-sized vessels within the
connective tissue septa.81 It may be acute and necrotizing, associated with thrombo-
sis and hemorrhage, or may manifest as chronic venular inflammation associated
with endothelial cell swelling (Figs 10.10, 10.11). The overlying dermis typically
shows a perivascular and periadnexal chronic inflammatory cell infiltrate.
Table 10.2
Erythema nodosum: etiology
Streptococcus Sarcoidosis
Tuberculosis Sweet’s syndrome
Chlamydophila psittaci Cat scratch disease
Crohn’s disease Yersinia infection
Drugs Ulcerative colitis Fig. 10.11
Behçet’s disease Malignancy Erythema nodosum: in this field there is a thrombosed venule associated with
marked hemorrhage.
In the early stages, the septal inflammation may be acute, characterized

by an infiltrate of neutrophil polymorphs, but this is soon replaced by
lymphocytes and histiocytes (Figs 10.12–10.14).82,83 Eosinophils are some-
times found and rarely they can be conspicuous. Septal collections of histio-
cytes surrounding a cleftlike space (so-called Miescher's radial granuloma)
are said to be a characteristic feature, although they have been reported in
Sweet's syndrome, nodular vasculitis, and necrobiosis lipoidica (Figs 10.15–
10.17).2,84,85 Further progression leads to the development of a frankly gran-
ulomatous infiltrate in which giant cells may be conspicuous. Coagulation
and caseation-like necrosis are never seen in erythema nodosum (compare
with nodular vasculitis below). Sometimes the connective tissue in the fibrous
septa shows fibrinoid necrosis, and hemorrhage is almost invariably present
(Figs 10.18–10.20).
Characteristically, the septal infiltrate (lymphocytes, histiocytes,
and granulomata) spills over to affect the periphery of the fat lobule
to give a delicate lacy appearance, but fat necrosis is not usually pres-
ent. On occasion, however, otherwise typical erythema nodosum may be
associated with fat necrosis and a neutrophil inflammatory cell infiltrate
(Fig. 10.21).81,86
If an older lesion is biopsied, septal fibrosis can sometimes be quite marked. Fig. 10.14
Erythema nodosum: close-up view of cellular infiltrate.
Residual granulomatous inflammation is usually present.
Fig. 10.12 Fig. 10.15

Erythema nodosum: there is septal thickening with a lymphohistiocytic infiltrate. Erythema nodosum: collections of histiocytes known as Miescher’s granulomata
are a common finding. Fibrinoid necrosis affecting a small venule is also present.
Fig. 10.13 Fig. 10.16

Erythema nodosum: this view shows the interface between the septum and the Erythema nodosum: in this example multiple small granulomata are evident in the
lobule. thickened septa.
Fig. 10.17 Fig. 10.20

Erythema nodosum: high-power view of granulomata. Erythema nodosum: in this example there is massive hemorrhage. Subsequent
breakdown with hemosiderin formation accounts for the clinical appearance of bruising.
Fig. 10.18 Fig. 10.21

Erythema nodosum: fibrinoid necrosis of the connective tissue septa is an occasional Erythema nodosum: focal fat necrosis associated with lipid-laden histiocytes.
feature.
A B
Fig. 10.19
Erythema nodosum: there is marked red cell extravasation.
Erythema nodosum migrans is characterized by densely scarred and

thickened interlobular septa accompanied by a conspicuous granulomatous
infiltrate (Figs 10.22, 10.23). Numerous giant cells may be seen and often
they form a palisade along the septal borders. Granulation tissue-like vascular
proliferation is often a conspicuous feature. Vasculitis is absent and hemor-
rhage is not usually seen.
In chronic erythema nodosum the histological changes are similar to, but
usually milder, than those of the acute variant.11
At scanning magnification, vasculitic processes affecting the septa of the subcu-
taneous fat may be mistaken for erythema nodosum. Occasionally, the features
of leukocytoclastic vasculitis are seen within the septa in the absence of the more
usual superficial dermal involvement.87 Such instances present as erythematous
nodules, usually affecting the lower legs. Similarly, superficial thrombophlebi-
tis presents within the subcutaneous fat septa. In this condition, however, the
vein is the focus of the inflammatory process with associated thrombosis and
there is little or no involvement of the lobule. Cutaneous polyarteritis nodosa
affects muscular arteries within the lower dermis and subcutaneous fat septa
and, therefore, should not be confused with erythema nodosum.87 Nephrogenic Fig. 10.23
Erythema nodosum migrans: close-up view showing granulomata and newly
systemic fibrosis can rarely be associated with mild septal mononuclear cell
formed blood vessels.
infiltrates and granulomata, thereby simulating erythema nodosum.88
Erythema nodosum-like lesions in

Behçet’s disease
Recurrent erythematous, tender, nodular lesions on the lower extremities
(clinically reminiscent of erythema nodosum) are a common manifestation
of Behçet's disease.1–6 Erythema nodosum-like lesions develop in more than
40% of the patients during the course of the disease.7 Erythema nodosum-like
lesions and superficial thrombophlebitis could represent predictive markers
for visceral involvement.8
The fronts of the shins are most often affected but lesions may also
occur on the arms, face, neck, and buttocks.2 Although histologically they
have been described as showing erythema nodosum-like features, more
commonly they are characterized by a lobular or mixed septal and lobular
panniculitis associated with a neutrophil-rich infiltrate, neutrophilic vas-
culitis (affecting arterioles and venules), and associated fat necrosis.2,9 Less
often, a lymphocytic vasculitis and, exceptionally, polyarteritis nodosa-
like features are encountered. Miescher's granulomata may sometimes
be present.2,10
Weber-Christian disease
As originally defined by Christian in 1928 (relapsing febrile nodular nonsup-
purative panniculitis), this disorder was characterized by recurrent attacks of
fever associated with the development of subcutaneous tender nodules (par-
ticularly over the extremities), which were histologically characterized by the
presence of nonsuppurative panniculitis which healed to leave a depressed
scar.1–4 Lesions were said to affect mainly young white females, and although
the lower extremities were predominantly affected, the upper extremities,
buttocks, abdominal wall, breasts, and face could also be involved. Arthritis,
arthralgias, and myalgias were often present.3 A systemic variant – which
was potentially fatal and affected the intestines, mesentery, lungs, heart, and
kidneys – was also recognized.3,5
Since 1928 there have been many case reports in the literature dealing with
this so-called ‘specific disease’. In general, however, many of the (particularly
earlier) studies used imprecise clinical and histological diagnostic criteria.
Some were certainly examples of erythema nodosum. In the light of cur-
rent knowledge of the panniculitides, many cases would now be reclassified.
A Weber-Christian-like disease may be seen in erythema nodosum, fac-
titial panniculitis, lupus panniculitis, pancreatic fat necrosis-associated
panniculitis, α1-antitrypsin deficiency-associated panniculitis, connective
Fig. 10.22 tissue diseases, subcutaneous panniculitic T-cell lymphoma, and gamma-
Erythema nodosum migrans: there is marked septal thickening with conspicuous delta T-cell lymphoma.6–15 The term has also been applied to cases of infective
granulomata. Granulation tissue extends into the adjacent lobule. panniculitis, and panniculitis following jejuno-ileal bypass surgery.16–19
Weber-Christian disease 333
It seems unlikely, therefore, that Weber-Christian disease represents a distinct antitrypsin inhibition, it is also responsible for inhibition of chymotrypsin,
entity in its own right. It is proposed, therefore, to take this opportunity to bury collagenase, elastase, factor VIII, and kallikrein.7 Its deficiency has been asso-
it once and for all. As suggested by Patterson, ‘a clinical diagnosis of Weber- ciated with panacinar emphysema, noninfective (neonatal and adult) hepati-
Christian disease should signal the beginning of a search for the true cause tis, and cirrhosis. More recently, associations have also been described with
of the disorder’.9 Likewise, the term Rothmann-Makai syndrome should be cutaneous vasculitis, atopic dermatitis, psoriasis, nodular prurigo, and cold
abandoned.20 More often than not it probably represents erythema nodosum. urticaria.24 It has been proposed that absence of the protease inhibitor is asso-
ciated with unrestrained complement activation with increased inflammatory
cell activity, endothelial injury, and resultant autolytic tissue damage.25
a1-Antitrypsin deficiency-associated Immunoglobulin (IgM) and complement (C3) have been identified in
panniculitis blood vessel walls in patients with this variant of panniculitis.6 The signifi-
cance of this is uncertain.
Clinical features The gene for α1-antitrypsin on chromosome 14 has in excess of 75 alleles
and is inherited as an autosomal dominant.7 Deficiency occurs in between
Deficiency of α1-antitrypsin is associated with a severe and particularly
1:3000 to 1:5000 of white North Americans.26 The MM genotype is most
intractable form of panniculitis.1–14 Patients have recurrent episodes of pain-
common and individuals with normal activity are coded PiMM. The ZZ
ful or tender nodules which are particularly resistant to therapy. The disease
genotype is associated with deficient α1-antitrypsin activity and the pan-
shows a slight male predominance (3:2), and although a wide age range can
niculitis is usually found in PiZZ individuals.27 Instances of panniculi-
be affected (7–73 years), most patients are in their fourth or fifth decade.5,7
tis in PiMZ, PiSZ, PiMS, PiSS, and Null patients, however, have also been
Children, however, may occasionally be affected.5 The nodules, which are
recorded.28–31 Panniculitis may also develop as a consequence of dysfunc-
often precipitated by trauma, develop most often on the trunk and proximal
tional α1-antitrypsin.31,32 Recognition of this particular form is of importance
extremities, but the buttocks, chest, back, and abdomen are sometimes also
as serum α1-antitrypsin levels are normal and therefore the diagnosis can eas-
affected (Fig. 10.24). Occasionally, the disease spreads to the genitalia and
ily be missed.
involvement of the abdominal fat has been described.
The earliest changes consist of necrosis of the connective tissue in the retic-
The nodules may be erythematous and are frequently associated with
ular dermis and septa of the subcutaneous fat accompanied by a neutrophil
ulceration and the spontaneous discharge of clear or serosanguinous fluid.5
polymorph inflammatory cell infiltrate (Fig. 10.25).33 The histological fea-
Deeply penetrating sinuses associated with liquefaction of the subcutaneous
tures of an established lesion are those of a predominantly acute panniculitis
tissues are an important complication.
(Fig. 10.26). The changes, which affect the septa and the paraseptal aspect
Fever is a common accompaniment and patients often have pulmonary prob-
of the lobule, are characteristically focal in nature. In acutely inflamed areas,
lems including panacinar emphysema, chronic obstructive pulmonary disease,
large numbers of neutrophil polymorphs infiltrate the lobule. Fat necrosis is
effusions, and embolic phenomena.5,15 Peripheral edema and anasarca are occa-
common and a characteristic feature is said to be the presence of normal fat
sional manifestations. This is a particularly severe form of panniculitis, which
adjacent to necrotic and inflamed fat (Figs 10.27, 10.28).6,34 Special stains
has recently been successfully treated by the use of infusions of commercial
often show fragmentation and loss of elastic tissue.6 Z-type α1-antitrypsin
α1-antitrypsin concentrate or liver transplantation.5,9,16,17 It is thought that many of
polymers have been demonstrated in the lesional as well as unaffected fatty
the previously reported cases of Weber-Christian disease belong to this group.18
tissue by immunohistochemistry in a single patient.35 Foci of hemorrhage
Panniculitis in association with α1-antitrypsin deficiency has been induced
associated with vascular thrombosis may be present, but there is no evidence
by cryosurgery,19 pregnancy, cesarean section delivery, and clarithromy-
of active vasculitis (Fig. 10.29).6 Elsewhere, a histiocytic infiltrate is conspic-
cin leak at the site of intravenous application.17,19–21 In one patient with
uous, involving both the deep vasculature and adjacent panniculus. Lipid-
the enzyme defect, Sweet's syndrome was followed by the development of
laden foamy macrophages are sometimes evident and multinucleate giant
acquired cutis laxa (Marshall's syndrome).22 An acquired α1-antitrypsin defi-
cells are occasionally found. Healing is by fibrous scarring.
ciency panniculitis following liver transplantation has been reported recently,
which was successfully treated with re-transplantation of the liver.23
Pathogenesis and histological features The clinical features may suggest traumatic or factitial panniculitis. The
α1-Antitrypsin (a glycoprotein of hepatic derivation) is a serine protease inhib- heavy neutrophil infiltrate can cause diagnostic confusion with an infectious
itor (PI) that greatly modifies the effects of proteolytic enzymes, account- etiology.10 In cases of doubt, special stains for microorganisms should be
ing for at least 90% of serum proteolytic enzyme inhibition. In addition to performed.
Fig. 10.24 Fig. 10.25

α1-Antitrypsin deficiency-associated panniculitis: note the extensive involvement of α1-Antitrypsin deficiency-associated panniculitis: early lesion showing necrosis and
the buttocks in this young female. By courtesy of M.R. Pittelkow, MD, Mayo Clinic, acute inflammation of the deep reticular dermis. Blood vessels are also affected.
Rochester, New York, USA. By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
Fig. 10.26 Fig. 10.29

α1-Antitrypsin deficiency-associated panniculitis: there is intense acute inflammation α1-Antitrypsin deficiency-associated panniculitis: note the organizing thrombus.
extending from the septum into the edge of the lobule. Note the necrosis of the By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
adjacent dermal connective tissue. By courtesy of M.R. Pittelkow, MD, Mayo Clinic,
Rochester, USA.
Factitial and traumatic panniculitis

Clinical features
Factitial panniculitis is by definition self-induced and vigorously denied, and
may be caused by mechanical, physical, or chemical means. The diagnosis is
always worth considering in those patients with bizarre clinical lesions and
inflammatory changes in the subcutaneous fat that defy ready classification.
It should be particularly sought in those patients with panniculitis who have
a known history of psychiatric illness or drug or alcohol abuse. Lesions are
most commonly found on the more accessible sites including the buttocks
and thighs.
Mechanical causes include local pressure and repeated blunt trauma; the
latter may be readily recognized by the presence of obvious bruising. Cold is
another possible cause of factitial panniculitis.
By far the most common etiology is the subcutaneous injection of chemical
substances including drugs, oily materials, and organic matter.1–4 Panniculitis
has been described as a complication of morphine and tetanus antitoxoid
injections. Similarly, repeated injections of pentazocine cause a characteris-
Fig. 10.27 tic woody fibrosis of the skin and subcutaneous fat accompanied by deeply
α1-Antitrypsin deficiency-associated panniculitis: in this field hemorrhage is evident penetrating ulcers and hyperpigmented halos.5–7 Pentazocine abuse has been
in addition to the inflammatory changes. By courtesy of M.R. Pittelkow, MD, Mayo described, particularly in members of the medical profession.5 There appears
Clinic, Rochester, USA. to be a relationship with a personal or family history of diabetes mellitus. It
has been suggested that peripheral ischemia may be the pathogenetic link.7
A similar problem has recently been described following injections of the
opioid ketobemidone.8
An important cause of factitial panniculitis is the repeated injection of
oily materials including paraffin and liquid silicon (paraffinoma, scleros-
ing lipogranuloma, lipogranulomatous panniculitis) (Fig. 10.30).1,2,4,9–13
Sclerosing lipogranuloma was a condition usually seen in the male genitalia
that developed as a consequence of the injection of paraffin oil and related
compounds into the penis in the mistaken belief that this would enhance erec-
tions. Povidone (polyvinylpyrrolidone), a synthetic dispersing or suspending
agent which has been used in both pharmaceutical products and hair sprays,
may result in a particular characteristic histological variant of panniculitis.14,15
Associated features have included pulmonary lesions, lymphadenopathy, and
hepatosplenomegaly. Organic substances that have been implicated in the eti-
ology of factitial panniculitis include food matter, milk, and even feces.
Nodular cystic fat necrosis is a distinct posttraumatic lesion that is seen
predominantly in adolescent boys and middle-aged women. Lesions, which are
usually found on the legs, are often associated with a history of trauma.16
Traumatic fat necrosis is a not uncommon condition and occurs predom-
Fig. 10.28 inantly in middle-aged or elderly females with large pendulous breasts. Its
α1-Antitrypsin deficiency-associated panniculitis: high-power view showing an intense importance is that it may be clinically mistaken for a malignancy. In addition, it
neutrophil infiltrate. By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA. can be seen to involve the arms, trunk, buttocks, and thighs of the very obese.
Factitial and traumatic panniculitis 335
careful examination may reveal foamy histiocytes or giant cells lining the
edges of these cystic cavities (Fig. 10.32).9 There is often associated dense
fibrous scarring. Early lesions sometimes show a marked granulomatous
component.9 Similar features have been described following a grease gun
injury.29
In panniculitis due to pentazocine abuse the histological features include
dense dermal fibrosis accompanied by variable scarring of the subcutaneous
fat.5 A ‘Swiss cheese’ appearance may be evident. Small-vessel thrombosis is
frequently present.5
Povidone panniculitis is characterized by histiocytic accumulation of
gray-blue, Congo red-positive foamy material accompanied by necrosis and
hemorrhage.14
Lesions caused by blunt trauma show the features of an organizing hematoma.
Granulomata and foci of hemosiderin pigment may additionally be present.30
Nodular cystic fat necrosis is thought to have an ischemic pathogenesis.
Histologically, it is characterized by an encapsulated nodule of necrotic (anu-
cleate) fat cells (Fig. 10.33).31,32 Variable inflammation is present.
Fat necrosis with histiocytes (lipophages) and giant cells is a com-
mon histological finding in specimens taken from sites of previous sur-
Fig. 10.30 gery of the subcutaneous fat (or deeper). Zelickson and Winkelmann have
Paraffinoma: note the infiltrated plaque with foci of retraction. By courtesy of the
A number of therapeutic injections have been associated with the devel-

opment of panniculitis including interferon-beta (IFN-β),17–21 glatiramer
acetate,22–24 nadroparin-calcium25 and granulocyte colony stimulating fac-
tor.26 Aluminum granuloma may present as a panniculitis. Panniculitis
has also been documented following vitamin K1 injections27. Two patients
with factitial panniculitis caused by electroacupuncture have been recently
described.28

The histological features of factitial panniculitis are not usually specific and
depend to some extent upon the cause. In some instances, therefore, the
changes are those of acute lobular inflammation associated with fat necrosis
and a neutrophil polymorph infiltrate. In older lesions, mononuclear cells,
lipid-laden histiocytes, and foreign body giant cells become predominant and
sometimes the response becomes frankly granulomatous. On other occasions
the septa may be primarily affected, thereby mimicking erythema nodosum.
Calcification is occasionally evident.2 It is sometimes rewarding to view the
sections with polarized light, as birefractile material may be identified, raising
the possibility of the factitious nature of the condition. Fig. 10.32
Paraffinoma is characterized by the presence of round or oval spaces Paraffinoma: on high-power examination, the cystic spaces can often be seen to be
lined by lipophages.
within the dermis and subcutaneous fat (‘Swiss cheese’ pattern) (Fig. 10.31);
Fig. 10.31 Fig. 10.33

Paraffinoma: empty spaces of variable size (due to the removal of lipid during Nodulo-cystic fat necrosis: typical low-power appearance; note the encapsulated
processing) characterize this lesion. The appearance is often likened to Swiss cheese. fatty cyst, scarring, and chronic inflammation.
described this as lipophagic panniculitis.31 Hemosiderin deposits are also

commonly found and in many instances fragments of suture material may
be identified.
The histological features of traumatic fat necrosis are not specific and are
characterized by fat necrosis accompanied by a variable inflammatory cell
infiltrate (Figs 10.34, 10.35). In early lesions this is predominantly composed
of neutrophils, later replaced by lymphocytes and monocytes. Aggregates of
lipophages are seen frequently and often the reaction becomes frankly granu-
lomatous. Fat cysts are a common feature. With resolution, fibrosis takes
place (Fig. 10.36). As evidence of the traumatic nature of the lesion, foci of
hemosiderin deposition are not uncommon (Fig 10.37). Occasionally, the
presence of fat necrosis is complicated by focal calcification (Fig. 10.38).
Panniculitis after subcutaneous injection of interferon-beta can mimic
histologically erythema nodosum, lupus panniculitis, and pancreatic
panniculitis.18–20
Glatiramer acetate-induced panniculitis is characterized histologically by
a predominantly lobular inflammatory infiltrate composed of lymphocytes,
plasma cells, and scattered neutrophils and eosinophils in the background of
lipophagic granulomata.23 Reactive germinal centers may also be seen.
Interferon-beta-induced panniculitis and glatiramer acetate-induced Fig. 10.36
Traumatic fat necrosis: scarring is a feature in more chronic lesions.
panniculitis are frequently associated with subsequent lipoatrophy.18,22
Fig. 10.37
Fig. 10.34 Traumatic fat necrosis: there is marked hemosiderin deposition.
Traumatic fat necrosis: there is intense lobular inflammation with septal fibrosis and
hemorrhage.
Fig. 10.35 Fig. 10.38

Traumatic fat necrosis: collections of lipophages are characteristic. Traumatic fat necrosis: in this example there is marked granular calcification.
Cytophagic histiocytic panniculitis 337
Cold panniculitis
Clinical features
This rare condition was originally described in infants and young children
who developed tender, warm, erythematous plaques on exposed sites, namely
the cheeks and submental region, after experiencing low temperatures,1–6 and
usually appeared within the first 72 hours after exposure.7 These plaques
resolved spontaneously after 2–3 weeks, with no residual sequelae. The appli-
cation of an ice cube to a child's skin may result in the development of simi-
lar lesions. Identical changes have also been described in infants following
the sucking of ice lollies (popsicles; ‘popsicle panniculitis’).8–11 Increased satu-
rated fat content having a higher melting point may precipitate the develop-
ment of panniculitis in children.
A similar phenomenon has been described in young women following
horse riding in cold weather (equestrian cold panniculitis); these patients
develop indurated red-violaceous plaques on the superolateral aspect of the
thighs following prolonged riding in freezing conditions (Fig. 10.39).12–14
There is a tendency to ulcerate; healing is associated with postinflammatory
Fig. 10.40
hyperpigmentation and the development of depressed scars. It is thought that
Cold panniculitis: an intense inflammatory cell infiltrate is present at the junction
these lesions occur as a result of extremely cold temperatures combined with between the dermis and subcutaneous fat. By courtesy of P.H. Cooper, MD,
the effect of noninsulated, but tight-fitting, clothes which impair the circula- University of Virginia Medical Center, USA.
tion around the thighs. Recently, two patients with cold agglutinins and this
condition have been described.13
Chilblains (perniosis) also represent localized, abnormal inflammatory
responses to the cold.15 They have an acral distribution (e.g,. dorsal surfaces
of the fingers and toes) and present as pruritic erythematous lesions, which
may blister or ulcerate.
The features of cold panniculitis are most noticeable at the interface between
the dermis and subcutaneous fat (Fig. 10.40).3,8 The infiltrate, which con-
tains lymphocytes, histiocytes, and neutrophils, extends from a perivascular
location into the adjacent fat where it is associated with adipocyte necrosis
and the development of small cysts (Fig. 10.41). Excess hyaluronic acid may
sometimes be present. Granulomata are not usually conspicuous.16 The blood
vessels show thickening of their walls and endothelial swelling, but frank vas-
culitis is not a feature.
Fig. 10.41
Cold panniculitis: the infiltrate consists of lymphocytes and histiocytes.
The histological features of perniosis include intense papillary dermal

edema and a superficial perivascular mononuclear infiltrate. The blood vessel
wall characteristically shows very marked edema and often there is fibrin
deposition.15
Cytophagic histiocytic panniculitis

Clinical features
Cytophagic histiocytic panniculitis (panniculitis associated with hemophago-
cytic syndrome) was originally described as a serious disorder of immune
dysregulation.1–3 It may develop in association with a number of underlying
conditions including viral infections such as cytomegalovirus and Epstein-
Barr virus.4–8 HIV infection has also rarely been incriminated.7 Bacteria,
Fig. 10.39 fungi, and parasites are sometimes of etiological significance.9–11 The condi-
Cold panniculitis: there are
tion has been described as a complication of phenytoin therapy, following
ulcerated lesions on this
patient’s thigh. From the bone marrow transplantation, in systemic lupus erythematosus (SLE), and as
collection of the late an adverse reaction to interferon-alpha (IFN-α) therapy.12–15 Some examples
N.P. Smith, MD, the in the earlier literature were described as Weber-Christian disease.16
Institute of Dermatology, Of particular importance, the hemophagocytic syndrome may also be
London, UK. associated with a number of malignancies, most commonly T-cell lymphoma
(nodal or cutaneous).8,16–18 It is likely that many of the cases of the entity myalgia may be present. Patients commonly develop hepatosplenomegaly,
described in the past represent examples of lymphomas including subcutane- lymphadenopathy, hypertriglyceridemia, anemia, leukopenia, thrombocy-
ous panniculitis-like T-cell lymphoma, nasal-type extranodal natural killer/T- topenia, and disseminated intravascular coagulopathy.2–4 Steatohepatitis may
cell lymphoma and, particularly, gamma delta T-cell lymphoma. Rarely, an complicate exacerbation of cytophagic hemorrhagic panniculitis.21
underlying systemic B-cell lymphoma has been incriminated.19 Most patients The course of the disease is variable and to some extent depends upon the
are immunosuppressed; however, very exceptionally, the cause is unknown underlying cause.22–31 Some patients have a prolonged indolent disease over
(idiopathic histiocytic cytophagic panniculitis).17,20 It is, therefore, of particu- many years before progressing to clinical evidence of systemic hemophago-
lar importance that all patients diagnosed with this condition are investigated cytosis. Rarely, patients may present with cutaneous lesions and a relatively
to exclude an underlying lymphoma, particularly of T-cell lineage. benign illness; 20,25,30,32 others have a rapidly progressive condition with
Clinically, the cutaneous manifestations of cytophagic histiocytic pan- hemophagocytosis and its sequelae from the outset. The mortality rate for
niculitis include erythematous to violaceous or hemorrhagic nodules, which these last patients is high. In addition to the direct effects of bone marrow fail-
particularly affect the lower limbs and trunk (Figs 10.42, 10.43). In many ure and disseminated intravascular coagulation, systemic infections including
patients however, the distribution is much more widespread. Ulceration is opportunist bacteria and fungi are important causes of death.8
sometimes seen. Severe localized or generalized edema may also be a feature.18
Constitutional symptoms including pyrexia, malaise, weight loss, fatigue, and Pathogenesis and histological features
Hemophagocytosis appears to develop as a consequence of excess T-cell
cytokine production, either virally induced or as a consequence of neoplas-
tic transformation. Tumor necrosis factor-alpha (TNF-α) and IL-2 may be of
particular importance.8 Perforin gene mutation has been detected in a child
with cytophagic lymphocytic panniculitis associated with fatal hemophago-
cytic lymphohistiocytosis.33
Histologically, the lesions are characterized by an infiltrate of histiocytes
with abundant eosinophilic cytoplasm and uniform, variably hyperchromatic
or vesicular nuclei containing small nucleoli. Variable numbers of lympho-
cytes and neutrophils are also present. Although the distribution is predomi-
nantly lobular, septal involvement is usually apparent and the lower dermis
is also often involved (Fig. 10.44). Red cell extravasation is typically pres-
ent and frequently the lesions are frankly hemorrhagic. Erythrophagocytosis
is invariably a feature and phagocytosis of lymphocytes or nuclear debris is
also often evident (Fig. 10.45). The enlarged and distended histiocytes are
sometimes described as ‘bean-bag’ cells (Fig. 10.46).2,3 Giant cells and gran-
ulomata are not usually a feature unless there is concomitant fat necrosis.
Lymphoid nuclear atypia is evident in those cases in which a T-cell lymphoma
is present (see below).
Fig. 10.42 Differential diagnosis

Cytophagic histiocytic panniculitis: an extensive, erythematous, indurated plaque Cytophagic histiocytic panniculitis must be distinguished from other condi-
is present on the upper arm. By courtesy of M. Cook, MD, St George’s Hospital, tions in which erythrophagocytosis or hemophagocytosis may be a feature
London, UK. including subcutaneous T-cell panniculitic lymphoma, angiocentric lym-
phoma, and cutaneous Rosai Dorfman disease.
In subcutaneous panniculitic T-cell lymphoma, the lymphocytes show cyto-
logical atypia with karyorrhexis and mitotic activity (Fig. 10.47). Angiocentric
T-cell lymphoma is characterized by an angioinvasive and frequently
Fig. 10.43
Cytophagic histiocytic
panniculitis: in this
example the lesions
are hemorrhagic and
ulcerated. By courtesy of Fig. 10.44
M. Cook, MD, St George’s Cytophagic histiocytic panniculitis: there is a cellular infiltrate associated with fat
Hospital, London, UK. necrosis.
Pancreatic panniculitis 339
a ngiodestructive atypical lymphoid infiltrate usually accompanied by wide-

spread coagulative necrosis. In cutaneous Rosai-Dorfman disease, the infiltrate
is usually centered on the dermis. Lymphophagocytosis is often marked but
erythrophagocytosis is not usually present. The histiocytes are characteristically
S-100 protein positive.
Subcutaneous Whipple’s disease

Clinical features
Whipple's disease is a rare condition which most often affects males and is due
to infection with the bacillus Tropheryma whippeli.1,2 It is characterized by
small intestinal involvement leading to malabsorption accompanied by fever
and arthritis, although virtually any organ system may be affected. Cutaneous
lesions include hyperpigmentation, erythroderma, purpura, vasculitis,
erythematous and urticarial lesions, eczematous dermatitis and lichenoid gran-
ulomatous lesions.3,4 Exceptionally, subcutaneous nodules have been described
3,5–7 with occasional symmetrical distribution on inner thighs and forearms.8
Fig. 10.45 Histological features

Cytophagic histiocytic panniculitis: note the histiocytes with abundant eosinophilic
cytoplasm, some of which show erythrophagocytosis. Involvement of the subcutaneous fat presents as a predominantly septal ‘pan-
niculitis’ characterized by a mixed inflammatory cell infiltrate consisting
of lymphocytes, neutrophils, and foamy periodic acid-Schiff (PAS)-positive
histiocytes.4,8
Electron microscopy reveals degenerate bacilli within membrane-bound
vesicles in the cytoplasm of the histiocytes.3
More recently, diagnostic polymerase chain reaction (PCR) and immuno-
histochemical techniques have become available.9
Pancreatic panniculitis
Clinical features
In pancreatic panniculitis the association of subcutaneous fat necrosis (meta-
static fat necrosis) with pancreatic disease is very rare, but is of particular
importance because sometimes the underlying pancreatic lesion is clinically
silent. The pancreatic diseases include acute pancreatitis, chronic pancreatitis,
pancreatic pseudocyst, pancreatic divisum, and pancreatic neoplasms (mostly
acinar cell carcinoma, but also ductal carcinoma, neuroendocrine carcinoma,
and intraductal papillary mucinous neoplasm).1–24 Pancreatic panniculitis has
also been described as a possible adverse drug reaction following renal trans-
Fig. 10.46 plantation for SLE and following simultaneous pancreas-kidney transplanta-
Cytophagic histiocytic panniculitis: in the center of the field are several multinucleated tion for type I diabetes.25,26 There are two additional reports of the disease
giant cells containing phagocytosed nuclear debris (‘bean-bag’ cells). developing in a background of lupus erythematosus.27,28 Pancreatic pannicu-
litis has also been reported following L-asparaginase treatment for acute lym-
phoblastic leukemia and in a patient with nephrotic syndrome due to rapidly
progressing glomerulonephritis.29,30
Patients present with multiple, exquisitely tender nodules, which are ery-
thematous or violaceous in appearance (Figs 10.48, Figs 10.49). The lower
extremities, buttocks, and trunk are most often affected, although occasion-
ally the upper arms, thorax, and scalp are involved. Occasionally, the nodules
ulcerate and release a creamy or oily discharge (Fig. 10.50). Joint manifesta-
tions (pain and swelling) are an important feature of this syndrome, occur-
ring in approximately 54% (pancreatitis-associated) to 88% (pancreatic
carcinoma-associated) of patients.5,31–35 The ankles are most often affected,
but the knees, elbows, wrists, metacarpophalangeal, and metatarsophalan-
geal joints are occasionally involved. A single case with chondronecrosis
and osteonecrosis has been reported.36 Additional features include pleural
effusions (in 25%), ascites (in 30%) and, very occasionally, pericardial effu-
sion.4 Intramedullary fat may also be affected and intestinal involvement has
rarely been documented.1,35 Peripheral blood eosinophilia is quite a com-
mon laboratory finding (19% in pancreatitis-associated; 65% in pancreatic
carcinoma-associated). Males are affected more often than females (pan-
Fig. 10.47 creatitis 2:1; carcinoma 7:1) and patients are most often in the fourth, fifth
Subcutaneous panniculitic T-cell lymphoma: numerous histiocytes showing or sixth decade. This disease is associated with a high mortality, 42% in
hemophagocytosis are present. In addition, however, there are conspicuous pancreatitis-associated variants and up to 100% in those cases presenting
hyperchromatic and irregular atypical lymphocytes. with an u nderlying carcinoma.4
Fig. 10.50
Pancreatic panniculitis: the nodules may ulcerate and release blood-stained fluid.
Fig. 10.48 By courtesy of J.C. Pascual, MD, Alicante, Spain.
Pancreatic panniculitis:
early lesions are often
erythematous. By courtesy
of J.C. Pascual, MD,
Alicante, Spain.
Fig. 10.51
Pancreatic panniculitis: the changes predominantly affect the lobules.
vasculitis, most frequently, however, the changes are lobular in distribu-

tion and are characterized by the presence of ghost cells (Fig. 10.52).38
Fig. 10.49 The latter are anucleate, composed of amorphous granular debris, and
Pancreatic panniculitis: a more advanced lesion. From the collection of the late
often show a rim of eosinophilia (Fig. 10.53). Stippled basophilia due
N.P. Smith, MD, the Institute of Dermatology, London, UK.
to calcification is commonly found (Fig. 10.54). A neutrophil poly-
morph response is usually evident around the foci of fat necrosis, and
hemorrhage is an almost invariable feature (Fig. 10.55). The uninvolved
Pathogenesis and histological features surrounding fat is heavily infiltrated by acute and chronic inflammatory
The development of subcutaneous fat necrosis in association with pancreatic cells including large numbers of macrophages, many of which have foamy
disease is due to the release into the peripheral circulation of trypsin, lipase, cytoplasm due to ingested lipid, and occasional multinucleate giant cells
phospholipase, and amylase.7,37 It has been postulated that trypsin damages (Fig. 10.56). There is no evidence of a vasculitis. Birefringent crystals
the vasculature, particularly in dependent sites, thereby permitting lipase to have been described in the mesenteric fat and within affected joints but
enter the surrounding tissues. In vivo evidence suggests that this may be too not in the subcutaneous fat.39,40
simplistic a viewpoint.9 Serum lipase levels do not always correlate with sub-
cutaneous fat necrosis and examples of patients with fat necrosis and normal
serum lipase levels have been documented.10 The reports of Wilson et al. and Subcutaneous fat necrosis of the newborn
Simkin et al., however, provide striking in vivo evidence to support a patho-
genetic role for released pancreatic enzymes.31,32 Clinical features
Histologically, the features are pathognomonic and are identical to This uncommon disease presents in full-term or post-term neonates in the
those seen in the peripancreatic adipose tissue following an episode first few weeks of life.1–4 Affected babies develop painless subcutaneous nod-
of acute hemorrhage pancreatitis (Fig. 10.51). Although very early ules measuring from a few millimeters to several centimeters in diameter.
changes can show features of septal panniculitis without fat necrosis or The overlying skin may appear normal or be erythematous or violaceous.
Subcutaneous fat necrosis of the newborn 341
Fig. 10.52 Fig. 10.55

Pancreatic panniculitis: there is extensive enzymatic fat necrosis. Note the Pancreatic panniculitis: there is a heavy neutrophil infiltrate.
characteristic ghost cells.
Fig. 10.53 Fig. 10.56

Pancreatic panniculitis: close-up view of ghost cells. Pancreatic panniculitis: as with other forms of fat necrosis, lipophages are often
evident.
Lesions are symmetrical and distributed over bony prominences, the arms,
shoulders, buttocks, thighs, and cheeks (Fig. 10.57). The nodules frequently
soften and become fluctuant, occasionally liquefying. The disease is usually
self-limiting and benign, spontaneous resolution occurring within a period of
weeks to months in the majority of cases. Occasionally, however, it is asso-
ciated with hypercalcemia, dyslipidemia, thrombocytopenia, and lactic aci-
dosis.4–11 Hypercalcemia may be asymptomatic and associated with failure
to thrive, fever, vomiting, irritability, and seizures.1,12 Calcium deposits have
been described in the kidneys, liver, inferior vena cava, and heart.4,13 Delayed
onset of hypercalcemia up to 6 months after occurrence of the subcutaneous
fat necrosis of the newborn is also possible.14 Exceptionally, this disease can
prove fatal.

The pathogenesis of the hypercalcemia is unknown. A number of theo-
ries have been proposed including calcium release from resolving plaques,
elevated parathormone and prostaglandin E2 levels, increased vitamin D
sensitivity and, most recently, lesional histiocytic production of excessive
Fig. 10.54 1,25-dihydroxyvitamin D3 with resultant increased intestinal absorption of
Pancreatic panniculitis: the stippled basophilia represents calcification. calcium.15–23
Fig. 10.58
Fig. 10.57 Subcutaneous fat necrosis of the newborn: multiple foci of fat necrosis with chronic
Subcutaneous fat necrosis inflammation are present.
of the newborn: crusted,
ulcerated nodules on both
cheeks. By courtesy of the
London, UK.
The cause of subcutaneous fat necrosis of the newborn is unknown, but

most cases are related to some form of fetal distress, including obstetric or other
birth trauma, cord accidents, meconium aspiration, infections, hypothermia,
placenta previa, cesarean section and neonatal asphyxia.2,4 Pre-eclampsia and
maternal diabetes have also been associated with this condition.4,7 A primary
abnormality of subcutaneous fat may be of some importance.24 Neonatal fat
is characterized by elevated levels of saturated fatty acids which have a high
melting point and are therefore susceptible to precipitation as a consequence
of neonatal hypothermia. Deficiency of brown fat has also been proposed
as a potential etiological factor.25 Although not histologically confirmed, a
case of simultaneous development of sclerema neonatorum and subcutane-
ous fat necrosis of the newborn was described in an infant following cesar-
ean section for fetal distress, hypothermia, neonatal respiratory distress, and
hypoglycemia.26
Subcutaneous fat necrosis has also been described after hypothermic car-
diac surgery, as a complication of congestive heart failure in an infant with A
ventricular septal defect and patent ductus arteriosus, associated with mater-
nal diabetes, increased blood pressure, smoking, thrombosis-related risk
factor, a possible complication of cocaine abuse, following the in partum use
of calcium-channel blockers and as a consequence of prolonged exposure in
very cold weather.4,27–33
The histological changes are characteristic.21,34–36 The subcutaneous fat
is the scene of intense necrosis. Individual adipocytes are swollen and con-
tain abundant radially arranged eosinophilic crystalline spaces resulting
from dissolved lipid (Figs 10.58, 10.59). The crystals are largely composed
of triglycerides.35 There is a heavy inflammatory cell infiltrate comprising
polymorphs, lymphocytes, histiocytes, and numerous foreign body giant
cells (Fig. 10.60). Large numbers of eosinophils have been described in two
cases.21 Multinucleated giant cells containing eosinophilic granules in their
cytoplasm have recently been reported.37,38 The significance of these granules
is unknown, and their origin from degranulating eosinophils has been pos-
tulated.37 Older lesions may show fibrosis and foci of calcification. Systemic
involvement is sometimes present.36
B
It is of interest to note that identical histological features were seen some years Fig. 10.59
ago in the poststeroid panniculitis syndrome.39–44 This condition occurred in (A, B) Subcutaneous fat necrosis of the newborn: individual adipocytes are swollen
children who had been treated for rheumatic fever or glomerulonephritis and contain characteristic, radial, eosinophilic crystals.
Cutaneous oxalosis 343
importance.9 Sclerema neonatorum is characterized by increased blood lipid

peroxidation and diminished superoxidase dismutase activity, which raises
the possibility that free radicals may play a role in its pathogenesis.10 There is
no evidence of vasculitis.
The histological features are surprisingly bland. The subcutaneous fat
is greatly thickened and the fibrous septa are broader than normal. The
adipocytes, which are increased in size, may contain radially orientated
fine crystals identical to those described in subcutaneous fat necrosis of
the newborn although often they are inconspicuous.1,11 In contrast to the
latter condition, however, there is no necrosis or significant inflammatory
cell infiltrate. Calcification is rarely a feature.1 The dermis may appear
sclerotic with hyalinization and the epidermis atrophic with loss of the rete
ridges.11
Cutaneous oxalosis
Clinical features
Oxalosis, in which there is widespread deposition of calcium oxalate in the
Fig. 10.60 tissues, may represent a primary metabolic disease or a secondary phenom-
Subcutaneous fat necrosis of the newborn: surrounding the foci of fat necrosis is a enon due to increased intake of oxalate precursors or defective excretion.1–5
chronic inflammatory infiltrate containing numerous foreign body giant cells.
Secondary oxalosis can also result from pyridoxine deficiency, glycerol
infusion, methoxyflurane anesthesia, excessive ascorbic acid, extensive hemo-
with very large doses of steroids; sudden withdrawal of the steroids resulted dialysis, peritoneal dialysis, and ethylene glycol poisoning.2
in the development of subcutaneous swellings up to 4 cm across on the Primary oxalosis, which is associated with overproduction of oxalate, is
cheeks, arms, and trunk. The disease is now of historic interest only due to an autosomal recessive condition and includes three subtypes:
the standard practice of steroid taper when withdrawing the drug. The skin • Type I, which is most often encountered, develops as a result of deficiency
overlying the nodules was erythematous, warm, and itchy. In mild cases the of the hepatic enzyme alanine:glyoxylate aminotransferase with resulting
panniculitis resolved spontaneously; in more severe examples it subsided fol- increased urinary excretion of oxalate, glycolate and glyoxylate.1–3
lowing the reintroduction of steroids. Poststeroid panniculitis has recently • Type II (L-glyceric aciduria) results from cytosolic D-glycerate
also been reported in an adult patient.45 dehydrogenase and glyoxylate reductase deficiencies with associated
increased urinary excretion of L-glycerate and oxalate accompanied by
normal glycolate and glyoxylate excretion.4
Sclerema neonatorum • Type III develops as a result of primary small intestinal disease associated
with excessive oxalate reabsorption.5
Clinical features Calcium oxalate crystal deposition occurs most commonly in the kidneys
Sclerema neonatorum is a very rare condition associated with high morbidity (calcium oxalate stones and chronic renal failure).4 With the onset of the
and mortality (75–90%).1 It is sometimes confused with, and therefore must latter, hyperoxalemia develops with resultant deposition of oxalate crystals
be distinguished from, subcutaneous fat necrosis of the newborn.2–4 Infants in the blood vessels, retina, myocardium, cardiac conducting system, central
present in the first week of life (average age of onset, 4 days; range, birth to nervous system, peripheral nerves, bones, and joints.6
70 days) with a diffuse, rapidly spreading, waxlike thickening and induration of Cutaneous manifestations may occur in both primary and secondary
the subcutaneous fat, resembling lard. This usually commences about the but- forms.6–24 Lesions most often result from vascular involvement, patients
tocks, thighs, and trunk and often spreads to involve the whole body, excluding presenting with acrocyanosis, livedo reticularis, Raynaud's phenomenon,
the palms, soles, and genitalia. The fat is typically tethered to the underlying and distal gangrene (Fig. 10.61).7–12 Ulceronecrotic lesions reminiscent
fascia and the skin cannot be grasped between the fingers. Pitting edema is not
a feature.
Affected infants are usually hypothermic, but body temperature may be
normal or, rarely, raised.5,6 Some of the infants are premature, but they are
a minority. The children commonly have some other associated illness, such
as septicemia, pneumonia, diarrhea, dehydration, intestinal obstruction, con-
genital heart disease or other congenital malformations.7 A patient with both
sclerema neonatorum and concurrent subacute fat necrosis of the newborn

The etiology and pathogenesis of this condition are uncertain. It is thought
that the structural alterations of the subcutaneous fat probably predate the
development of the clinical features. Neonatal subcutaneous fat is character-
ized by a higher content of saturated fatty acids (palmitic and stearic) and a
lower content of unsaturated fatty acids (oleic) than adult subcutaneous fat.2
It also has higher melting and solidification points. It has been suggested that
infants with sclerema neonatorum have an inadequately developed enzyme
system for converting saturated to unsaturated fatty acids.2 It is thought that
this, in association with stress, might result in the precipitation of triglycerides
and consequent solidification of the subcutaneous fat. Recently, it has been Fig. 10.61
proposed that redistribution of blood flow to the systemic circulation with Cutaneous oxalosis: this child shows gangrene with ulceration. By courtesy of
resultant relative ischemia of the subcutaneous fat may be of pathogenetic N. Saxe, MD, Groote Schuur Hospital, Cape Town, South Africa.
Fig. 10.62 Fig. 10.64

Cutaneous oxalosis: note the radially orientated, needle-shaped crystals. Cutaneous oxalosis: in this field there is dramatic vascular involvement with
destruction of the media and massive intimal thickening.
Calciphylaxis
Clinical features
Calciphylaxis was originally defined by an experimental model in rats, in
which sensitization with parathormone or dihydrotachysterol followed by
the injection of a challenging agent such as a metal salt resulted in localized
necrosis and calcification.1 The term was subsequently adopted to describe
a condition in which an abnormality of calcium/phosphate metabolism is
followed by calcification of the vasculature of the subcutaneous fat with
subsequent thrombosis accompanied by extensive skin necrosis.2–7
Calciphylaxis presents clinically as an often bilateral and symmetrical,
pruritic, and frequently painful/tender eruption most often affecting the
lower limbs (Fig. 10.65). Less often, lesions may affect the breasts, but-
tocks, abdomen, and penis.8–24 Lesions are often well-delineated, livedoid,
violaceous plaques and nodules associated with ischemic necrosis of the under-
lying tissues, sometimes extending down to the fascia. Ulceration is typically
present and sometimes bullae are a feature. Gangrene and autoamputation
may accompany acral involvement.6 Intestinal involvement with massive
Fig. 10.63 hemorrhage has exceptionally been documented.16
Cutaneous oxalosis: note the radial crystals viewed under polarized light.
of calciphylaxis have also been documented.13–15 Less often, crystals are

deposited in the skin of the face and the fingers as miliary deposits, as dermal/
subcutaneous nodules or as painful subungual nodules.16–21 Exceptionally,
generalized cutaneous nodules have been documented.22 Vascular involve-
ment is said to be more common in patients with primary disease whereas
cutaneous extravascular lesions are predominantly seen in patients with sec-
ondary disease.21
Calcium oxalate crystals are yellow to brown, radially arranged, needle-
shaped or rectangular in shape (Figs 10.62, 10.63). In the skin they may
be found in the reticular dermis or within the subcutaneous fat. Vascular
involvement may also be seen where the media of arteries is predomi-
nantly affected (Fig. 10.64). Less commonly, crystals may be seen within
the lumina of smaller arteries or arterioles.1,11,12 The crystals show striking
yellow or blue birefringence when examined in polarized light. They are
sometimes accompanied by a foreign body giant cell reaction, particularly Fig. 10.65
when present as dermal or subcutaneous deposits.8,18,22–24 In those cases Calciphylaxis: ulcerated gangrenous lesion with surrounding erythema. By courtesy
associated with gangrene or livedo reticularis, fibrin thrombi may also be of A. Qureshi, MD, Department of Dermatology, Brigham and Women’s Hospital,
detected.8 Boston, USA.
Calciphylaxis 345
Calciphylaxis is associated with considerable morbidity and a high mortal-

ity of up to 60%.4,14 The majority of patients succumb to secondary infection.
Calciphylaxis due to the end-stage kidney disease can exceptionally develop
in children, with four patients reported to date.25

The precise mechanism by which the subcutaneous vasculature undergoes
calcification is uncertain but is probably multifactorial. In the majority of
patients, however, sensitization occurs as a consequence of abnormal cal-
cium/phosphorus metabolism in a setting of chronic renal failure and second-
ary or tertiary hyperparathyroidism. Frequently, the patients are undergoing
dialysis. Less often, there is a background of primary hyperparathyroidism
or hypervitaminosis D.4,12,14,17 Although in many patients calcium deposition
occurs in association with an increased calcium-phosphorus product, in a
significant proportion of patients calcium and phosphorus levels are nor-
mal.4 It has been suggested that in such patients the calcification develops as
a direct response to excess parathormone or vitamin D. Challenging agents
resulting in the vascular precipitation of calcium salts are unknown but a
number of substances (including albumin, corticosteroids, and immunosup-
Fig. 10.67
pressives) have been incriminated.12 Calciphylaxis has also been described in Calciphylaxis: calcification of the small vessels and capillaries within the subcutaneous
association with decreased functional protein C.13 Very rarely, the condition fat is evident.
has presented in a patient with no evidence of a renal disorder or increase
in parathormone level.17 Malignant tumors, rheumatoid arthritis, giant cell
arteritis, as well as alcoholic liver disease have been implicated in these
patients.26
Histologically, the characteristic feature is calcification of the small- to
medium-sized arteries and arterioles (Figs 10.66, 10.67). Calcified debris
may sometimes be present within the lumina and occasionally the vessels
are thrombosed (Fig. 10.68). Intimal fibroblastic proliferation with luminal
narrowing has also been described (Fig.10.69).9 Hemorrhage within the
subcutaneous fat may be seen and fat necrosis accompanied by a lobu-
lar lymphohistiocytic infiltrate has been documented in a number of cases
(Fig. 10.70). Interstitial calcification is only rarely a feature.9 Exceptionally,
pseudoxanthoma elasticum-like changes have been documented.27 In a related
phenomenon, epidermal and follicular calcification have been described in
the absence of vascular lesions in a patient with toxic epidermal necrolysis in
a background of hyperparathyroidism.28
Calcification involving small arteries and arterioles not accompanied by
thrombosis has been described in patients with nephrogenic systemic fibro-
sis.29 Furthermore, incidental vascular calcifications can also be found in
patients with peripheral vascular disease, renal insufficiency, and diabetes Fig. 10.68
mellitus.30 Calciphylaxis: note the thrombosed vessel in the center of the field.
Fig. 10.66 Fig. 10.69

Calciphylaxis: there is focal fat necrosis and widespread calcification affecting the Calciphylaxis: in addition to mural calcification, there is marked intimal fibroblastic
small vessels. Note the thickened and fibrosed septa. proliferation.
Fig. 10.70 Fig. 10.72

Calciphylaxis: fat necrosis with conspicuous lipophages. In addition there is widespread Crystal-storing histiocytosis: within the dermis are large histiocytes with abundant
calcification. eosinophilic cytoplasm.
Crystal-storing histiocytosis
Clinical features
Crystal-storing histiocytosis is an extremely rare condition which has been
described in patients with lymphoplasmacytic neoplasms associated with kappa
light chain monoclonal gammopathy including lymphoplasmacytic lymphoma
(immunocytoma), monoclonal gammopathy of uncertain significance, multiple
myeloma, extramedullary plasmacytoma, maltoma, and large cell B-cell lym-
phoma.1–5 Primary cutaneous involvement is exceptional and the literature on
this aspect is limited to only three case reports.6–8 These patients presented with
erythematous asymptomatic subcutaneous nodules and tumors (Fig. 10.71).
The condition is characterized by the presence of histiocytes containing eosino-
philic crystals which have been likened to Gaucher cells (pseudo-Gaucher
cells) admixed with lymphoma cells (Fig. 10.72).3 The crystals are variably
Fig. 10.73
Crystal-storing histiocytosis: the cytoplasm contains large eosinophilic crystals.
olygonal to rhomboid or needle-shaped and stain positively with PAS and

p
phosphotungstic acid hematoxylin (Fig. 10.73).6,7 Erythrophagocytosis may
also be evident.3
The histiocytes express CD68, and sometimes immunoglobulin heavy and
light chains may be stained weakly.3
Ultrastructurally, the crystals are sometimes membrane bound (of lysosomal
derivation) and display platelike, rectangular, trapezoid, and rhomboid
shapes with a distinct hexagonal lattice structure.3,6,7 The tumor cells may
also contain intracytoplasmic crystals.3
Gouty panniculitis
There are very occasional reports of gout presenting as a crystalline lobular
panniculitis.1–5
Nodular vasculitis
Fig. 10.71
Crystal-storing
histiocytosis: this
Clinical features
patient presented with Nodular vasculitis (erythema induratum) is a rare condition which usually
marked swelling of the presents in young or middle-aged women, often in those with an eryth-
face and the eyelids. rocyanotic circulation.1 Males are only rarely affected.2 Patients present
Nodular vasculitis 347
Fig. 10.74
Nodular vasculitis: early Fig. 10.76
lesion presenting as an Nodular vasculitis: the nodules frequently ulcerate. By courtesy of R.A. Marsden,
erythematous nodule MD, St George’s Hospital, London, UK.
on the calf of a middle-
aged female. By courtesy
of M.M. Black, MD,
St Thomas’ Hospital,
London, UK.
Fig. 10.77
Nodular vasculitis: in this severely affected patient ulcerated lesions are present on
the shins in addition to the calves. By courtesy of R.A. Marsden, MD, St George’s
Fig. 10.75
Nodular vasculitis: typical bilateral involvement of the calves. By courtesy of the
Institute of Dermatology, London, UK. Pathogenesis and histological features
The relationship between erythema induratum and nodular vasculitis has for
many decades been the subject of controversy. Similarly, the association of
the former condition with an underlying tuberculous infection has been the
with painful, tender, violaceous, indurated nodules particularly affecting subject of prolonged debate.
the calves although the shins, feet, ankles, thighs, and upper limbs may As outlined above, the more recent literature gives considerable support to
sometimes be involved (Figs 10.74, 10.75). Lesions are often bilateral and the notion that occult tuberculosis is present in many patients with erythema
the overweight with fat calves are most often affected. Seasonal variation induratum and that the two terms are, therefore, synonymous in a substan-
has been noted with an increased incidence being recorded in the cold win- tial proportion of cases. Thus, erythema induratum may be associated with
ter months. Skin lesions often recur over many years. Ulceration is com- evidence of active tuberculosis.7–11 Although cultures of lesions are invari-
mon and scarring with hyperpigmentation frequently accompanies healing ably negative, the more recent demonstration of Mycobacterium tuberculosis
(Figs 10.76–10.78). DNA by PCR in lesional tissue adds strong additional support to the proposal
In those cases that represent a manifestation of underlying tuberculo- of an underlying tuberculous etiology.12–21
sis, the term erythema induratum (Bazin's disease) is frequently applied. In Nodular vasculitis can, therefore, be regarded as a hypersensitivity reaction
this condition, there is invariable hypersensitivity to intradermal injection in which mycobacterial antigens are one important cause. Immune complex
of purified protein derivative (PPD) at a dilution of 1:10 000 and a com- and delayed hypersensitivity mechanisms have both been proposed.13 Other
plete clearing of all skin lesions following treatment with antituberculous predisposing factors for this condition have not yet generally been identi-
chemotherapy.3–6 fied although nodular vasculitis has been described in association with acute
Fig. 10.78 Fig. 10.80

Nodular vasculitis: Nodular vasculitis: well-formed epithelioid granulomata and multinucleate giant cells
multiple scarred lesions. are present.
Note the marked
hyperpigmentation.
By courtesy of the
London, UK.
myeloid leukemia, chronic hepatitis C infection, and as an adverse drug reac-

tion associated with propylthiouracil.20,22–25 Nodular vasculitis has recently
been reported in a patient with ulcerative colitis.26 Bacille Calmette-Guerin
(BCG) vaccination, distal painful peripheral neuropathy, and granulomatous
aortic valve stenosis may on occasion be associated with erythema induratum
of Bazin.27–29
The histological features combine septal and lobular changes (Fig.
10.79). The presence of vasculitis has traditionally been regarded as a
sine qua non for the diagnosis of nodular vasculitis (erythema indura-
tum). Nevertheless, a recent study analyzing 101 biopsy specimens from
86 patients with clinical features of erythema induratum failed to detect
the presence of vasculitis in 9.9% of specimens, even after examination of
multiple serial sections.30
In a biopsy from an established lesion, the septa are widened and chron-
ically inflamed (Fig. 10.80). Acute vasculitis (affecting septal and lobular
veins and venules) with a heavy inflammatory cell infiltrate consisting of Fig. 10.81
Nodular vasculitis: vascular involvement as seen in this field is a characteristic
feature.
eutrophils, lymphocytes, and histiocytes is typically present, sometimes

n
accompanied by vessel wall necrosis and thrombosis (Fig. 10.81). The most
frequently affected are small lobular veins, followed by both septal veins and
lobular venules.30 In addition, septal arteries may also be involved by the vas-
culitic process.30
Occasionally, septal granulomatous inflammation can also be evident.
Lobular inflammation may occasionally be limited to a focal ele-
ment adjacent to an acutely inflamed vessel.31 More frequently, how-
ever, it presents as nodular lesions scattered throughout the whole lobule
or affecting multiple lobules. Fat necrosis is invariably present and is
often florid. The features are varied and range from typical lipophagic
fat necrosis to coagulative or more rarely caseation-like necrosis ( Figs
10.82, 10.83 ).32 Neutrophils, lymphocytes, and histiocytes with xan-
thomatized forms are typically seen. Granulomata are often present and
giant cells of both foreign body and Langerhans type are frequently a
feature ( Fig. 10.84 ).
Fig. 10.79 In biopsies from chronic or resolving lesions, fibrosis of both the septa
Nodular vasculitis: note the distinct nodules of granulomatous inflammation at the and lobules is often present. Giant cells and granulomata may still be
periphery of the lobule. present.
Neutrophilic lobular panniculitis associated with rheumatoid arthritis 349
Due to the frankly granulomatous nature of the histology, it is mandatory to
exclude infective causes of panniculitis, particularly mycobacterial and fungal
infections, including cryptococcosis, mycetoma, chromomycosis, sporotricho-
sis, and aspergillosis. Subcutaneous sarcoidosis should also be considered,
although in this condition granulomata are also seen in the dermis. Asteroid
inclusions and Schaumann bodies, which are both features of sarcoidosis (see
below), are not characteristic of erythema induratum.
Subcutaneous sarcoidosis
Clinical features
Involvement of subcutaneous fat in patients with sarcoidosis is rarely encoun-
tered by histopathologists even though it may occur in as many as 1.4% to
6% of all patients with this disease.1–3 Most often it presents as asymptomatic
or tender, flesh-colored to erythematous, subcutaneous nodules with frequent
clustering, principally affecting the extremities although a more general-
Fig. 10.82 ized distribution has also been documented.2–10 Exceptionally, subcutaneous
Nodular vasculitis: note the presence of numerous lipophages. involvement may be the initial or even the only feature of sarcoidosis.6,11
Isolated subcutaneous sarcoidosis has also been reported following inter-
feron treatment for melanoma.12,13 More commonly, however, subcutane-
ous lesions are associated with visceral disease, particularly bilateral hilar
lymphadenopathy.
Subcutaneous sarcoidosis shows a predilection for females and the major-
ity of patients are in the fifth and sixth decades.6
The changes, which predominantly involve the lobule, consist of well-formed,
noncaseating granulomata, sometimes associated with fibrosis, which may
extend into the septa. Typically, the granulomata are of the ‘naked’ type, i.e.,
devoid of a peripheral rim of lymphocytes, and giant cells of both foreign
body and Langerhans types are usually present. Exceptionally, caseation and
calcification have been described.14,15
Subcutaneous sarcoidosis is a diagnosis of exclusion; other causes of gran-
ulomatous inflammation – including mycobacterial and fungal infections,
foreign body reactions, and so-called ‘metastatic Crohn's disease’ – must be
Fig. 10.83 considered in the differential diagnosis.16,17
Nodular vasculitis: the eosinophilic necrotic debris reminiscent of caseation is a
typical feature.
Neutrophilic lobular panniculitis associated
with rheumatoid arthritis
Clinical features
Also known as pustular panniculitis, this rarely described entity has been
documented in middle-aged females who presented with painful nodules
predominantly affecting the lower legs.1–5 Similar changes have also been
reported on the back, upper arms, forearms, and nasal bridge in an infant
with juvenile rheumatoid arthritis.6 Blister formation, pustulation, ulceration,
and discharge of oily, necrotic debris may occur.3–5

The pathogenesis may be related to circulating immune complexes since high
levels have been identified in patients with this condition.3,4
The lobules and septa are infiltrated by neutrophils with central lobu-
lar necrosis accompanied by a histiocytic and giant cell response.2–5 Small
numbers of eosinophils are sometimes present.4 Nuclear dust can be con-
spicuous and cyst formation with membranous change has been described.4,5
Leukocytoclastic vasculitis affecting the dermal arterioles and venules may
Fig. 10.84 be seen.4 Endothelial swelling, hemorrhage, and fibrin deposition may also
Nodular vasculitis: granulomata may be seen within the lobule and also in the septa. be present.7
Neutrophilic lobular panniculitis has also been reported in a patient with

nonrheumatoid arthritis.8
Factitial disease and infections must always be excluded in neutrophil-rich
panniculitides. Similarly, pancreatic disease-associated panniculitis and α1-
antitrypsin deficiency-associated panniculitis are typically linked with a lobu-
lar neutrophil-rich infiltrate. The lobular panniculitis associated with bowel
bypass is also typically neutrophil rich.9,10
Eosinophilic panniculitis
Clinical features
Eosinophilic panniculitis is not a disease in its own right, but represents a
reaction pattern that may be found under a variety of circumstances.1 It is
seen more often in females than males (3:1). Although a wide age range is
affected, there are two peaks: one in the third decade and the other in the
sixth decade and above. Patients present predominantly with nodules and Fig. 10.86
plaques, although papules and pustules are sometimes seen.2–5 Lesions, which Eosinophilic panniculitis: note the massive eosinophilic infiltrate.
may be single or multiple, affect the legs, arms, trunk, and face in decreasing
order of frequency.
Eosinophilic panniculitis may be found in association with erythema
nodosum, immune complex-mediated vasculitis, atopic dermatitis, refractory
anemia, chronic recurrent parotitis, artifact, leukocytoclastic vasculitis, drug
reactions, eosinophilic cellulitis, insect bites, toxocariasis, gnathostomiasis,
Fasciola infection, human immunodeficiency virus (HIV), specific immuno-
therapy with aqueous lyophilized bee venom, injection site reactions, trauma,
and in patients with lymphoma.5–19 On rare occasions, no obvious underlying
condition can be detected.19 Other than in those patients with an associated
neoplasm, eosinophilic panniculitis appears to be a self-limiting and benign
condition.7
The histological features affect the lobules and the septa and are character-
ized by an intense infiltrate of eosinophils, which may be accompanied by
variable numbers of other inflammatory cells including neutrophils, lym-
phocytes, and monocytes (Figs 10.85, 10.86). Vasculitis is usually not seen.
Fig. 10.87
Eosinophilic panniculitis: note the flame figure in the center of the field.
Fat necrosis is sometimes present. On occasions, typical ‘flame figures’, as

seen in eosinophilic cellulitis, may be noted (Fig. 10.87). The changes some-
times extend into the reticular dermis and occasionally the underlying fascia
is involved.
Infective panniculitis
Clinical features
The clinical features in patients with infective panniculitis are not spe-
cific and include nodules, ulcerated lesions, abscesses, and erythema
nodosum-like lesions.1 Patients are usually, but not invariably, immuno-
suppressed. The legs and feet are the sites most often affected. Specific
infections, which have presented with panniculitis, include Histoplasma
capsulatum, Pseudomonas aeruginosa, Candida albicans, Aspergillus spp.,
Zygomycetes, Cryptococcus neoformans, Fusarium spp., Mycobacterium
Fig. 10.85 avium intracellulare, Mycobacterium ulcerans, Mycobacterium mari-
Eosinophilic panniculitis: num, Mycobacterium tuberculosis, Mycobacterium chelonei, Brucella
there is a heavy, ssp, Neisseria meningitidis, Streptococcus pyogenes, Staphylococcus
predominantly lobular aureus, Actinobacillus, Actinomyces spp., Coxiella burnetii and cytome
inflammatory cell infiltrate. galovirus.2–28
Infective panniculitis 351
Epidermal changes may include parakeratosis, acanthosis and spongio-
sis.1 The dermis is edematous and often shows a perivascular and intersti-
tial inflammatory cell infiltrate containing many neutrophils. Hemorrhage is
sometimes present.
Most commonly, the subcutaneous fat shows features of a mixed septal/
lobular panniculitis (Figs 10.88–10.92).1 Erythema nodosum-like features
may be evident.1 Changes suggestive of an infective etiology include a promi-
nent neutrophilic infiltrate, hemorrhage, basophilic necrosis and necrosis of
sweat glands, vascular proliferation, and discrete abscess formation.1,29
Granulomata are sometimes conspicuous in atypical mycobacterial infec-
tions. On other occasions acute inflammatory changes with abscess forma-
tion are seen (e.g., Mycobacterium chelonei infection). In the latter condition,
organisms may be identified in microcysts lined by neutrophil polymorphs.1
Mycobacterial infection may also occasionally manifest as phlebitis.30 Deep
fungal infections commonly involve the subcutaneous fat, presenting as granu-
lomatous or mixed suppurative and granulomatous inflammatory processes.
From the above description, it is obvious that special stains for bacteria
and fungi should be performed in all cases of panniculitis where the etiology Fig. 10.90
is uncertain. Culture may also be necessary in some instances. Infective panniculitis: in this example, there is a granulomatous infiltrate.
Fig. 10.88 Fig. 10.91

Infective panniculitis: there is intense acute inflammation with abscess formation. Infective panniculitis: a twisted hypha typical of zygomycosis is present.
Fig. 10.89 Fig. 10.92

Infective panniculitis: this example is due to cryptococcal infection. Note the typical Infective panniculitis: numerous cocci are present in this section from a patient with
yeast forms (arrowed). necrotizing fasciitis.
Acute infectious id panniculitis –

panniculitic bacterid
This is a recently described variant of lobular neutrophilic panniculitis, which
likely represents an id reaction to infections other than Mycobacterium
tuberculosis.1
Clinical features
Following primary infection elsewhere (sinusitis, breast and dental abscess,
impetigo, cellulitis, viral pharyngitis, Pseudomonas pneumonia, and ulcer-
ative colitis) all 10 patients (4 males, 6 females) presented with sudden
development of tender nodules on the lower extremities, with additional
involvement of the upper extremities in three patients. The lesions resolved
completely after adequate therapy of the primary focus. Hyperviscosity con-
ditions were present in three patients.
A
Fat lobules and septa were infiltrated by a prominent inflammatory cell
infiltrate composed predominantly of neutrophils forming small microab-
scesses, accompanied by fat necrosis. Lymphocytes and histiocytes were also
present in the infiltrate, with occasional granuloma formation. Spilling of
the inflammation into the dermis was seen. Vascular changes consisted of
necrotizing vasculitis involving arterioles and venules in the fat lobules and
lower dermis, but also of thrombotic microangiopathy of the capillaries in
the subcutaneous fat.
Special stains for microorganisms were negative in all cases. Infection with Fig. 10.93
Sclerosing panniculitis
Mycobacterium tuberculosis was excluded in all patients.
(A & B): (A) the skin
shows features of stasis.
Dense fibrosis has
Differential diagnosis resulted in this inverted
Infection should be excluded with appropriate stains. Neutrophilic lobular bottle appearance.
panniculitis associated with rheumatoid arthritis can have a similar morpho Note the characteristic
logy, and clinicopathological correlation is vital. symmetry; (B) close-up
view of an early lesion
showing an indurated,
markedly erythematous
plaque. (A) By courtesy
Sclerosing panniculitis of the Institute of
Dermatology, London, UK;
Clinical features (B) By courtesy of J.C.
Sclerosing panniculitis (stasis-associated sclerosing panniculitis, hypo- B Pascual, MD, Alicante,
Spain.
dermatitis sclerodermaformis, lipodermatosclerosis, lipomembranous
change in chronic panniculitis) is a relatively common condition which
most often develops in middle-aged or elderly, overweight females with
a history of peripheral venous disease including varicose veins, throm-
bophlebitis, and deep venous thrombosis.1–7 Less often, the condition
follows arterial ischemia. Patients present with indurated, wood-like, The histological features are variable depending upon whether the biopsy
sclerodermiform plaques affecting the lower legs in a stocking distri- represents an early stage in the development of this disorder or an established
bution and characteristically resembling an inverted bottle appearance lesion.5,11
(Fig. 10.93).1,3 Often the changes are bilateral and symmetrical.2 The Within the subcutaneous fat, early lesions are characterized by cen-
overlying skin may show additional changes of venous stasis including trilobular ischemia with infarction of fat cells and vascular congestion/
atrophy, ulceration, hyperpigmentation and telangiectasia. Patients with hemorrhage.5 Vascular thrombosis may also be seen but there is no evidence
sclerosing panniculitis and systemic sclerosis frequently have associated of vasculitis. A lymphocytic infiltrate is present in the septa and this may spill
pulmonary hypertension.8 over to affect the edge of the lobule. Hemosiderin deposition is commonly
present.
In established lesions, ischemic changes may still be evident but more
Pathogenesis and histological features often there is microcystic change with hyalinization within the fat lob-
The pathogenesis of sclerosing panniculitis is venous stasis within the centri- ule (Figs 10.94–10.96). Membranous fat necrosis is often present and
lobular capillaries leading to ischemia and eventual infarction of the subcu- lipophagic changes may be evident. Septal scarring is present, which in
taneous fat. Increased interstitial fibrinogen as a result of excessive capillary advanced lesions can be marked with resultant atrophy of the subcutane-
permeability due to venous hypertension is thought to be of importance.4 ous fat.
Fibrin deposition around the dermal capillaries results in hypoxia. In addi- The dermis typically shows the features of stasis including chronic inflam-
tion, there is some evidence to suggest that increased matrix metalloprotei- mation, fibrosis, vessel-wall thickening, lobular capillary proliferation, and
nases and urokinase-type plasminogen activator may be of importance in the hemosiderin deposition. Acanthosis, spongiosis, and lichenification may be
pathogenesis.9,10 evident.
Membranous fat necrosis 353
The absence of sclerodermiform dermal changes and the presence of features
of venous stasis distinguish end-stage sclerosing panniculitis from morphea
profunda, scleroderma and acrodermatitis chronica atrophicans (a late mani-
festation of Lyme disease).
Membranous fat necrosis

Clinical features
Membranous fat necrosis is a non-specific change found predominantly in the
subcutaneous fat. It was first described, however, in patients with progressive
sudanophilic leukoencephalopathy (Nasu-Halola's disease).1–3 This is a rare
condition in which cystic lesions develop in subcutaneous fat and bone mar-
row associated with pathological fractures and cerebral lesions resulting in
seizures and presenile dementia.
Subsequently membranous change has been recognized as a common
manifestation of venous stasis-associated disease.4–7 It has, however, also
been observed in association with numerous other conditions includ-
ing arterial insufficiency, diabetes mellitus, erythema nodosum, nodular
vasculitis, infective panniculitis, pancreatic disease-associated panniculitis,
subcutaneous sarcoidosis, morphea, morphea profunda, cytophagic histio-
Fig. 10.94
cytic panniculitis, dermatomyositis, systemic sclerosis, lupus panniculitis,
Sclerosing panniculitis:
there is typical microcystic
necrobiosis lipoidica, and nodular cystic fat necrosis.6–16 It has also been
change. described in the breast, in appendices epiploicae, within an ovarian cys-
tic teratoma and following subcutaneous elemental mercury injections.17–21
Membranocystic change accompanied by myospherulosis has also been
documented.22

Although in the majority of cases an ischemic pathogenesis is likely, its pres-
ence following trauma and in a background of infection suggests that other
mechanisms are sometimes responsible. The membrane change likely repre-
sents altered adipocyte cell membranes although recently a contribution by
histiocytes has been postulated.5–7
Histologically, it presents as amorphous, autofluorescent, eosinophilic,
PAS-positive membranes outlining cysts within the lobules of the subcutane-
ous fat (Fig. 10.97). Pseudopapillary and arabesque patterns are commonly
present (Figs 10.98, 10.99). The membrane also stains for lipid using Sudan
black and is luxol fast blue positive.5 This is thought to represent ceroid, at
least in part.23
Ultrastructurally, the membrane is composed of perpendicularly orien-
tated microvilli alternating with dilated tubular crypts reminiscent of smooth
endoplasmic reticulum with adjacent electron-dense material.5
Fig. 10.95
Sclerosing panniculitis: close-up view of microcysts.
Fig. 10.96 Fig. 10.97

Sclerosing panniculitis: membranous fat necrosis is evident. Membranous fat necrosis: note the delicate membranes lying within small cystic spaces.
Fig. 10.98 Fig. 10.99

Membranous fat necrosis: close-up view. Membranous fat necrosis: the features are highlighted with a Masson’s trichrome
stain.
Lipodystrophy
Classification and clinical features The genes for congenital generalized lipodystrophy have been mapped
to human chromosome 9q34 and 11q13, and are designated AGPAT2 and
The lipodystrophies are a complex group of disorders characterized by a
BSCL2 (seipin gene), respectively.8–10 Not all patients have mutations in these
familial or acquired, complete or partial loss of subcutaneous fat.1–5 They
genes, suggesting the presence of additional yet unidentified genetic loci.11
have been classified as follows:1
Diagnostic criteria as outlined in Table 10.3 have recently been
• Familial lipodystrophy including:
recommended.1
– generalized lipodystrophy (Berardinelli-Seip syndrome)
– partial lipodystrophy (Dunnigan and Köbberling variants)
• Acquired lipodystrophy including: Familial partial lipodystrophy (Dunnigan
– generalized lipodystrophy (Lawrence syndrome)
– partial lipodystrophy (Barraquer-Simons syndrome) variant)
– HIV-associated lipodystrophy This is another exceedingly rare condition with an estimated prevalence
• Localized lipoatrophy (localized lipodystrophy) including: of less than 1 in 15 000 000 of the population.1 The original cases were all
– drug-induced lipoatrophy females and therefore a sex-linked dominant mechanism, lethal in hemizy-
– pressure-induced lipoatrophy gous males, was postulated.12,13 The more recent publication of families with
– panniculitis-associated lipoatrophy affected male members suggests, however, that an autosomal dominant mech-
– centrifugal variant lipoatrophy anism is at play.14
– idiopathic lipoatrophy. Patients are normal at birth but at puberty they lose subcutaneous fat from
the extremities and to a lesser extent from the trunk.15 The face is spared and,
Familial lipodystrophy indeed, in some patients, excessive fat deposition on the face and neck has
been documented. Diabetes mellitus, hypertriglyceridemia, and low serum
high density lipoprotein (HDL) cholesterol levels become manifest in early
Congenital generalized lipodystrophy adulthood.1,16,17 Patients may develop chylomicronemia and pancreatitis.1
(Berardinelli-Seip syndrome) Acanthosis nigricans, hirsutism, menstrual abnormalities, and polycystic ova-
ries are also sometimes evident.1
This exceedingly rare variant of lipodystrophy is inherited in an autosomal
The gene responsible for familial partial lipodystrophy has been mapped
recessive mode and is usually recognizable at birth.1–4 Its prevalence has been
to chromosome region 1q21-22.18–20 It has been identified as the lamin A/C
estimated as 1:12 000 000.1 The sex incidence is equal.
gene, which codes for a nuclear envelope protein lamin.21–23
It is characterized by a complete absence of metabolically active subcutane-
Diagnostic criteria as outlined in Table 10.3 have recently been
ous fat in association with insulin resistance, hyperinsulinemia, hypertriglyc-
recommended.1
eridemia with normal or slightly raised cholesterol, and nonketotic diabetes
mellitus.4 Mechanical fat such as is found in the orbits, on the palms and
soles, and around the external genitalia is unaffected.1 Patients also have a Familial partial lipodystrophy (Köbberling
voracious appetite associated with a hypermetabolic state and marked hyper-
hidrosis. Additional features include an anabolic syndrome with increased
variant)
height velocity, advanced bone age, muscular hypertrophy, masculine body This is an exceedingly rare variant in which only a small number of affected
build, acromegaloid stigmata, hepatomegaly, enlarged external genitalia in pedigrees have been documented.1,24–26 Sporadic variants have also been
childhood, abundant curly hair on the scalp, hypertrichosis, umbilical hernia, described.1,26,27 In these patients, loss of fat is limited to the extremities. There
acanthosis nigricans, mild mental retardation with hydrocephalus, and may be increased truncal fat.1,26 Hypertriglyceridemia, arterial hypertension,
hypothalamic–pituitary dysfunction.4,5 insulin resistance or diabetes mellitus are usually present, and the patients
Diabetes is thought to develop as a consequence of extensive pancreatic have increased risk for premature cardiovascular disease and pancreati-
amyloid deposition with loss of β-cells.6 Postmortem studies have demon- tis.1,26 Acanthosis nigricans has been described in a single patient.26 To date,
strated fatty liver with cirrhosis.7 documented affected patients have been female.
Acquired lipodystrophy 355
Table 10.3
Lipodystrophies: diagnostic criteria
Disorder Essential criteria Confirmatory criteria

Congenital generalized Generalized lack of body fat Acanthosis nigricans
lipodystrophy Extreme muscularity from birth Acromegaloid features
Umbilical hernia
Clitoromegaly and mild hirsutism
Severe fasting or postprandial hyperinsulinemia
Onset of diabetes or impaired glucose tolerance test in teenage years
Hypertriglyceridemia with low HDL cholesterol concentration
Characteristic body fat distribution on MRI
Familial partial Normal physical appearance at birth Normal or excessive facial adipose tissue
lipodystrophy Loss of subcutaneous fat of the extremities Acanthosis nigricans
(Dunnigan variant) commencing at puberty Mild to moderate fasting or postprandial hyperinsulinemia
Muscular-appearing extremities Onset of diabetes or impaired glucose tolerance after age 20 years
commencing at puberty Hypertriglyceridemia with low serum HDL cholesterol concentrations
Characteristic body fat distribution on MRI
Acquired generalized Generalized loss of subcutaneous fat Loss of fat from palms and soles
lipodystrophy developing in childhood or later Severe fasting or postprandial hyperinsulinemia
Extreme muscularity appearing in childhood Impaired glucose tolerance or diabetes
or later Hypertriglyceridemia with low serum HDL cholesterol concentrations
Nodular panniculitis preceding onset of lipodystrophy
Coexistence of autoimmune diseases
Acquired partial Gradual loss of subcutaneous fat of the Normal or excess fat on hips and lower extremities
lipodystrophy face, neck, trunk, and upper extremities Proteinuria
developing in childhood or adolescence Biopsy proven mesangiocapillary glomerulonephritis
Low serum C3 levels
Presence of C3 nephritic factor
Absence of insulin resistance
Presence of other autoimmune diseases
Characteristic body fat on MRI
HDL, high density lipoprotein; MRI, magnetic resonance imaging. Derived from Garg, A. (2000) American Journal of Medicine, 108, 143–152.
Familial partial lipodystrophy associated panniculitis).34,38,39 These patients appear to have less severe fat loss and lower
prevalence of hypertriglyceridemia and diabetes in comparison with patients
with mandibuloacral dysplasia having the autoimmune or idiopathic variant of the disease.34
This autosomal recessive variant of lipodystrophy is characterized by the Autoimmune diseases associated with acquired generalized lipodystrophy
presence of a variety of bony defects including mandibular and clavicular include juvenile dermatomyositis in particular, followed by Hashimoto's thy-
hypoplasia, acroosteolysis, delayed closure of cranial sutures, and joint roiditis, juvenile rheumatoid arthritis, adult-onset dermatomyositis, systemic
contractures associated with cutaneous hyperpigmentation.28,29 Genetically, lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and vitiligo.1,40–42
it is a heterogeneous disorder. Mutations in genes encoding nuclear lamina Liver involvement may be marked with steatosis, autoimmune hepatitis,
proteins and zinc metalloproteinase have been detected.30–33 Lipodystrophy and cirrhosis supervening in a substantial number of cases.4,43 Additional
varies from loss limited to the extremities (type A) through to general- features include severe insulin resistance, diabetes, hyperinsulinemia, and
ized loss (type B). Patients also have insulin-resistant hyperinsulinemia and hypertriglyceridemia accompanied by low serum HDL cholesterol con-
hypertriglyceridemia and diminished serum HDL cholesterol levels.29 centrations.1,34 Acquired generalized lipodystrophy can also be associ-
ated with cerebellar degeneration, unicameral bone cysts, and proteinuric
nephropathy.44–46
Acquired lipodystrophy A preceding viral illness has frequently antedated the development of acquired
generalized lipodystrophy although whether this is causal or not is unclear.1,4
Acquired generalized lipodystrophy A case of panniculitis of the acquired generalized lipodystrophy variant was
reported recently, presumably triggered by pulmonary tuberculosis.47
Acquired generalized lipodystrophy (Lawrence syndrome, lipoatrophic dia- Diagnostic criteria as outlined in Table 10.3 has been recommended.1
betes, lipoatrophic panniculitis, lipodystrophic diabetes) can be subclassified
into three variants:
• Type 1: the panniculitis variant,
Acquired partial lipodystrophy
• Type 2: the autoimmune disease variant, Acquired partial lipodystrophy (Barraquer-Simon syndrome, progressive lip-
• Type 3: the idiopathic variant, odystrophy, cephalothoracic progressive lipodystrophy) is one of the more
and affect 25%, 25%, and 50% of the patients, respectively.34 common variants of lipodystrophy. Females are affected three times more
Acquired generalized lipodystrophy is similar to the congenital form often than males.1 Patients present in late childhood or adolescence with grad-
although there is a predilection for females (3:1).1,34–37 Patients present in ual loss of the subcutaneous fat of the face followed by the neck, shoulders,
childhood or adolescence with fat loss, which progresses over a period of arms, thorax, and upper abdomen (Fig. 10.100).1,48–50 The distal subcutane-
months or years.1 The entire body is affected, particularly face, arms, and ous fat is typically spared and sometimes, in contrast, there is even excessive
legs. The muscles of the extremities appear unduly prominent. Children with fat deposition around the pelvis and on the legs.
this disorder may have a voracious appetite. Mesangiocapillary (membranoproliferative) glomerulonephritis (MCGN II)
Features of an inflammatory nodular panniculitis appear to have pre- and hypocomplementemia often accompany this variant.51–53 C3 levels are usu-
ceded the onset of lipodystrophy in a number of cases (lipoatrophic ally low in contrast to C1q, C4, C5, C6, factor B, and properdin, which are
Fig. 10.100
(A, B) Partial lipodystrophy:
note the striking loss of
symmetry due to diminished
fatty tissue of the left side
of the face. By courtesy of
A B the Institute of Dermatology,
London, UK.
normal.54,55 The glomerulonephritis and low C3 have been shown to be due (profundus), dermatomyositis, polymyositis, linear morphea, facial hemiatro-
to an IgG autoantibody, the C3 nephritic factor (C3NeF).56 It has been shown phy, lichen sclerosus et atrophicus and progressive systemic sclerosis.70–72
that the latter has the capacity to induce adipocyte lysis.57 Three patients have Other types of localized lipodystrophy include annular lipodystrophy and
recently been described that presented with low C4 complement levels, wide- a variant that affects only half the circumference of an extremity (lipoatro-
spread acquired lipodystrophy, and chronic autoimmune hepatitis.58 phia semicircularis). These distinctive annular lesions are likely to result from
An association with a number of other autoimmune diseases including a localized pressure effect such as that which may occur with tight cloth-
Sjögren's syndrome, dermatomyositis, hypothyroidism, and SLE has also been ing or persistent localized trauma.73–76 Idiopathic variants are also recognized
documented.59–62 Patients may in addition develop hyperlipidemia, nonketotic including lipoatrophy associated with Becker's nevus and lipodystrophia
diabetes mellitus, acanthosis nigricans, and hirsutism.1 Hepatomegaly due to centrifugalis abdominalis infantilis.77–80
fat accumulation is occasionally present. Extrinsic allergic alveolitis has been
reported in a single patient.63 Pathogenesis and histological features
Expression gene analysis in a single patient with acquired partial The exact pathogenesis of lipodystrophy is unknown. A variety of theories has
lipodystrophy demonstrated down-regulation of the PPARγ gene, which is nor- been proposed, including hypothalamic–pituitary dysfunction (overproduc-
mally associated with adipocyte differentiation, as well as reduced expression tion of fat-mobilizing peptides and amines), disordered fat metabolism, infec-
of mitochondrial genes.64 In addition, heterozygous mutations of the LMNB2 tion, and heredity. A currently favored area of research is directed towards
gene have been detected in three out of four analyzed patients.65 the role of abnormal insulin receptors on fat cells. It has been postulated that
Diagnostic criteria as outlined in Table 10.3 have recently been abnormal insulin receptors are associated with diminished uptake of lipid by
recommended.1 fat cells with resultant lipodystrophy, hyperlipidemia, and hyperinsulinemia.
In general, the histopathology of lipodystrophy is noninflammatory in
Localized lipoatrophy nature.81–83 There is a progressive diminution of adipocyte lipid accompanied
by a decrease in cell size so that the cells become separated from one another
Clinical features (Fig. 10.101). The stroma becomes hyalinized or myxomatous and contains
clusters of tortuous capillaries. As the end result resembles embryonic fat, this
Localized disease (lipoatrophy) is a much more common phenomenon. The process of atrophy is sometimes called ‘reversal of embryogenesis’.
subject has, however, been made extremely complicated by virtue of the large Patients with multiple areas of localized lipoatrophy may show mild
number of synonyms that have been used to describe the same disease process inflammatory changes comprising perivascular and periseptal lymphocytic
over the years (e.g., lipodystrophy, annular lipoatrophy, annular lipodystrophy, infiltration accompanied by minor septal fibrosis.
semicircular lipoatrophy, postinjection lipoatrophy, involutional lipoatrophy,
lipodystrophia centrifugalis abdominalis infantilis, centrifugal lipodystrophy).
Essentially, localized lipodystrophy may result from a range of injurious stim-
Lipoatrophic panniculitis
uli and present at a wide variety of sites but essentially all of the subtypes listed
above are variations of the same disease process which may therefore follow Clinical features
localized panniculitis, connective tissue diseases, injections, trauma, etcetera. Lipoatrophic panniculitis (atrophic connective tissue panniculitis) represents a
Lesions affecting the proximal extremities or buttocks should raise the possi- very rarely documented inflammatory form of localized lipoatrophy.1–7 In the
bility of infection or trauma. Localized lipoatrophy has been described follow- original report, three children developed centrifugally enlarging erythematous
ing subcutaneous injections of insulin, triamcinolone acetate and iron dextran, nodules and plaques with atrophic centers on the lower extremities. Healing
and following vaccinations.66–69 It has also been described as a complication of of the lesions resulted in the clinical appearances of localized lipoatrophy.
idiopathic connective tissue diseases including systemic lupus erythematosus The areas of lipoatrophy coalesced to give an appearance resembling partial
Localized lipoatrophy 357
A B
Fig. 10.101
Lipodystrophy: (A) there is only a very small residual amount of subcutaneous fat in the center of the field; (B) these tiny adipocytes are reminiscent of embryonic fat. By courtesy
of W.P. D. Su, MD, Mayo Clinic, Rochester, USA.
or total lipodystrophy.1 All three patients had elevated ESRs. Two patients have a raised ESR, thrombocytosis, and microcytic anemia. Antinuclear fac-
had associated diabetes mellitus (one with coexistent Hashimoto's thyroidi- tor may be present.1 A similar disorder has rarely been described in adults
tis) and one developed juvenile rheumatoid arthritis. Peters and Winkelmann (adult lipophagic atrophic panniculitis).2 Winkelmann postulates that many
described a similar condition under the rubric ‘atrophic connective tissue dis- cases of Weber-Christian disease documented in the earlier literature belong
ease panniculitis’.2 Nowadays, this entity would probably be best included in to this disorder (literature summarized in reference 1).
the spectrum of acquired total or partial lipodystrophy.
Histological features Histological features

Histologically, lipophagic panniculitis is characterized by panlobular inflam-
In atrophic connective tissue panniculitis the histological features are those
mation with histological features of lipoatrophy.1 The inflammatory cell
of a lobular panniculitis.1,7 The deep dermis may manifest a perivascular
infiltrate consists of histiocytes and Touton-like lipophages. Occasional
lymphocytic and histiocytic infiltrate. Lymphocytes and mononuclear
lymphocytes, neutrophils, and plasma cells may be evident. Eosinophils are
phagocytes extensively infiltrate the fatty lobules. Eosinophils and multi-
sometimes numerous. There is no evidence of vasculitis.1
nucleate giant cells are uncommon. In more advanced lesions, there is fatty
atrophy accompanied by an infiltrate composed mainly of foamy mac-
rophages.3 Vasculitis is not a feature of this disorder.1 Connective tissue panniculitis
Lipophagic panniculitis of childhood Clinical features
This extremely rare chronic condition, originally described in two female
Clinical features patients by Winkelmann and Padilha-Goncalves, comprises recurrent tender
Lipophagic panniculitis of childhood (lipophagic-granulomatous lipoatro- subcutaneous nodules mainly on the shoulders and upper arms, but the cheek,
phy) is exceedingly rare and presents in children as erythematous asymp- breast, trunk, neck or leg may also be affected.1 Healing is sometimes asso-
tomatic or tender plaques and nodules affecting the arms or legs, which are ciated with lipoatrophy and hyperpigmentation, which can be particularly
later associated with lipoatrophy.1 Fever is common and the children usually disfiguring (Fig. 10.102).2
A B
Fig. 10.102
(A, B) Connective tissue panniculitis: this patient shows diffuse hyperpigmentation associated with generalized scarring and deformity. By courtesy of M.M. Black, MD, London, UK.
Laboratory findings include leukopenia, anemia, a raised ESR, positive anti-

nuclear antibody, and an unclassifiable antibody to extractable nuclear antigen.3
A lymphohistiocytic panniculitis associated with both acute and caseation
necrosis characterizes the lesions. Lipophagic histiocytes and giant cells may
be present, but granulomata are not a feature and there is no evidence of sep-
tal involvement or vasculitis.1,2
At present, this variant of chronic panniculitis has defied further
classification.
Lupus erythematosus profundus

Clinical features
Lupus erythematosus profundus (lupus panniculitis) is an uncommon variant of
panniculitis, which may develop in association with either discoid lupus erythe-
matosus (DLE) or systemic lupus erythematosus (SLE).1–8 The incidence of lupus
panniculitis in SLE ranges from 2% to 10%;4,9–11 DLE is present in from 33%
to 70% of cases.4,5 Lupus panniculitis may, however, also present in the absence Fig. 10.104
of any other manifestations of lupus erythematosus.9 In a recent series from the Lupus erythematosus
Mayo Clinic, 50% of patients had no evidence of any autoimmune-associated profundus: a depressed
disease.4 Lupus panniculitis shows a predilection for females (4:1) and most scarred area due to end-
patients are middle aged.4 Rarely, however, children (including infants) may be stage lipoatrophy.
By courtesy of the
affected.7,12 Rarely, lupus panniculitis may signify recurrence of SLE.13
Patients develop discrete, firm, asymptomatic or painful nodules, one to
London, UK.
several centimeters across, in the subcutaneous fat; the nodules are often
associated with trauma.9 Linear distribution of lupus panniculitis has rarely
In cases with associated SLE, patients frequently manifest arthralgia and
been reported and is likely associated with a more aggressive clinical behav-
Raynaud's phenomenon; there appears to be a relatively low incidence of
iour.14 The overlying skin may appear clinically normal or show discoid lupus
renal and neurological involvement.10 Positive serology may include antinu-
plaques, poikiloderma, erythema, atrophy or ulceration (Fig. 10.103).10,15
clear antibody, anti-DNA antibody, anti-extractable nuclear antigen (ENA)
Anetodermic lupus panniculitis has been associated with antiphospholipid
antibodies, and rheumatoid factor.9,15 In those patients in whom there is no
antibodies.16 Lupus erythematosus profundus is characteristically chronic, evidence elsewhere of lupus erythematosus, a raised antinuclear factor may be
patients developing recurrent crops of lesions. Spontaneous resolution may the only serological abnormality.4 Although in these latter patients the prog-
occur and leave depressed atrophic disfiguring scars (lipoatrophy) (Fig.
nosis is generally thought to be good, in some patients there is considerable
10.104). Sites of predilection include the face, upper and outer parts of mortality and the disfigurement a source of considerable distress.24,25 Partial
the arm, the breasts, back, and buttocks. Breast involvement with scarring
C4 deficiency has been described in a patient with lupus erythematosus
and calcification may be clinically mistaken for carcinoma (so-called ‘lupus
profundus.26
mastitis’).17,18 Salivary gland and primary periorbital lesions have also been
documented.19–23 Rarely, the disease may present with generalized lesions.8
In an established lesion the histological features of lupus erythematosus
profundus are virtually diagnostic. The overlying epithelium and super-
ficial dermis may show features of DLE, poikiloderma or be unaffected
(Figs 10.105–10.108).27,28 Within the deep dermis, and extending into the
widened septa of the subcutaneous fat, is a dense chronic inflammatory
cell infiltrate consisting predominantly of nodules of lymphocytes with
lesser numbers of plasma cells (Figs 10.109–10.111).11,13,28 Lymphocytic
nuclear debris or dust within a lymphoplasmocytic infiltrate is frequently
seen.13 Occasionally, lymphoid follicles with germinal centers are evident
(Fig. 10.112). The infiltrate may surround and permeate the walls of
blood vessels and sweat glands; involvement of the perineural sheath is
occasionally a feature (Fig. 10.113).27,29 Less often, frank lymphocytic
vasculitis with mural fibrinoid necrosis and luminal thrombosis is seen
(Fig. 10.114).
The infiltrate often extends into the periphery of the fat lobules and when
associated with fat necrosis there may also be moderate numbers of neutro-
phil polymorphs. The collagen of the deep dermis and the fibrous septa of the
subcutaneous fat show striking fibrinoid degenerative changes. Fibers may be
markedly swollen and intensely eosinophilic, or fragmented into amorphous
Fig. 10.103 granular debris. Similar changes are seen surrounding individual adipocytes.
Lupus erythematosus In more advanced examples, glassy eosinophilic necrosis gives a diffusely
profundus:
hyalinized appearance to the subcutaneous fat (Fig. 10.115). The foci of col-
erythematoviolaceous
plaques showing
lagenous degeneration are sometimes associated with mucin deposition, and
focal ulceration at the foci of calcification which may on occasion be very prominent.10,13,15,27,28,30
characteristic site. By Extensive endarteritis obliterans has been reported in a single case of lupus
courtesy of the Institute of panniculitis, which was associated with membranocystic changes and
Dermatology, London, UK. dystrophic calcification.31
Fig. 10.105 Fig. 10.108

Lupus erythematosus profundus: low-power view showing epidermal atrophy Lupus erythematosus profundus: the epidermis appears normal.
with hyperkeratosis and a dense dermal lymphocytic infiltrate with extension into
subcutaneous fat.
Fig. 10.106 Fig. 10.109

Lupus erythematosus profundus: in this example, there are typical features of Lupus erythematosus profundus: the septa are thickened and there is a dense
discoid lupus erythematosus. infiltrate.
Fig. 10.107
Lupus erythematosus profundus: in contrast, this patient showed disease limited to Fig. 10.110
the subcutaneous fat. Lupus erythematosus profundus: the infiltrate is largely lymphocytic.
Fig. 10.111 Fig. 10.114

Lupus erythematosus profundus: plasma cells, as shown in this field, are sometimes Lupus erythematosus profundus: lymphocytic vasculitis, as noted in this field, is
conspicuous. not uncommon.
Fig. 10.115
Fig. 10.112 Lupus erythematosus profundus: hyalinization of the fat is a characteristic feature.
Lupus erythematosus profundus: lymphoid follicles, as shown in this field, may be
a prominent feature.
By immunohistochemistry, the predominant cells are α/β T-helper lymphocytes,
intermingled with B lymphocytes.13 Molecular analysis by polymerase chain
reaction generally reveals a polyclonal phenotype.13
Immunofluorescence commonly reveals immunoglobulin and complement
at the dermoepidermal junction and sometimes around the superficial blood
vessels.15,27
Similar histological features may be seen in other connective tissue diseases
including linear morphea, morphea profunda, systemic sclerosis, dermatomyo-
sitis, mixed connective tissue disease, and polymyositis.32–35 Recently, Sjögren's
syndrome has been added to the causes of so-called plasma cell panniculitis.36
Lobular panniculitis with sclerosis reminiscent of lupus panniculitis has also
been described in a patient with Degos' disease (malignant atrophic papulosis).37
Distinction between lupus profundus and subcutaneous panniculitis-like T-cell
lymphoma can, on occasion, be extremely difficult on clinical as well as on
histological grounds.38–41 The presence of atypical lymphocytes with immuno-
histochemical features of cytotoxic T cells (CD3+,CD8+) accompanied by high
proliferation rate and monoclonal TCR-γ gene rearrangement is suggestive
of lymphoma.38 Nevertheless, lupus profundus and panniculitis-like T-cell
Fig. 10.113 lymphoma may coexist in the same patient.38 Overlapping histological features
Lupus erythematosus profundus: blood vessel walls are commonly thickened and with characteristics of both lupus profundus and subcutaneous panniculitis-like -
hyalinized. cell lymphoma are seen in these patients.38,42,43
Scleroderma panniculitis The overlying epidermis may show interface change with basal cell
vacuolation and lymphocytic exocytosis.1,7
Immunofluorescent findings are variable. In the majority of cases it is neg-
Clinical features ative, but C3 was found at the dermoepidermal junction in one case and,
Sclerosis and chronic panniculitis have been recorded as main features in in another, C3 and IgM were identified within the blood vessel walls in the
both generalized morphea and progressive systemic sclerosis.1–3 In addition, superficial dermal vasculature.6,7
morphea profunda has been described as a sclerosing variant of morphea,
which primarily affects the subcutaneous fat analogous to lupus erythemato- Differential diagnosis
sus profundus.4,5 This condition, which shows a female predominance (3:1),
An association of childhood dermatomyositis with subcutaneous panniculitic
affects a wide age range (9–62 years) and presents primarily as subcutaneous
T-cell lymphoma has been described in a single case report.15
sclerosis.6 The sclerosis may be generalized and extend to the digits, or present
as solitary or multiple, localized, inflamed, hyperpigmented or erythematous,
asymmetrical and ill-defined plaques with a predilection for the shoulders, Postirradiation pseudosclerodermatous
upper arms, and trunk.6–8 A variant localized to the paraspinal region in panniculitis
children has also been described.9,10 Patients with systemic sclerosis can
also develop sclerosing panniculitis. These patients have systemic sclerosis Clinical features
associated with pulmonary hypertension.11
This is a rare complication of high-dose radiotherapy. Thus far, it has only been
Histological features described in female patients who have received this treatment modality for breast
carcinoma following radical mastectomy.1–4 Patients present with deep-seated
The significant features include thickening and hyalinization of the con- and progressive induration of the subcutis in the area of previous irradiation
nective tissue of the deep dermis, subcutaneous fat, and muscular fascia.3 (Fig. 10.116), usually within the first year after radiation therapy.1–3
Lipomembranous fat necrosis can also be a feature.12 A perivascular and focal
interstitial lymphocytic and plasma cell infiltrate is present in the subcutane- Histological features
ous fat. Exceptionally, plasma cells may be very numerous – so-called plasma
The main histological features are localized to the subcutaneous fat where
cell panniculitis.13–15 Lymphoid nodules (usually without germinal center for-
there is a lobular panniculitis characterized by fat necrosis with foreign body
mation) are evident and mast cells may be increased in number.6 Scattered
(lipophagic) granulomata and a lymphocyte and plasma cell infiltrate.1,2 The
eosinophils are occasionally seen. Mucin deposition is sometimes a feature
septa are grossly thickened by hyalinized collagen. Dermal changes may be
and diminished elastic tissue is a frequent finding, although in some cases it
absent or there can be a perivascular and interstitial lymphocyte and plasma
appears increased in quantity.8 Localized osseous metaplasia with transepi-
cell infiltrate with atypical myofibroblasts.1 Dilated lymphatics may occasion-
dermal elimination has been documented.16 The changes in the fascia are
ally be found in the dermis.3 Epidermal changes of radiotherapy are absent.2
similar to those described in the subcutaneous fat.
Differential diagnosis Differential diagnosis

In patients with this condition, sections should be very carefully scrutinized
Morphea profunda differs from conventional generalized morphea by the
for evidence of recurrent/metastatic breast carcinoma. Immunohistochemistry
deeper involvement of the sclerotic process and the more intense chronic
may prove invaluable.
inflammatory cell infiltrate.6 Some authors regard eosinophilic fasciitis as
Postirradiation pseudosclerodermatous panniculitis can be histologically
part of the spectrum of morphea profunda.6
confused with both morphea profunda and lupus erythematosus profundus.2
Clinicopathological correlation should readily establish the correct diagnosis.
Dermatomyositis panniculitis
Clinical features
Panniculitis has been described as a non-specific incidental finding in biopsy
specimens of skin or muscle from patients with dermatomyositis.1–3 Rarely,
however, it presents as a symptomatic disorder, patients complaining of indu-
rated, erythematous, tender, painful plaques and nodules, located about
the arms, thighs, abdomen, and buttocks.3–11 In some cases, the panniculi-
tis precedes the onset of the myositis.3 With chronicity, patients can develop
lipoatrophy.12 Both children and adults may be affected.
Dermatomyositis panniculitis is characterized by a predominantly lobular
infiltrate of lymphocytes and plasma cells, sometimes accompanied by lym-
phoid follicles with germinal centers.4,5 Focal fat necrosis may be present
and lymphocytic vasculitis has occasionally been documented.6 The septa
of the subcutaneous fat become progressively thickened and hyalinized.
Membranocystic changes have been described in a number of cases,
particularly in the Japanese.1,12,13 Calcification is a late change, but can be
very prominent.1,14
Mild inflammatory changes may be seen in the subcutaneous fat in Fig. 10.116
patients with dermatomyositis in the absence of panniculitis including focal Postirradiation pseudosclerodermatous panniculitis: erythematous irregular plaque.
lymphocytic infiltration, fibrosis, and calcification.5 By courtesy of the Institute of Dermatology, London, UK.
11
Chapter
Diseases of the oral mucosa See

for references and
Sook-Bin Woo additional material
Introduction 363 Lipoma and atypical lipomatous tumor 387 SALIVARY GLAND DISEASE 412
Denture-associated fibrous Reactive conditions 412
HEREDITARY CONDITIONS 364
hyperplasia 387 Mucocele 412
Macular lesions 364 Sialolithiasis 414
Gingival nodules 389
White sponge nevus 364 Necrotizing sialometaplasia 414
Hereditary benign intraepithelial dyskeratosis 364 Gingival fibroma 389 Nicotinic stomatitis 415
Pachyonychia congenita 365 Cheilitis glandularis 416
Pyogenic granuloma 390 Salivary gland neoplasms 416
Dyskeratosis congenita 366
Darier's disease 366 Peripheral ossifying fibroma 391 Pleomorphic adenoma 417
Warty dyskeratoma 366 Canalicular adenoma 418
Peripheral giant cell granuloma 392 Mucoepidermoid carcinoma 418
Tumor-like lesions 366 Polymorphous low-grade adenocarcinoma 419
Parulis 393
Choristomas 366 Adenoid cystic carcinoma 419
Heterotopic brain tissue 368 Peripheral odontogenic fibroma 393 Papillary ductal lesions 420
Epidermoid and dermoid cysts 368
Dermoid tumor (dermoid), teratoma, and Gingival cyst of the adult 395
PREMALIGNANT CONDITIONS 421
epignathus 368 Generalized gingival
Oral lymphoepithelial cyst 369 Leukoplakia, erythroplakia and epithelial
hyperplasia 396
Lingual thyroid 370 dysplasia 421
Congenital granular cell tumor/epulis 370 Varix 398
Submucous fibrosis 424
Lymphangioma of the alveolar ridge 371
Gingival fibromatosis 371
INFECTIONS 399 MALIGNANT LESIONS 425
Juvenile hyaline fibromatosis 372
Hairy leukoplakia 399 Squamous cell carcinoma 425
REACTIVE CONDITIONS 372 Focal epithelial hyperplasia 400 Sarcomatoid carcinoma 427
Leukoedema 372 Basaloid squamous cell carcinoma 428
Morsicatio mucosae oris 373 LICHENOID AND HYPERSENSITIVITY
Adenoid squamous cell carcinoma 429
REACTIONS 402
Benign alveolar ridge keratosis 374 Adenosquamous carcinoma 429
Oral lichen planus and lichenoid
Benign migratory glossitis 375 stomatitis 402 Verrucous carcinoma 429
Median rhomboid glossitis 376
Plasma cell gingivostomatitis 406 Midline destructive disease 430
Smokeless tobacco keratosis 377
Orofacial granulomatosis 407
Foreign body gingivitis 379 PIGMENTED LESIONS 431
Oral Crohn's disease 408
Pyostomatitis vegetans 379 Amalgam tattoo 431
AUTOIMMUNE CONDITIONS 409 Oral melanocytic lesions 432

ULCERATIVE CONDITIONS 380 Oral melanotic macule 432
Desquamative gingivitis 409 Melanoacanthosis 433
Recurrent aphthous stomatitis 380
Mucous membrane pemphigoid 409 Oral melanocytic nevus 434
Traumatic ulcerative granuloma 381 Oral melanoma 434
Pemphigus 411
Medication-induced oral
PAPILLARY LESIONS 383
Paraneoplastic pemphigus 411 pigmentation 435
Squamous papilloma 383
OTHER TUMORS 435
Verruciform xanthoma 384
Dermatitis herpetiformis 411
Granular cell tumor 435
TUMOR-LIKE CONDITIONS 385 Epidermolysis bullosa acquisita 411
Ectomesenchymal chondromyxoid
Fibroma 385 Lupus erythematosus 411 tumor 436
Giant cell fibroma 386 Wegener's granulomatosis 412
Introduction 363
Keratinized sites include the hard palate mucosa, the attached gingiva
Introduction (extending from the tooth for a band of 3–7 mm) and the tongue dorsum.
The tongue is a specialized structure because of its role in taste sensation and
Oral and maxillofacial pathology is the specialty of dentistry that is involved in has filiform, fungiform, and circumvallate papillae, the last two also contain-
the diagnosis and management of diseases of the oral mucosa and supporting ing taste buds (Fig. 11.3).
bone and soft tissues, teeth, salivary glands, lip vermilion, and perioral skin. The oral mucosa consists of epithelium and underlying lamina propria that
It would be impossible to discuss diseases affecting all of the above entities can be arbitrarily divided into superficial and deep portions, and underlying
in one chapter. As such, this chapter is confined to common and uncom- muscle or bone. Since there is no muscularis mucosa, there is no true sub-
mon mucosal lesions that are often seen and biopsied by the oral and max- mucosa. The epithelium of the oral mucosa is thickest on the tongue dorsum
illofacial surgeon, dermatologist or an otorhinolaryngologist. If a condition and thinnest on the floor of mouth and is generally two to four times thicker
presents on the skin in addition to the mouth (such as pemphigus), only a than the epidermis (Fig. 11.4). Pathologists not familiar with this feature tend
brief mention of the oral manifestations is made since the topic will have been to diagnose normal mucosa as acanthosis or psoriasiform hyperplasia. The
covered in detail elsewhere in this book. attached gingiva and mucosa of the hard palate abut the periosteum so that
From a histological perspective, the oral mucosa is divided into nonkera- the deep lamina propria appears densely fibrotic (Fig. 11.5). A diagnosis of
tinized and keratinized sites. The former include the labial mucosa (wet sur- ‘fibrosis’ is therefore inappropriate since this feature is normal for the site.
face of the lip), buccal mucosa, maxillary and mandibular sulci (sometimes The tooth is composed of an outer highly calcified thin shell of enamel on the
also called the ‘vestibule’), ventral tongue, floor of mouth, soft palate, nonat- visible crown of the tooth; the non-visible portion within the bone is covered by
tached gingiva and crevicular epithelium (Fig. 11.1). The crevicular epithe- cementum, which is similar in composition and appearance to bone. The bulk
lium is the continuation of marginal gingiva where it turns to face the tooth. of the tooth consists of dentin and through the tooth runs the pulp containing
Any keratin on these surfaces is considered abnormal and should be reported fibrovascular and neural tissues (the source of most toothaches). Odontogenic
as such. The linea alba (‘bite line’) which is located on the buccal mucosa epithelium is often seen within the gingival tissues and in odontogenic tumors in
where the upper and lower teeth meet may be thinly parakeratinized and this the gingiva. This consists of nests of squamous epithelium that may have clear
is considered within the realm of normal (Fig. 11.2). cytoplasm and sometimes show palisading of the basal cell nuclei (Fig. 11.6).
Fig. 11.1 Fig. 11.3

Normal mouth: note the maxillary sulcus, attached and nonattached gingiva and teeth. Normal tongue: the filiform papillae are spires of parakeratin usually associated with
bacterial colonies.
Fig. 11.2
Normal mouth: the linea alba on the buccal mucosa usually exhibits leukoedema Fig. 11.4
and may be thinly parakeratinized. Normal buccal mucosa: the epithelium is nonkeratinized and is 5–25 cells thick.
364 Diseases of the oral mucosa
Fig. 11.5 Fig. 11.7

Normal palate: the palate and gingiva both are thinly keratinized. The dense fibrous White sponge nevus: typical white, thickened, spongy-appearing mucosa. By courtesy
tissue beneath is normal for these sites. of C. Allen, DDS, Columbus, USA.
Fig. 11.6
Odontogenic epithelium: note the small nests composed of squamous cells,
sometimes with subtle palisading at the periphery.
Hereditary conditions
insertions resulting in keratin filament instability and abnormal aggregation of
Macular lesions tonofilaments.7–9 Since some cases remit with antibiotic therapy, this suggests that
infections and/or inflammation may play a role in the e xpression of disease.10,11
White sponge nevus There is parakeratosis, acanthosis with the formation of large, blunt rete
ridges, vacuolation of cells; anucleate keratinocytes are present superficially
Clinical features (Fig. 11.8). Dyskeratotic cells exhibit dense peri- and paranuclear eosino-
philic condensations and there is insignificant inflammation (Fig. 11.9).5,12,13
White sponge nevus (Canon white sponge nevus, leukoedema exfoliativum
Parakeratin plugs and streaks have been noted beneath the superficial kera-
mucosae oris, familial white folded dysplasia of mouth) is an autosomal domi-
tinocytes. One case that exhibited foci of epidermolytic hyperkeratosis has
nant condition with high penetrance and variable expressivity. Onset is in early
been documented.14
childhood with 50% of patients diagnosed before age 20.1–3 The buccal mucosa
The eosinophilic condensations correspond to tonofilament aggregates in
is almost invariably affected and other common sites are the labial mucosa,
a peri- and paranuclear location.1,12,13,15 Organelles tend to segregate and are
tongue, alveolar mucosa, and the floor of mouth. Nasal, esophageal, vaginal,
absent in vacuolated cells. Odland bodies are abundant within keratinocytes
anal, and penile mucosae may be involved, but not that of the conjunctiva,
but few are present in the intercellular spaces, suggesting a lack of acid phos-
although there is one report of associated colobomas.4 Lesions appear as dif-
phatase leading to retention, rather than normal shedding, of superficial cells.1
fuse, white-to-gray, painless, spongy, folded plaques with a tendency to slough
off (Fig. 11.7).2,5,6 There may be periods of exacerbation and remission.
Hereditary benign intraepithelial dyskeratosis
White sponge nevus has been traced to a mutation in the helical domain of Clinical features
mucosal-specific keratins K4 (on chromosome 12q) and K13 (on chromosome This autosomal dominant disorder of the eye and oral cavity was first
17q). The mutations are in the form of amino acid deletions, substitutions, and described in a tri-racial isolate (Caucasian, Native American, and African)
Macular lesions 365
Fig. 11.10
Hereditary benign intraepithelial dyskeratosis: the mucosa appears white and
thickened. By courtesy of J. McDonald, DDS, Cincinnati, USA.
Fig. 11.8
White sponge nevus:
the epithelium exhibits
vacuolation, acanthosis,
and dyskeratosis.
Fig. 11.11
Hereditary benign intraepithelial dyskeratosis: there is hyperkeratosis, dyskeratosis,
and acanthosis. By courtesy of J. McDonald, DDS, Cincinnati, USA.
Fig. 11.9
White sponge nevus: there are perinuclear eosinophilic keratin condensations and
cytoplasmic vacuolation. There is hyperkeratosis and acanthosis (Fig. 11.11). Dyskeratotic cells (also
called ‘tobacco cells’ because of their orange-brown color on Papanicolaou-stained
in North Carolina called the Halowar, Haliwa, or Haliwa-Saponi Indians.1 smears) are present in the mid to upper one-third of the epithelium, appearing
Because of migration, cases have been reported in descendants living now in engulfed by adjacent normal keratinocytes; this ‘cell-within-a-cell’ appearance is a
New York, Pennsylvania, Virginia, and Washington DC. characteristic feature and is well seen in cytological smears (Fig. 11.12)4,7,8
The eye lesions, which usually present by the first year of life, are foamy, gelat- The dyskeratotic cells are packed with tonofilaments and vesicular bodies
inous plaques in the bulbar conjunctiva in a perilimbic distribution both nasally that may represent Odland bodies.7 Some keratinocytes also show disappear-
and temporally. Patients experience irritation and photophobia and there may be ance of cellular interdigitations and desmosomes.
exacerbations in spring. Corneal vascularization sometimes leads to visual loss.2
Oral involvement is asymptomatic and is therefore generally not noticed Pachyonychia congenita
until the second decade. Lesions involve the buccal and labial mucosa, floor
of mouth, lateral and ventral tongue, and gingiva but not usually the dorsum
Clinical features
of tongue or uvula.3–5 The mucosa is white, opalescent, spongy, macerated,
folded, and shaggy, often resembling white sponge nevus (Fig. 11.10). There This rare genodermatosis is characterized by nail dystrophy, disorders of the
is generally no involvement of genital, nasal or rectal mucosa. palmoplantar skin and hair and leukoplakia; the larynx and eye may also be
affected.1 The oral findings, usually noted within the first two decades of life,
are characterized by focal or generalized white hyperkeratotic plaques on the
Pathogenesis and histological features dorsum and lateral borders of the tongue and buccal mucosa, and are present
Genetic studies have localized the gene for this condition to chromosome in 75–95% of cases.1–4 Natal teeth (teeth present at birth) are a common
4q35 with a duplication segregating in affected individuals.6 finding in the type 2 form of the disease.1,5,6
parotid or submandibular swelling may be reported in up to approximately

one-third of cases and is most likely the result of strictures in the main duct
causing obstruction.4,5 In general, the degree of oral involvement parallels the
extent of skin lesions.2,5

This disease is associated with a mutation on the ATP2A2 gene on chromo-
some 12q that is involved in cytoplasmic calcium transport which is required
for proper functioning of desmosomes and keratin formation.6
The typical findings are hyperkeratosis, acanthosis, and suprabasal clefting
with acantholysis forming vertical villous-like projections protruding into
lacunae. Corps ronds and grains may not be as prominent as in skin lesions.2,5
Papanicolaou-stained smears show an orange-brown staining of the dyskera-
totic ‘grains’ and refractile concentric perinuclear rings and granular bands in
corps ronds.7 The excretory salivary ducts may become metaplastic or involved
by the same process leading to stricture formation and obstruction.1,8,9
Fig. 11.12
Pemphigus vulgaris and pyostomatitis vegetans both exhibit acantholysis but
Hereditary benign
intraepithelial
not generally dyskeratosis; in addition, pemphigus shows intercellular IgG
dyskeratosis: note the deposits on direct immunofluorescence.
dyskeratosis with the
typical ‘cell-within-a-cell’ Warty dyskeratoma
structures. By courtesy
of J. McDonald, DDS,
Cincinnati, USA.
Clinical features
This usually solitary lesion resembles Darier's disease and may present as a
papule or nodule (oral focal acantholytic dyskeratosis) in the oral cavity. It
Pathogenesis and histological features generally occurs in the fifth or sixth decade and almost always arises on the
Pachyonychia congenita is generally inherited as an autosomal dominant disor- keratinized and attached mucosa of the palate or gingiva with a 2:1 female
der characterized by missense mutations of the gene for keratin 6a and 16 (type predominance.1 Most lesions measure less than 1 cm and rare cases develop
1), and 6b and 17 (type 2) located on chromosome 17q.1,7. There is a defect in on the buccal mucosa and tongue.2–4 Interestingly, the majority of cases occur
the association of protein subunits in the assembly of keratin filaments. on the left side of the mouth, raising the possibility that trauma plays an
Histologically, there is hyperparakeratosis or hyperorthokeratosis, acan- important role since most individuals are right-handed and may brush the left
thosis, and intracellular vacuolization.3,6,8 Because pachyonychia congenita side of the mouth more vigorously. The papular variety appears as a white
and dyskeratosis congenita are generally diagnosed on skin biopsy, there are papule or plaque while the nodular variety has an umbilicated or crateriform
few detailed reports on the histology of oral lesions. appearance. There is an association with tobacco use.3,5
Dyskeratosis congenita Oral warty dyskeratoma is characterized by Darier's disease-like features
including suprabasilar clefting with lacunae formation, villous-like projections,
Clinical features corps ronds and grains.3 The papular lesions show multifocal involvement
Dyskeratosis congenita is another genodermatosis that is associated with nail and sometimes papillary epithelial hyperplasia.6 There is no association with
dystrophy, poikiloderma, oral leukoplakia, and development of pancytope- underlying sebaceous or salivary glands.
nia, often requiring hematopoietic stem cell transplantation. The mucosa
of the conjunctiva, urethra, and genital tract may also be involved.1,2 Oral Differential diagnosis
leukoplakia, particularly of the tongue, presents in the second decade of life Pemphigus vulgaris can be readily distinguished by the clinical history
and has a high propensity for developing dysplasia and/or squamous cell and the characteristic presence of intercellular IgG deposition on direct
carcinoma at an early age.3,4 immunofluorescence.
It is generally considered to be a premature aging syndrome caused by telom- Tumor-like lesions
erase dysfunction with mutations in the DKC1, TERC or TERT genes.5
Histologically, dyskeratosis congenita shows hyperpara- or orthokeratosis Choristomas
with dysplasia or squamous cell carcinoma.
Osseous choristoma
Darier's disease Clinical features
The majority of these lesions (93%) occur as sessile or pedunculated masses on
Clinical features the posterior dorsum of the tongue, near the foramen cecum, although other sites
Oral findings occur in approximately 50% of patients with Darier's disease may be involved.1–4 Most develop in the second and third decades and females
(Darier-White disease, keratosis follicularis). Mild involvement comprises are three to five times more likely to be affected.2,4 There may be dysphagia.
minute white or pink keratotic papules, while in more extensive disease
coalescence results in larger plaques or a cobblestone surface. Lesions are gen- Pathogenesis and histological features
erally asymptomatic.1–4 The palate is the most common site affected, perhaps Theories of origin include ossification of branchial arch remnants, metaplas-
because of its normally keratinized nature, followed by the gingiva, tongue, tic bone formation secondary to trauma, and osteogenesis of unknown cause
buccal mucosa, and floor of mouth. The lips are rarely involved.5 Recurrent from pluripotent mesenchymal cells in the area.
Tumor-like lesions 367
The lesion consists of a well-circumscribed mass of viable lamellar bone Differential diagnosis
with haversian systems surrounded by fibrous connective tissue; osteoblastic
Metaplastic cartilaginous nodules are often seen in cases of denture-associated
rimming, hematopoietic and fatty marrow or even cartilage may be present
fibrous hyperplasia but these occur in the maxillary and mandibular vestibules
(Figs 11.13, 11.14).1,5,6
associated with denture flanges. Cartilaginous rests are also common in the
area of the nasopalatine canal. Some authors believe that cartilaginous rests
Cartilaginous choristoma of the soft palate/tonsillar area are a metaplastic phenomenon, occurring in
Clinical features 20% of tonsils examined.7 A pleomorphic adenoma with extensive chondroid
Cartilaginous choristomas present as discrete nodules, usually along the lat- metaplasia should also be considered.
eral border of the tongue (85% of cases) and less often on the buccal mucosa
and soft palate.1–3 Most occur in adults.4
Sebaceous choristoma, hyperplasia and adenoma
Clinical features
Pathogenesis and histological features Sebaceous glands occur as 1–3-mm yellow macules or papules in the
They may represent developmental malformations that arise from pluripotent buccal and labial mucosa in approximately 80% of the adult population
mesenchymal cells of the tongue, metaplastic change secondary to trauma or (Fig. 11.15).1 However, these may become hyperplastic or adenomatous, form-
cartilaginous rests. ing painless papules, plaques or nodules, and are termed sebaceous hyperplasia
Cartilaginous choristoma consists of a mass of benign mature hyaline car- or adenoma, respectively.2,3 They occur in the same sites as Fordyce granules.
tilage surrounded by dense perichondrium; loose myxoid tissue akin to primi- Rare cases of sebaceous choristomas have been reported in the tongue of
tive mesenchyme or even mature fat may also be present.2,4,5 Some cases show adults. They present as dome-shaped masses in the midline of the dorsum in
ossification and association with salivary glands.2,3 Rare cases of chondrosar- the area of the middle or posterior one-third of the tongue, often associated
coma have been reported.6 with a thyroglossal duct.4,5
Fordyce granules consist of mature lobules of sebaceous glands that communi-
cate with the surface epithelium via a duct. There may be pseudocyst formation
with retention of secretions and adenomatous hyperplasia; the rare occurrence
of hair follicle and Demodex within a Fordyce granule has been reported.6–8
In sebaceous hyperplasia, at least 15 lobules of mature sebaceous glands
empty into ducts that communicate with the surface (Fig. 11.16).2 In the
sebaceous choristoma, mature sebaceous units may be associated with eccrine
glands, hair follicles, and apocrine glands.5 Sebaceous adenomas also show a
proliferation of basaloid cells at the periphery of the lobules.9,10 Some of these
may represent sebaceous adenoma of the minor salivary gland.11
Gastrointestinal choristoma
Clinical features
Almost all of these are cystic lesions that present as swellings of the tongue,
usually on the ventral surface, or the floor of mouth.1–3 Sometimes they appear
as sinuses.4 They are most often seen in infancy or early childhood and may
be associated with orofacial malformations.3
Fig. 11.13 Many theories of pathogenesis have been postulated including epithelial
Osseous choristoma from the tongue: there is a discrete nodule of bone and fatty entrapment, incomplete coalescence of lacunae, and persistence of intestinal
tissue. epithelial buds.4,5
The cystic lesions are lined by epithelium typical for the cardiac, fundic
or pyloric regions of the stomach with parietal and Paneth cells.4 However,
Fig. 11.14
Osseous choristoma from the tongue: the woven bone shows osteoblastic rimming Fig. 11.15
and is laid down by the surrounding mesenchymal cells. Fordyce granules: typical yellow papules of the buccal mucosa.
Fig. 11.17
Heterotopic brain tissue: note the presence of glial and ependymal tissue.
Fig. 11.16
Sebaceous hyperplasia: Pathogenesis and histological features
numerous lobules of
sebaceous glands empty The pathogenesis is uncertain. One theory suggests that they arise from
into a central duct. entrapped epithelial rests in the line of fusion of facial processes. Another
proposes that the lining develops from displaced embryonic rests or traumatic
implantation, possibly occurring even in utero.3
some are lined by colonic and/or ciliated epithelium.5 Smooth muscle is Both epidermoid and dermoid cysts are lined by orthokeratinized squamous
usually identified. The presence of pancreatic tissue has also been reported.6 epithelium and the lumen is filled with keratinaceous material. Epidermoid
If ectodermal and mesodermal elements are also present, the lesion should be cysts (also called epithelial inclusion cysts) have no adnexa in the wall, while
considered a teratoma. dermoid cysts always have skin adnexal structures in the wall. Oral dermoid
cysts are three times more common than epidermoid cysts.2
Some cysts also contain gastrointestinal mucosa.6,7 If tissues from all
Pathogenesis and histological features three germ layers are represented, the term ‘teratoid cyst’ may be more
appropriate.
Heterotopic brain tissue
Clinical features Gingival cyst of the adult is generally nonkeratinized and is lined by low
This uncommon condition presents in the first year of life, most often affect- cuboidal to columnar or stratified squamous epithelium, with occasional
ing the palate, tongue (especially the foramen cecum area) or oropharynx, epithelial plaques and clear cells.8 Gingival cysts of the newborn, which are
as a result of displacement of primitive neural elements in an early stage of generally not biopsied because they exteriorize on their own, are filled with
development or neuroglial differentiation from pluripotent cells.1,2 Some keratinaceous material.9 Both can be differentiated from epidermoid cysts by
patients have associated palatal defects.3 Respiratory obstruction is a major their location on the gingiva.
cause of morbidity and feeding difficulties if lesions are large.4
Histological features Dermoid tumor (dermoid), teratoma, and

Mature elements of the central nervous system including astrocytes, oligoden- epignathus
drocytes, ependymal tissue, choroid plexus-like tissue and, rarely, neuronal
tissue may all be identified (Fig. 11.17).1,2,5,6
Clinical features
These rare conditions generally present congenitally or in infancy as masses
Epidermoid and dermoid cysts protruding from the mouth, causing respiratory distress and feeding difficul-
ties. They have been classified as follows:
Clinical features • dermoid where only ecto- and mesodermal structures are present, and
The floor of the mouth is the most common site of presentation and there may therefore the tumor is not strictly a teratoma,
be a slight female predilection; some cases are congenital.1–3 Classification of • teratoid tumor and teratoma with tissue from all three germ layers
these lesions is based on anatomical location such as lingual, submental or represented (in general, the tissues in teratoid tumor are not as well
submandibular and on the histological appearance.1,2,4 organized as in a teratoma),
They present as dome-shaped, yellow masses with a rubbery or doughy con- • epignathus where there is recognizable organ and limb formation;
sistency. Intraoral lesions cause feeding, swallowing, and speech difficulties however, this term is also often applied to any teratoid tumor or
while extraoral variants below the myohoid muscle lead to a noticeable submen- teratoma that arises from the nasopharyngeal or palatal areas.
tal mass. Dumbbell-shaped cysts have both intra- and extraoral swellings.5 Of these, the dermoid is the most common.1
While epidermoid and dermoid cysts are cystic structures that occur in Dermoids tend to occur in females (six to seven times more often than in
the midline of the floor of mouth in children and young adults, dermoid males) as pedunculated masses in the nasopharynx, oropharynx, and soft
tumors or hairy polyps are usually large congenital lesions occurring in the palate.2,3 The mass is covered by skin, hence its other name, ‘hairy polyp’.
nasopharynx and soft palate. It may also grossly resemble an accessory auricle.4
Teratomas, teratoid tumors, and epignathi present as masses that may Epignathi consist of tissues organized to form grossly recognizable specific
rotrude from the mouth, and airway obstruction is a frequent presenting
p organ systems such as limbs, a head or eyes.7,10
symptom; there is a female predilection and most are present at birth.5 Unlike
dermoids, these tumors are often associated with other malformations and
findings such as elevated alpha fetoprotein and polyhydramnios.6,7 Oral lymphoepithelial cyst
Epignathi in particular may be associated with severe congenital malfor-
mations, and stillbirth is a common occurrence. They most often arise from Clinical features
the hard palate (hence its name), although the posterior nasopharynx and
Oral lymphoepithelial cysts generally occur in the fourth decade of life
upper lip can be involved, and there may be palatal clefts and cranial exten-
with an equal sex distribution.1,2 These also occur in the parotid gland in
sion.7–9 Grossly, the tumor sometimes contains rudimentary limbs, or even a
particular in HIV-positive individuals.3 They present as painless yellowish
head resembling an incomplete twin or fetus in fetu.10
nodules, usually less than 1 cm in diameter, most commonly affecting the
Lingual (tongue) teratomas are generally not associated with such devel-
floor of mouth followed by the posterior ventral tongue, soft palate, and
opmental defects.11
tonsillar fauces (Fig. 11.20).3–5 They are commonly filled with cheesy, ker-
Histological features atinaceous material. Some authors consider lesions which present at sites
where tonsillar tissue is normally found to be inflammatory/obstructive
Dermoids are covered by skin with its constituent adnexa. In addition, tonsillar reactions.4
cartilage, bone, muscle, adipose tissue, and even salivary glands may be
present (Fig. 11.18).3,7,12 Teratomas contain all of the above. In addition,
neural, brain, lung, gastrointestinal, and respiratory tissues are sometimes Pathogenesis and histological features
present (Fig. 11.19).6,11 Three theories of pathogenesis have been proposed:
• There is enclavement of epithelium within oral lymphoid tissue during
embryogenesis and subsequent proliferation and cystic degeneration.1
• Such lymphoid aggregates are ectopic oral tonsils, where the crypt
openings have been blocked, resulting in retention of secretions.5,6
• The epithelium represents normal excretory salivary ducts and the
lymphoid tissue is a reaction to inflammation or immunological
stimulation.3
The last theory pertains primarily to floor of mouth lesions, a site where
tonsillar/lymphoid tissue is not normally found.
The cyst is lined by parakeratotic stratified squamous epithelium and the
lumen is filled with desquamated keratinaceous material (Fig. 11.21).3,4,7 Rare
cases may be lined by pseudostratified columnar epithelium with or without
mucous cells.5 The epithelium usually demonstrates lymphocytic exocytosis
(Fig. 11.22). The surrounding lymphoid tissue may encircle the cyst epithe-
lium completely or partially, and germinal centers are usually well formed
although not always present. Some cases demonstrate communication with
the overlying surface epithelium, often through a narrow opening.
Salivary glands and ducts may be present in the vicinity, especially floor of
mouth lesions.1,3
Fig. 11.18 Differential diagnosis

Dermoid tumor: note the presence of cartilage and columnar epithelium. Mucoceles of the retention type are lined by stratified squamous, columnar,
By courtesy of the Registry of Oral Pathology, AFIP, Washington DC, USA. oncocytic or respiratory epithelium, sometimes with mucous cell metaplasia.
Fig. 11.19 Fig. 11.20

Teratoma: in addition to endodermal elements, glial tissue is present. Oral lymphoepithelial cyst: note the yellow nodule located behind the anterior
By courtesy of the Registry of Oral Pathology, AFIP, Washington DC, USA. faucial pillar.
i.e., the first and second decades and the fifth and sixth decades, probably
related to hormonal influences;4,5 it is uncommon in children.6 One-quarter
of patients may be hypothyroid.

Since the thyroid anlage develops in the area of the foramen cecum and
descends from there into the neck, failure to descend or persistence of rem-
nants of the anlage which then proliferate, resulting in a noticeable mass.
In most cases, a biopsy is not indicated if technetium scans are positive
for thyroid tissue. Thyroid follicles may contain mature or embryonic thy-
roid epithelium and exhibit microfollicular, macrofollicular or adenomatous
changes.1,5 There may be an associated thyroglossal duct.2 Follicular and pap-
illary carcinomas can sometimes occur, in the same frequency as one would
expect in the normal thyroid gland.7,8; even medullary carcinoma has been
reported.9
Congenital granular cell tumor/epulis

Fig. 11.21 Clinical features
Oral lymphoepithelial cyst: the cyst is completely encircled by lymphoid tissue. The congenital granular cell tumor presents as a pink, pedunculated mass,
usually on the anterior alveolar ridge with an intact surface (Fig. 11.23).
There is a 10:1 female predilection and it is three times more common in the
maxilla.1 It may cause problems with nursing. Approximately 9% of patients
have multiple nodules and some may have concurrent tongue lesions.2–4

Theories of histogenesis have included epithelial, pericytic, and neural deriva-
tion. The current hypothesis is that it represents a mesenchymal tumor (some
believe of myofibroblastic origin) with evidence of degenerative change. The
latter is supported by lack of growth after birth of the infant, resolution of
some cases over time, histological evidence of degeneration, and lack of recur-
rence in spite of incomplete removal.1,5,6
Histologically, a Grenz zone may or may not be present and the overlying
epithelium is typically atrophic. The cells are round or polygonal with abun-
dant eosinophilic granular cytoplasm, distinct cell borders, eccentric small
nuclei, and inconspicuous nucleoli; a prominent delicate and arborizing cap-
illary network is usually evident (Fig 11.24).3,6 The granules are period acid-
Schiff (PAS) positive and diastase resistant; odontogenic rests may also be
present.4,7
The granular cells do not express S-100 protein but are always vimentin
Fig. 11.22 positive; macrophage/histiocytic markers (such as MAC387 and lysozyme)
Oral lymphoepithelial cyst: there is lymphocyte exocytosis through the epithelium are usually negative although CD68 and Ki-M19 immunohistochemistry is
and a small germinal center is present.
They may show foci of chronic inflammation but not usually the thick mantle
of lymphocytes with germinal centers. Dermoid and epidermoid cysts lack the
lymphoid mantle, and dermoid cysts contain adnexa in their wall.
Masses and clumps of bacteria may mat together and plug tonsillar crypts,
presenting as an opaque yellow mass that is not covered by epithelium and
that can readily be scraped off.8
Lingual thyroid
Clinical features
Approximately 10% of cadaveric tongues contain nests of thyroid tissue,
with no sex predilection.1,2 However, when thyroid tissue occurs as a mass in
the tongue, the term ‘lingual thyroid choristoma’ or ‘ectopic lingual thyroid’
is used. Since approximately 86% of such tumors consist of the only thyroid
tissue in the body, the terms ‘lingual thyroid ’or ‘ectopic lingual thyroid’ are
more accurate.3
The lesion presents as a rounded, soft-to-firm mass within the base of the
tongue between the foramen cecum and the epiglottis. It may cause dysphagia, Fig. 11.23
dyspnea, dysphonia or hemorrhage.2–4 Females are three to seven times more Congenital granular cell epulis: the maxillary alveolus is a typical location for this
likely to be affected than males and there are two peaks of presentation, tumor. By courtesy of B. Padwa, MD DDS, Boston, USA.
Gingival fibromatosis
Clinical features
In this condition, there is a benign, diffuse, nonhemorrhagic, and fibrotic gin-
gival enlargement, often occurring bilaterally and involving the maxillary and
mandibular gingiva, sometimes to the extent that it may reach the occlusal/
incisal edges of the teeth.1,2 Several forms are recognized. The inherited form
(usually an autosomal dominant trait, but occasionally autosomal recessive),
which is less common, tends to present congenitally or in the first decade of
life, coinciding with eruption of teeth, and often exhibits generalized gingi-
val involvement (Fig. 11.25). There is a strong association with hypertricho-
sis and mental retardation and/or epilepsy. Gingival fibromatosis may also
be a feature of Zimmerman-Laband, Ramon, Rutherford, and Cross syn-
dromes.2,3 An idiopathic form more often occurs later in life with usually
limited involvement of the upper or lower jaw or just one quadrant. There is
no tendency to regression. The most common presentation is overgrowth of
tissue in the area of the maxillary tuberosity and lingual mandible, frequently
in a symmetric fashion.1
Fig. 11.24
Congenital granular cell epulis: note the large pale cells with granular cytoplasm;
they are S-100 negative. Pathogenesis and histological features
The gene for the nonsyndromic form has been localized to chromosome
2p21–22.4
positive, indicating the presence of phagolysosomes.6,8 Antichymotripsin is The gingival overgrowth is caused primarily by an increased produc-
sometimes present.8 Stains for smooth muscle actin, estrogen and proges- tion and reduced metabolism of connective tissue. Native fibroblasts
terone receptors, glial fibrillary acidic protein (GFAP), myelin basic protein show elevated rates of proliferation and increased synthesis of fibronectin
(MBP), and neurofilament protein are negative.1,6 One report identified and type I collagen.5 Reduced matrix metalloproteinase levels – possibly
neuron-specific enolase (NSE) within the granular cells.9 mediated by increased production of transforming growth factor beta-1
Ultrastructural studies reveal the presence of membrane-bound granules (TGF-β1) – may result in excess accumulation of extracellular matrix.6
with electron-dense contents that most likely represent phagolysosomes.1,3,8,10 Histologically, there is a diffuse proliferation of bands and whorls of
The presence of subplasmalemmal dense bodies, pinocytotic vesicles contain- collagen within a background of excessive ground substance (Fig. 11.26).
ing precollagenous material, and intracytoplasmic laminin and fibronectin Some lesions contain plump, stellate-shaped fibroblasts (Fig. 11.27).
suggests myofibroblastic differentiation.3,7,8 Dystrophic calcification may be seen in up to 43% of cases.2 The overly-
ing epithelium may be slightly acanthotic and there are few inflammatory
Differential diagnosis cells.
The cells of granular cell tumor are histologically indistinguishable from
those of congenital granular cell tumor. However, in congenital granular cell Differential diagnosis
tumor, there is no pseudoepitheliomatous hyperplasia and there is a prominent Generalized gingival hyperplasia caused by local irritation or sys-
arborizing delicate vascular network; importantly, the cells are S-100 negative. temic influences (such as medications or hormones) is distinguished
Angulate bodies, seen ultrastructurally in granular cell tumor, are absent. from gingival fibromatosis on clinical grounds and by more prominent
Congenital gingival leiomyomatous polyp/hamartoma has a similar clini- inflammation.
cal presentation (usually in the midline of the maxilla) but histologically con-
tains a nonencapsulated proliferation of fusiform and spindle smooth muscle
cells that, as expected, express HHF-35, smooth muscle actin, and desmin but
not S-100 protein.11–13 This condition may also occur at other sites.14
Lymphangioma of the alveolar ridge

Clinical features
Lymphangioma has been identified in approximately 4% of infants, all of
whom were black. They present as dome-shaped, bluish, fluid-filled nodules
usually affecting the posterior maxillary and mandibular alveolar ridge and
are typically 3–4 mm in diameter. Females are twice as likely to be affected as
males and 74% of subjects have more than one lesion.1,2 Many (if not most)
regress by 6 months of age.1,3,4
Lymphangioma is characterized by slitlike spaces lined by flattened endothe-
lial cells and filled with red blood cells or sparse, fibrillar, eosinophilic material
consistent with lymph.1,2 Rests of odontogenic epithelium may sometimes be
present.
Differential diagnosis Fig. 11.25

Lymphangioma circumscriptum has an identical histology but is seen in older Hereditary gingival fibromatosis: there is extensive involvement of the maxillary soft
patients. tissues. By courtesy of G. Gallagher, DMD, Boston, USA.
Juvenile hyaline fibromatosis

Clinical features
Juvenile hyaline fibromatosis is a rare, autosomal recessive disease charac-
terized by pearly papules and larger fibrotic nodules on the skin (around
the face, ears, scalp, neck, and trunk), gingival overgrowth, flexural con-
tractures of the joints, and osteolytic lesions.1–3 Infantile systemic hyalinosis
(another autosomal recessive condition) presents, in addition, with visceral
involvement and is fatal within the first 2 years of life.4

Mutations of capillary morphogenesis protein 2 (CMG2) causes defects in
basement membrane matrix assembly and mutations in chromosome 4q21.5,6
The hyaline material consists of glycoproteins, glycosaminoglycans, collagens,
and possibly components of plasma. There is reduced type III collagen pro-
duction and metabolism, and possibly secondarily elevated type I collagen
metabolism and reduced collagen II and IV.3,7,8
The gingival and skin lesions of juvenile hyaline fibromatosis show depos-
its of PAS-positive, diastase-resistant and Congo red-negative homogenous,
eosinophilic, hyalinized material in the connective tissue (Fig. 11.28).1,3
Fig. 11.26 Fibroblasts are sometimes nested, appearing similar to chondrocytes, and,
Hereditary gingival
on occasion, present as ‘streaks of cells’. The fibroblasts are plump or
fibromatosis: there is
spindled-shaped with large vesicular nuclei.1
massive accumulation of
fibrous tissue and ground Ultrastructurally, there is discontinuity of the basal lamina with absent
substance. anchoring fibrils; the fibroblasts have distended endoplasmic reticulum
and Golgi filled with fibrillogranular material similar to that present in the
extracellular space.1–3
Fig. 11.28
Fig. 11.27 Juvenile hyaline fibromatosis: note the abundant eosinophilic, hyalinized fibrocollagenous
Hereditary gingival fibromatosis: plump, stellate-shaped fibroblasts are seen in a material and scattered fibroblasts. By courtesy of J. Sciubba, DDS, Baltimore, USA.
densely collagenized stroma.
Reactive conditions
The prevalence ranges from 20% to 36% among those who do not use
Leukoedema tobacco or chew coca leaves, to 51–68% in those who use tobacco, coca,
or cannabis.3–6 Its incidence increases with age.7 A prevalence of 51% was
Clinical features reported in African-Americans but without mention of tobacco habits.8
This is a benign, painless condition usually affecting the buccal mucosa bilat- Another study found a prevalence of 93% in a Caucasian population lead-
erally. The mucosa has a diffuse gray-white opalescent hue with white wrin- ing the author to question whether this condition is merely a variation of
kles and faint reticulations that usually disappear on stretching except in normal.2 Of all tobacco habits, pipe smoking, cigarette smoking, and snuff
severe cases (Fig. 11.29).1,2 are associated with decreasing rates of occurrence.
Morsicatio mucosae oris/Factitial keratosis 373
Fig. 11.29
Leukoedema: note the pale, milky film on the buccal mucosa. Fig. 11.31
Leukoedema: the
Pathogenesis and histological features superficial cells
characteristically are
It is generally believed that a low-grade topical injury, such as occurs with anucleate with a ‘jigsaw-
the use of tobacco or coca leaves, gives rise to this condition. As such, most like’ pattern of cell
changes are limited to the more superficial layers of keratinocytes. membranes.
There is acanthosis with little or no parakeratosis. The characteristic fea-
ture is the presence of degenerated and swollen cells in the superficial and swelling, possibly caused by failure of the sodium pump, but insufficient to
mid-epithelial layers, respectively, sometimes (but not always) with a layer of cause death and disintegration of the whole cell. Similar features have also
compact cells sandwiched between (Fig. 11.30).9 The most superficial cells been reported in the sucking pads of neonates.11
have pale cytoplasm with many anucleate forms and prominent cell mem-
branes somewhat collapsed upon one another, forming a jigsaw puzzle pat- Differential diagnosis
tern (Fig. 11.31). The ballooned cells in the mid epithelium are large with
In morsicatio mucosae oris, there is papillary and shaggy parakeratosis asso-
pale, watery cytoplasm; pyknotic nuclei are often present. There is usually no
ciated with many bacterial colonies also without inflammation; leukoedema
inflammation in the lamina propria.
is often present beneath areas of such factitial keratosis (see below).
Ultrastructural studies show abnormal keratohyaline granules and loosely
Smokeless tobacco keratosis presents with keratin chevrons and shows
dispersed tonofilaments with fragmented organelles in the superficial degen-
a band of coagulated and degenerate cells with anucleation similar to leu-
erated cells. The mid-level swollen cells contain abnormal swollen mito-
koedema. The transition zone from normal to degenerate is often abrupt
chondria.9,10 These features support the theory of limited cell damage with
in smokeless tobacco keratosis (see below). Hairy leukoplakia may exhibit
leukoedema and concomitant morsicatio mucosae oris, but will also exhibit
viral cytopathic change.
Morsicatio mucosae oris/Factitial keratosis

Clinical features
In morsicatio mucosae oris (pathominia mucosae oris), cheek, lip or tongue
chewing habits occur either subconsciously at night or as a conscious para-
functional habit. It is usually seen in adults, is often bilateral and may involve
the buccal mucosa (most common), lateral tongue and lower labial mucosa.1–3
The site of injury exhibits shaggy white plaques that have a peeling, thready,
desquamative surface; erosions are often present, and occasionally ulcers are
seen (Figs 11.32, 11.33). Similar lesions have been noted in areca nut chew-
ers and glass blowers.4,5
Histological features,
There is hyperparakeratosis, which may be severe and acanthosis. Character-
istically, the keratin is thrown into papillations with fissures and clefts,
rimmed by bacteria (Fig. 11.34).2,6,7 Spongiosis or leukocyte exocytosis are
usually absent. Ballooned and swollen superficial keratinocytes typical for
leukoedema are present. Inflammation in the lamina propria is insignificant
unless there is erosion and ulceration. In betel nut chewers, there is a yellow-
Fig. 11.30 brown pigment on the surface of the keratin and within epithelial cells, repre-
Leukoedema: note the senting fragments of the betel quid.5,7 Interestingly, a biopsy of the linea alba
pale superficial cells and (the white line on the buccal mucosa bilaterally where the upper and lower
acanthosis. teeth meet) essentially reveals identical histological features.
Morsicatio mucosae oris may occur as a primary mucosal disorder such
as has been described above, or it may present as a secondary finding
related to chronic injury of protuberant plaques and nodules, such as
fibromas.
Hairy leukoplakia may show similar shaggy hyperparakeratosis and some-
times there is concurrent bite injury. However, the typical changes of chromatin
condensation, eosinophilic inclusions, and the presence of Epstein-Barr virus
easily afford their distinction.
Smokeless tobacco keratosis shows sharply demarcated coagulation of the
superficial cells, sometimes accompanied by hyalinized, amorphous eosino-
philic material in the lamina propria.
White sponge nevus exhibits perinuclear eosinophilic keratin condensations.
Benign alveolar ridge keratosis/Oral lichen

simplex chronicus
Fig. 11.32 Clinical features
Morsicatio mucosae oris (chronic bite keratosis): note the rough, shaggy plaques on
the buccal mucosa. These are white, often rough papules and plaques that occur on the crest of
the alveolar ridge, in particular in the area of extracted mandibular third
molars and adjacent retromolar pad (Fig. 11.35).1 They also occur in any
other part of the ridge where a previous extraction has occurred. They have
no malignant potential.
Lesions reported as alveolar ridge keratosis are any white lesion on the
alveolar ridge and gingiva with no histologic connotations and include both
benign and dysplastic/malignant keratotic lesions of the gingiva and alveolar
ridge; they are not synonymous with benign alveolar ridge keratosis, which
has the specific histologic appearance of lichen simplex chronicus.2

These lesions are caused by chronic frictional trauma to the ridge, not nec-
essarily by direct tooth-to-ridge contact, but by food being crushed by teeth
against the opposing edentulous ridge.
They have the typical histopathology of skin lesions of lichen sim-
plex chronicus. There is hyperorthokeratosis (often marked) with
wedge-shaped hypergranulosis, surface papillomatosis and acanthosis
(Fig. 11.36 ). Rete ridges are tapered and generally uniformly elongated
and often confluent at the base. There is usually minimal to insignificant
Fig. 11.33 chronic inflammation in the lamina propria. Lesions from the retromo-
Morsicatio mucosae oris (chronic bite keratosis): note the macerated, shaggy lar pad often contain stellate-shaped fibroblasts, which are normal for
plaques on the buccal mucosa and lateral border of the tongue. that area.
A B
Fig. 11.34
Chronic bite injury: (A) there is marked shaggy hyperparakeratosis with acanthosis and leukoedema but little inflammation; (B) the characteristic fissures and clefts in the
parakeratin are rimmed by bacteria with little or no inflammation.
Benign migratory glossitis 375
A A
B Fig. 11.36
Benign ridge keratosis:
(A) there is hyperkeratosis,
Fig. 11.35
wedge-shaped
Benign alveolar ridge keratosis: (A) the site of a previous mandibular third molar
extraction is a typical location for this condition; (B) the crest of the alveolar ridge,
acanthosis with minimal
site of a previous tooth extraction, is another typical location for this condition.
to no inflammation;
(B) note the marked
hyperkeratosis,
Differential diagnosis B hypergranulosis, and
Verrucous hyperplasia may have a similar histology and often occurs on the psoriasiform hyperplasia.
gingiva or alveolar ridge. However, the papillomatosis is usually more marked
and epithelial atypia is usually present, as well as bulky epithelial hyperplasia
and an endophytic growth pattern. Clinically, lesions of proliferative verru-
cous leukoplakia are extensive.
buccal and labial mucosae.4–6 The role of atopy in its pathogenesis is still
unsettled.3,7
Benign migratory glossitis Only 0.5% who present with benign migratory glossitis have psoriasis
but 5–14% of patients with psoriasis are affected by this condition.8–10 This
Clinical features prevalence is likely higher in patients with pustular disease.11,12 The condition
Benign migratory glossitis (geographic stomatitis, stomatitis/erythema also occurs in patients with Reiter's syndrome.13 Oral psoriasiform lesions
areata migrans, geographic tongue, annulus migrans, erythema circinata) (excluding benign migratory glossitis) have a predilection for the palate.
occurs in 1–2% of the population (usually adults) although this figure Lithium carbonate (which can exacerbate psoriasis) has also been reported to
may be low because of the evanescent nature of the condition.1,2 Lesions precipitate migratory glossitis.14
are recurrent, erythematous, and atrophic areas with a serpiginous white, Human leukocyte antigen (HLA)-B15 (now Bw62 and Bw63) is seen
slightly raised border that may appear annular or scalloped (Fig. 11.37).2,3 with higher frequency in affected patients and atopic individuals, as well
These ‘map-like’ areas migrate and change in shape over the tongue dor- as in patients with associated type II diabetes mellitus lesions;15–17 how-
sum as the condition resolves at one edge and involves another. Some ever, the association with diabetes mellitus has been recently refuted.
lesions, however, are stationary. Pain, in the form of a burning or sensitiv- There is also an increased incidence of HLA-Cw6 and HLA-B13 in addi-
ity, may or may not be present. Twenty to 60% of patients have concurrent tion to a reduced incidence of HLA-Cw4.18 Other authors have shown
fissured tongue.1–3 increased incidences of HLA-DRw6, and -DR5 with reduced incidences
‘Ectopic geographic tongue’ or, more appropriately, geographic stom- of -B51 and -DR2.19 There is also an increase in polymorphism in the
atitis, refers to a similar-appearing lesion at other sites, in particular the interleukin-1beta gene.20
Fig. 11.37
Benign migratory glossitis: (A) note the erythematous
A B depapillated area rimmed by a white margin; (B) more
extensive involvement of the tongue which is fissured.
The tongue dorsum exhibits loss of the filiform papillae (Fig. 11.38). There
are superficial spongiotic pustules and microabscesses (often involving up to
one-third of the thickness of the epithelium) in the absence of Candida infec-
tion (Fig. 11.39).2,4,21 The adjacent epithelium shows variable spongiosis and
leukocyte exocytosis. Additional features commonly present are psoriasiform
epithelial hyperplasia with broad rete ridges sometimes becoming conflu-
ent at their bases, edema of the lamina propria, and a variable lymphocytic
infiltrate with conspicuous capillary dilatation.
Candidiasis, which must always be excluded, more typically presents with
spongiotic pustules affecting only the top two to three layers of keratinocytes.
A PAS stain should routinely be performed for all pustular oral lesions. Median
rhomboid glossitis, a form of candidiasis, also enters the differential diagno-
sis since it may have a somewhat similar clinical presentation with atrophy of
filiform papillae, although the area does not ‘migrate’ (see below).
Fig. 11.39
Benign migratory glossitis:
note spongiotic pustules
and neutrophilic exocytosis.
The epithelium at the edge of a healing ulcer often shows spongiotic

pustules devoid of Candida and accompanied by neutrophilic exocytosis.
Oral lesions of patients with cutaneous psoriasis are histologically
indistinguishable from lesions of benign migratory glossitis.22
Median rhomboid glossitis

Clinical features
Fig. 11.38 Median rhomboid glossitis is a form of oral candidiasis that occurs specifi-
Benign migratory glossitis: note the absence of filiform papillae (filiform papillary cally in the midline of the tongue just anterior to the circumvallate papillae
atrophy) and psoriasiform epithelial hyperplasia. (Fig. 11.40).1–3
Smokeless tobacco keratosis 377
Fig. 11.42
Median rhomboid glossitis: Candida pseudo-hyphae are present with the PAS stain.
Fig. 11.40
Median rhomboid
glossitis: there is a typical
rhomboidal-shaped area
in the posterior midline of
the tongue.
Fig. 11.43
Median rhomboid
glossitis: note the
psoriasiform epithelial
hyperplasia and the dense
Fig. 11.41 median raphe just above
Median rhomboid glossitis: note the presence of spongiotic pustules.
the muscle fibers.
Diagnosis depends on the presence of psoriasiform mucositis with spongiotic of smokeless tobacco in contact with the mucosa.2 Discontinuation of use
pustules associated with candidal pseudo-hyphae (Figs 11.41, 11.42). The usually results in resolution of oral lesions.5 Sudanese snuff (toombak) is a
identification of the median raphe, a densely hyalinized fibrous band within mixture of tobacco and sodium bicarbonate and is high in tobacco-specific
the lamina propria, confirms that the tissue is from the midline of the tongue nitrosamines.6
(Fig. 11.43). It is unclear why this particular area of the tongue is predis- Early and mild lesions show slight wrinkling and pallor of the mucosa
posed to candidiasis. while more advanced lesions show deep furrows and thickened white mucosa,
more typical of leukoplakia (Fig. 11.44).
Smokeless tobacco keratosis Pathogenesis and histological features

Smokeless tobacco takes the form of snuff (moist or portion-packed) and
Clinical features chewing tobacco. Scandinavian snuff, and particularly moist snuff which has
In smokeless tobacco keratosis (snuff dipper's keratosis), smokeless tobacco greater alkalinity (pH 8–9), has a greater propensity to cause lesions com-
is usually placed in the mandibular sulcus and its use is associated with the pared with American snuff.1,2 In general, the risk of developing oral cancer
development of white lesions at the site of contact in 13–46% of cases.1–4 The is less with smokeless tobacco than with cigarette smoking although this has
severity of oral lesions is proportionate to the duration of use and the amount been disputed.7,8
Fig. 11.44
Smokeless tobacco keratosis: note the grey white, pale, wrinkled mandibular
sulcular mucosa. Fig. 11.46
Smokeless tobacco
keratosis: note the keratin
The term ‘smokeless tobacco keratosis’ is a misnomer since early lesions chevrons and anucleate
are not markedly hyperkeratotic. Rather, the clinical appearance of whiteness and degenerate superficial
is a result of degeneration of the superficial keratinocytes from direct contact keratinocytes.
injury.
Lesions show a characteristic pale-staining surface layer of coagulated
and degenerate, often anucleate, cells occasionally covered by a thin layer
of parakeratin (Fig. 11.45). Typically, this superficial pale layer is sharply
demarcated from the underlying viable epithelium, which shows hyperplasia
and variable chronic inflammation. In addition, spires of keratin – ‘chevrons’ – are
usually present within this pale surface zone (Fig. 11.46).9–11 Keratin chev-
rons may also be seen in oral lesions associated with pipe smoking and the
use of other tobacco products.10 Sialadenitis of minor salivary glands has
been reported in up to 42% of cases.12 There is a reduction in the number of
intraepithelial Langerhans cells.13
Hyaline deposits may be seen as a dense homogenous, eosinophilic band
in the lamina propria in 8–17% of cases, usually located between the salivary
glands and the surface epithelium but also sometimes involving the gland
parenchyma and surrounding ducts (Fig. 11.47).12,14,15 This PAS-positive
material does not represent amyloid and is thought to be altered collagen
resulting from increased synthesis and/or reduced degradation of collagen.16
Fig. 11.47
Smokeless tobacco keratosis: the eosinophilic amyloid-like material is often seen
within underlying salivary gland parenchyma.
Epithelial atypia (generally mild) is present in up to 8% of cases, usually

in areas unassociated with chevrons and more often in areas of dense hyper-
keratosis.10 Squamous cell carcinoma is an infrequent complication of pure
smokeless tobacco usage in the absence of cigarette smoking and/or alcohol
consumption.3,4,9,10,15 The epithelial atypia is likely reactive since it resolves on
discontinuation of the habit.5,17
There is disturbed differentiation of keratin as evidenced by increased
expression of K13 and K14 in patients using toombak as compared with those
using Swedish snuff.18 Mutations in the p53 gene have been described.19
Fig. 11.45 Hyaline deposits may also be seen in lesions of submucous fibrosis. The hya-
Smokeless tobacco keratosis: the superficial coagulated and degenerate cells are line material does not stain with Congo red and is not amyloid. Hyalinosis
sharply demarcated from the underlying acanthotic epithelium. mucosae et cutis has a different clinical presentation.
Pyostomatitis vegetans 379
Fig. 11.48 Fig. 11.49

Foreign body gingivitis: there is non-specific mild chronic inflammation in the lamina Foreign body gingivitis: small granules of foreign material that are refractile in polarized
propria. light are present with mild surrounding chronic inflammation.
Foreign body gingivitis

Clinical features
This condition occurs more often in females than in males (4:1), usually in
the fifth decade. The gingiva presents with multifocal or diffuse erythema that
is sore or painful in the majority of patients. Some lesions are ulcerated and/
or inflamed.1–3

Energy dispersive X-ray microanalyses have revealed Si, Al, Fe, Cu, and Ti in
the majority of cases and, in many lesions, the analyses match those of den-
tal abrasives. It is therefore thought that some of these cases result from such
abrasives forced into the gingiva during professional dental cleaning. Some
analyses also match those of amalgam.3,4
The epithelium is acanthotic or atrophic, and basal cell degeneration
is present in up to 50% of cases. The inflammatory infiltrate varies in
severity and is lichenoid (bandlike and lymphocytic) in half the cases
(Fig. 11.48). In one-quarter of cases, granulomatous inflammation may be Fig. 11.50
seen, sometimes accompanied by foreign body and/or Langhans-type giant Pyostomatitis vegetans: note the yellow pustular papules and linear lesions on the
cells.1,2,5 Plasma cells may be abundant. Foreign bodies, ranging from 1 to buccal mucosa. By courtesy of B. Neville, DDS, Charleston, USA.
5 microns in diameter, are present in all cases, and 44% may be refractile
(Fig. 11.49). Histological features
Differential diagnosis There is epithelial hyperplasia, sometimes accompanied by papillomatosis,
and spongiosis. Suprabasilar clefting with acantholysis may also be seen
Plasma cell gingivitis exhibits an intense plasmacytic infiltrate, usually in (Fig. 11.51). Characteristically, neutrophilic and eosinophilic abscesses are
sheets, and foreign material is not identified although there is probably over- present in the connective tissue papillae at the interface, and sometimes
lap between these two conditions. within the epithelium itself (Fig. 11.52).1,5,8–10 Eosinophils and neutrophils
may permeate the epithelium and chronic inflammatory cells are abundant
in the lamina propria.
Pyostomatitis vegetans Direct immunofluorescence studies for IgG and C3 are generally negative.
When positive, the staining is usually weak and represents a secondary reac-
Clinical features tion to epithelial inflammation and damage rather than a primary autoim-
This is the oral counterpart of pyoderma vegetans. Men are twice as com- mune phenomenon.1,11
monly affected as women.1 The most common associations are ulcerative
colitis (approximately 70%), Crohn's disease (10–15%), and liver disease Differential diagnosis
(21%).1–4 Patients present with numerous shallow ulcers and erosions, Pemphigus vulgaris may appear similar although typically there is more obvi-
miliary abscesses, and pustules that coalesce to form ‘snail track’ lesions ous acantholysis. In addition, neutrophilic and eosinophilic abscesses are
(Fig. 11.50).5–7 These develop on erythematous mucosa in which vegetations absent and papillary epithelial hyperplasia is not usually a feature. Pemphigus
may be a feature. There is sometimes folding and fissuring of the buccal vegetans shows considerable histological overlap although oral lesions are
mucosa. The dorsal surface of the tongue is usually spared.8,9 Peripheral rare. Distinction from both of these conditions is readily made by direct
blood eosinophilia is present in 90% of cases.1 immunofluorescence studies which show intercellular IgG deposition.
Fig. 11.51
Pyostomatitis vegetans: note the intraepithelial clefting and abscesses.
Fig. 11.52
Pyostomatitis vegetans:
there is acantholysis and
an abscess is present
suprabasally.
Ulcerative conditions
Recurrent aphthous stomatitis

Clinical features
Recurrent aphthous stomatitis occurs in 15–20% of the adult population,
generally below the age of 40.1,2 It is a chronic, painful, relapsing, ulcer-
ative condition of the nonkeratinized mucosa (Fig. 11.53). There are three
variants: minor, major and herpetiform.
• Ulcers of the minor form (the most common variant) are less than 1 cm,
last 7–14 days and heal without scarring.
• Ulcers of the major form are usually greater than 1 cm, last many weeks,
and heal with scarring.
• Ulcers of the herpetiform variety occur in small crops of 10–100 ulcers in
any one episode.2,3
Some conditions frequently associated with the minor variant include
Behçet's disease, anemia, inflammatory bowel disease, gluten-sensitive
enteropathy, food hypersensitivity, and neutropenia.4,5 Aphthous stomati-
tis presenting in association with rheumatological or mucocutaneous dis-
orders is sometimes referred to as complex aphthosis.6 There is also often
Fig. 11.53
a family history of aphthous ulcers but there is no evidence at present
Recurrent aphthous ulcer: a typical aphthous ulcer covered by yellow fibrin
that the condition is infectious in nature. More recent studies suggest that membrane with surrounding erythema on the upper labial mucosa.
Helicobacter pylori may play a role and they may reside in a reservoir
in the tonsils or dental plaque.7–9 In children, aphthous stomatitis may
be syndromic and associated with periodic fever, lymphadenopathy and destruction of the epithelium. Early lesions show a predominance of T-helper
pharyngitis (PFAPA syndrome, periodic fever syndrome).10–12 Interestingly, cells followed by an increase in T-suppressor cells during the ulcerative phase;
such patients often show complete response after tonsillectomy and/or T-helper cells re-emerge during the healing phase.16–18 Increased numbers of
adenoidectomy.13 peripheral gamma-delta cells have been noted, suggesting that antibody-
dependent cell-mediated cytotoxicity may play a role in the immunopathogen-
Pathogenesis and histological features esis of this disease.19 Cell lysis may be mediated through tumor necrosis factor
Cross-reaction of antigens of Streptococcus mutans with a mitochondrial heat alpha (TNF-α).20
shock protein may play an important role in the pathogenesis of this condi- The histological appearances are non-specific. There is ulceration of the
tion.14 Expression of HLA class I and class II antigens on epithelial cells may mucosa with a thick fibrin clot enmeshed with neutrophils (Fig. 11.54).
result in targeting for cytotoxic attack.15 There is no evidence of increased The adjacent epithelium may exhibit reactive atypia; viral inclusions are not
circulating immunoglobulins or immune complexes. seen. The ulcer bed consists of granulation tissue with acute and chronic
The ulcerative process results from T-cell activation. Although the target inflammatory cells.21 Inflammatory changes and degeneration of superficial
antigens have yet to be clearly and consistently elucidated, the end result is skeletal muscle fibers may also be evident.
Traumatic ulcerative granuloma 381
Fig. 11.54 Fig. 11.55

Recurrent aphthous ulcer: the mucosa exhibits non-specific ulceration. Traumatic ulcerative granuloma: this indurated ulcer had developed after a tongue
biopsy at that site.
Traumatic ulcers and the ulcers of Behçet's disease are histologically indis-
tinguishable and their distinction is dependent upon clinicopathological
correlation. If there is inflammation of the muscle associated with a histio-
cytic mononuclear cell infiltrate and a significant number of eosinophils,
a diagnosis of traumatic ulcerative granuloma is more appropriate (see
below). If the fibrin clot and underlying granulation tissue contain few
neutrophils, neutropenia-associated ulceration – such as is seen in human
immunodeficiency virus (HIV) disease and cyclic neutropenia – must be
considered.
Traumatic ulcerative granuloma

Clinical findings
Traumatic ulcerative granuloma (traumatic ulcerative granuloma with
stromal eosinophilia, eosinophilic ulcer/granuloma of the tongue, Riga-Fede
disease) may present in two quite different ways. The less common form –
and one that is not usually biopsied – occurs in infants in the first year of life. Fig. 11.56
Painful ulcers that may be elevated occur on the ventral tongue or lower lip Traumatic ulcerative granuloma: this patient had bitten her tongue during a seizure
as a result of the child rubbing the mucosa against the developing lower ante- and the indurated mass developed over a few days.
rior deciduous teeth (Riga-Fede disease).1 The second presentation, and the
more common, is in the fifth and sixth decades of life. The lateral tongue (up
to 64% of cases), followed by the buccal mucosa, are most often affected.2–5
An ulcer or indurated area develops and persists for weeks or months (Figs
11.55, 11.56). The lack of pain, often a feature of this condition, raises the
clinical suspicion of squamous cell carcinoma.4 A history of trauma is elic-
ited in only 50% of cases.2,3 Lesions are often multifocal and up to 30% of
lesions recur.5

Lesions similar to but not identical with this condition can be experimentally
induced in animals by crush injury.6 It is thought that the inciting factor is
trauma, which leads to acute and chronic inflammation that for unknown
reasons becomes deep, penetrating, chronic, and exaggerated. It is possible
that cytokines released by activated lymphocytes recruit eosinophils. Whether
muscle degeneration is primary to the process or merely a secondary phenom-
enon is unclear.2,3 Infectious agents and foreign material have not been identi-
fied in these lesions.
There is loss of the surface epithelium with abundant granulation tis-
sue at the ulcer base accompanied by a polymorphous inflammatory infil- Fig. 11.57
trate of T lymphocytes and plasma cells, which penetrates into the deep Traumatic ulcerative granuloma: note the ulcerated surface and the penetrating
mucosa and underlying muscle (Figs 11.57, 11.58). The presence of many inflammation that separates muscle fascicles.
Fig. 11.58
Traumatic ulcerative granuloma: there is prominent interfascicular inflammation and
muscle degeneration.
Fig. 11.60
Atypical histiocytic
granuloma: there is
a diffuse and dense
lymphohistiocytic infiltrate.
Fig. 11.59
Traumatic ulcerative granuloma: note the presence of histiocyte-like mononuclear
cells and many eosinophils.
Fig. 11.61
ononuclear histiocyte-like cells accompanied by eosinophils and some-
m Atypical histiocytic granuloma: many lymphocytes, mononuclear cells, and
times mast cells is diagnostic (Fig. 11.59).2,3,7,8 Muscle fragmentation, eosinophils are present; there is a mitotic figure.
interfascicular inflammation with degeneration, and the presence of strap
cells are common additional features.6,9 In some cases, the granulation tis-
sue proliferation is so exuberant as to result in an exophytic pyogenic gran-
uloma-like mass. between these two conditions. Atypical histiocytic granuloma regresses spon-
The large histiocyte-like cells express either CD68 or factor XIIIa.7 taneously in the majority of cases. However, diffuse positivity for CD30 may
Scattered CD30+ cells may be present in this lesion. 4,10 indicate T-cell lymphoma. 10
Angiolymphoid hyperplasia with eosinophilia may sometimes present in the
Differential diagnosis buccal mucosa or lip.15,16 Epithelioid endothelial cells stain for vascular markers.
In its most florid form, traumatic ulcerative granuloma shares histological Lymphocytes, plasma cells, and eosinophils are commonly seen and occasional
features with atypical histiocytic granuloma (pseudolymphoma).11–14 This lymphoid follicles with germinal centers are p resent (Figs 11.62, 11.63).16,17
condition, which may or may not involve the underlying muscle, is character- Histiocyte-like cells and eosinophils are a feature of Langerhans cell
ized by a dense infiltrate of lymphocytes, including transformed variants and histiocytosis. However, Langerhans cells have the characteristic grooved
centroblasts, often raising the suspicion of lymphoma (Figs 11.60, 11.61).12 nuclei and can be identified with S-100 protein, CD1a and langerin
Clonality and gene rearrangement studies are often necessary to differentiate immunohistochemistry.
Squamous papilloma 383
Fig. 11.62 Fig. 11.63

Angiolymphoid hyperplasia with eosinophilia: note the pale lobular areas with Angiolymphoid hyperplasia with eosinophilia: there are plump epithelioid endothelial
central vessels and prominent germinal centers. cells associated with many lymphocytes and eosinophils.
Papillary Lesions
Squamous papilloma
Clinical features
Squamous papilloma generally presents in adults in the second to fourth
decades. Sites of predilection include the soft palate–uvula complex and the
tongue, although any region in the oral cavity may be affected. Lesions may
be white or erythematous with a warty, finger-like or cauliflower-like appear-
ance (Figs 11.64, 11.65).1,2
The epithelium is thrown into papillary folds and there may be prominent
or absent hyperparakeratosis or hyperorthokeratosis. In general, if the pap-
illoma arises from a nonkeratinized site (such as the uvula, soft palate, ven-
tral tongue or floor of mouth), it will often be non- or only thinly keratinized
Fig. 11.65
Squamous papilloma: there is a rough, white warty lesion of the lateral tongue.
but may exhibit keratinocyte edema (especially soft palate lesions) (Fig.
11.66).1 Koilocytes are not usually apparent. The epithelium may be thick-
ened but rete ridges are not bulbous. The connective tissue cores usually
contain congested vessels with perivascular hyaline cuffs. Depending on
whether the papilloma has been traumatized or not, there is variable inflam-
mation.1,2 In situ hybridization and polymerase chain reaction (PCR) stud-
ies have identified human papillomavirus (HPV) (usually -6 and -11) in up
to 67% of cases; HPV-2 is occasionally present.3,4
Verruca vulgaris may occasionally occur in the oral cavity and, as in the skin,
it is characterized by marked hyperorthokeratosis with prominent coarse ker-
atohyaline granules and axial inclination of epithelial papillary projections.
HPV-2 is identified in up to 20% of cases of intraoral and up to 100% of lip
verruca vulgaris.5–7
Fig. 11.64 Oral condyloma acuminatum shows large, bulbous rete ridges and prom-
Squamous papilloma: there is a rough, warty lesion of the soft palate. inent koilocytosis; rare cases have an intrasalivary duct component and
HPV-6 and -11 are often identified (Figs 11.67, 11.68).8–10 This condition
occurs most frequently in patients who are on long-term immunosuppres-
sion such as organ transplant recipients or those who have pre-existing
genital lesions.
Irritated and inflamed papillomas often exhibit spongiosis. The condition
juvenile localized spongiotic gingival hyperplasia may represent such irritated
papillomas or be a distinct entity.11
Focal epithelial hyperplasia (Heck's disease), which is associated with
infection by HPV-13 and HPV-32, may show papillary epithelial hyperplasia
although this is not invariably present. Importantly, ‘mitosoid’ figures (cells
showing karyorrhexis) are a characteristic feature.
Rare cases of oral acanthosis nigricans have been reported and these are
generally associated with gastrointestinal malignancy.12,13
Verruciform xanthoma
Clinical features
Fig. 11.66 Verruciform xanthoma affects adults in the fourth and fifth decades with
Squamous papilloma: note the finger-like projections of epithelium keratinocyte
no significant sex predilection.1–3 It presents as a well-circumscribed rough,
edema is present.
granular or pebbly, raised or depressed, yellowish, reddish or gray plaque
(Fig. 11.69). Seventy percent occur primarily on the keratinized attached
mucosa of the palate, gingiva or alveolar ridge mucosa. Lesions on the skin
(especially of the anogenital area) and other mucosal sites have also been
reported.4 Although there is one report of a patient with multiple lesions and
lipid storage disease, most patients do not exhibit hypercholesterolemia or
disorders of lipid storage.5

It has been postulated that the epithelial cells are damaged and degener-
ate, releasing lipid that becomes engulfed by macrophages. Neutrophils
are also recruited to the area by the degenerating cells.4,6 The gingiva
and palate are constantly traumatized by mastication, in support of this
hypothesis. Verruciform xanthoma also occurs in association with other
conditions where epithelial damage occurs such as lichen planus, pemphi-
gus vulgaris, discoid lupus erythematosus, epidermolysis bullosa, follow-
ing bone marrow transplantation, and possibly graft-versus-host disease
(GVHD).7–12
Histologically, there is hyperparakeratosis with the parakeratin exhibit-
ing a bright orange hue. Loose keratin squames are present on the surface
Fig. 11.67 or within epithelial crypts. The surface of a verruciform xanthoma generally
Condyloma acuminatum: this larger warty lesion on the gingiva occurred in a
patient on long-term immunosuppression after lung transplantation.
Fig. 11.68 Fig. 11.69

Condyloma acuminatum: unlike squamous papilloma, the rete ridges are large and Verruciform xanthoma: note the warty sessile lesion on the left hard palate.
bulbous and koilocytes are readily identified. By courtesy of C. Allen, DDS, Columbus, USA.
Fibroma 385
Fig. 11.70
Verruciform xanthoma: there is marked hyperparakeratosis and papillomatosis with
confluence of rete ridges at the tips; note the unusually brightly stained keratin.
Fig. 11.72
Verruciform xanthoma:
the lamina propria
contains numerous foamy
macrophages.
has a papillary configuration although some lesions are flat.1 Rete ridges are
uniformly long and sometimes coalesce at their bases (Figs 11.70, 11.71).
Large, foamy, lipid-laden macrophages are found within the connec-
tive tissue papillae (Fig. 11.72); rarely, such cells extend beyond the
deepest portion of the rete ridges or are seen within the epithelium.13,14
Multinucleate forms are not a feature. Lymphocytes (primarily T cells)
are present at the base.15,16 Neutrophils may be present superficially and a
reduction of Langerhans cells has been noted in the affected epithelium.8,15
Rarely, nonmucosal cases may show a cystic and inverted, crateriform
configuration.4,17
Ultrastructurally, the xanthoma cells contain membrane-bound
granules consistent with lysosomes, myelin figures, and fragments of des-
mosomes, the last supporting the theory of phagocytosis of epithelial cell
debris.6,13,18
Fig. 11.71 The xanthoma cells express CD68 and sometimes S-100 protein.15,16,19
Verruciform xanthoma: Most of the xanthoma cells represent reparative (RM3/1) and resident (25F9)
parakeratotic squames on foam cells. 20 Slight granular staining for cytokeratin within the foam cells also
the surface of the keratin supports the presence of epithelial fragments.4 HPV immunohistochemistry
and in the crypts are a is negative.4,16
characteristic feature.
Tumor-like conditions
Fibroma Histological features

The fibroma consists of a proliferation of fibrocollagenous tissue with vari-
Clinical features able vascularity and usually mild to insignificant inflammation unless there is
Fibroma (fibrovascular polyp, fibroepithelial polyp, irritation fibroma, bite overlying ulceration (Figs 11.75, 11.76). On occasion, the lesion may resem-
fibroma) is the most common tumor-like (but non-neoplastic) condition in ble a hypertrophic scar or keloid. Sclerotic fibroma (collagenous fibroma)
the mouth. It is usually located at sites of trauma, namely the buccal mucosa has been reported in the oral cavity and the collagen in these lesions has a
at or near the linea alba, the lateral borders and tip of the tongue and the storiform appearance with clefts between the collagen and stellate or multi-
lower labial mucosa, as well as on the gingiva.1,2 It presents as a fleshy, nucleated fibroblasts with dendritic processes. The cells sometimes stain for
pedunculated or sessile dome-shaped nodule that may be mucosal-colored, CD34.3 Epithelium may be hyperkeratotic, acanthotic or atrophic. If adipose
ulcerated or hyperkeratotic (Figs 11.73, 11.74). tissue is present, the term ‘fibrolipoma’ is sometimes applied.
Fig. 11.73 Fig. 11.76

Fibroma: there is a fleshy pink fibroma on the lower labial mucosa. Fibroma: often, the collagen in fibromas may be extremely hyalinized and almost
keloidal in appearance.
Giant cell fibroma

Clinical features
Giant cell fibroma occurs in the first three decades of life and the most com-
mon sites affected are the keratinized regions of the gingiva (44–49%), tongue
(17–22%) and palate (15–18%).1,2 It often has a papillary or bosselated sur-
face configuration. It bears some resemblance to the fibrous papule of the
nose, angiofibroma, and the pearly penile papule. The retrocuspid papilla has
a similar histology and is located on the lingual mandibular gingiva in the
area of the cuspid.3,4
The most characteristic feature of the giant cell fibroma is the presence of giant,
angulated and stellate-shaped fibroblast-like cells, usually clustered beneath
the epithelium (Figs 11.77, 11.78).1,2,5 Multinucleated giant fibroblast-like
Fig. 11.74
Fibroma: the lateral border of the tongue is a common site for a fibroma.
Fig. 11.77
Fig. 11.75 Giant cell fibroma: note
Fibroma: this fibroma from the buccal mucosa exhibits hyperkeratosis as compared the undulating surface and
to the base which is nonkeratinized. spiky rete ridges.
Denture-associated fibrous hyperplasia 387
Fig. 11.79
Lipoma: note the yellowish nodule on the buccal mucosa.
Fig. 11.78
Giant cell fibroma: note
the stellate-shaped and
multinucleated cells.
cells (‘manta ray cells’) are common. The overlying epithelium is usually hyper-
plastic, forming spiky, saw-tooth-shaped rete ridges, and there may be surface
papillomatosis.
The cells express vimentin, occasionally factor XIIIa, but not S-100 pro-
tein or CD68.5,6
The multinucleate cell angiohistiocytoma occurs rarely in the oral cavity
and contains multinucleated giant cells, branching capillaries, and a myxoid
stroma.7,8
Lipoma and atypical lipomatous tumor

Clinical features
This presents as a yellowish, soft and doughy, painless, sessile or pedun- Fig. 11.80
culated nodule that generally occurs on the buccal mucosa or sulcus (Fig. Atypical lipomatous tumor:
the tumor has infiltrative
11.79). It usually occurs in adults in the sixth and seventh decades.1–3 Other
margins and cells with
sites include the tongue, lips, and floor of mouth. Infiltrating or intramus- variably sized vacuoles.
cular lipomas tend to occur two decades earlier and generally involve the
tongue.2,4,5
Some lipomas of the buccal mucosa are not true tumors but represent
tumors containing lipoblasts (uni-, bi- or multivacuolated) with hyperchro-
herniation of the buccal fat pad.
matic and atypical nuclei (Figs 11.80, 11.81).7-9 Foci of spindled cells and
dedifferentiation have also been reported.
Lipomas represent circumscribed proliferations of mature adipocytes iden-
tical to normal adipose tissue.3 Cartilaginous and osseous metaplasia has Denture-associated fibrous hyperplasia
occasionally been reported.6,7 Similar benign adipocytes are present within
skeletal muscle fibers in an infiltrating (intramuscular) lipoma.4 Oral spindle Clinical features
cell lipoma has also been reported and this consists of spindle cells showing Denture-associated fibrous hyperplasia (inflammatory fibrous hyperpla-
slight nuclear pleomorphism within a myxoid stroma with ropey collagen sia, epulis fissuratum, denture hyperplasia, papillary hyperplasia, inflam-
and mast cells.3 matory papillary hyperplasia) presents as a linear mass of tissue arising in
the mucobuccal sulcus around the flange of a poorly fitting denture. The
Differential diagnosis redundant tissue cushions the mucosa against ongoing trauma. The anterior
Distinction must be made between a banal lipoma and an atypical lipoma- maxillary and mandibular sulci are the preferred sites of involvement (Figs
tous tumor that generally occurs on the tongue of adults, and that represents 11.82, 11.83). There is a 3:1 female predisposition and most occur in the
a superficial variant of well-differentiated liposarcoma. These are infiltrative sixth decade.1–3
Fig. 11.81
Atypical lipomatous tumor: note the lipoblasts with atypical, hyperchromatic, and
indented nuclei. Fig. 11.84
Denture-induced papillary
hyperplasia of the palate:
note the typical pebbly
papillary structures on the
palate.
A clinically different form of denture-associated fibrous proliferation is

also referred to as papillary hyperplasia or inflammatory papillary hyperpla-
sia of the palate. The movement of a poorly fitting maxillary denture results
in the development of an erythematous, edematous and pebbly, multinodular
appearance to the mucosa of the hard palate (Fig. 11.84).4,5
Denture-associated fibrous hyperplasia is characterized by proliferation of
dense fibrous tissue with variable vascularity. Lymphocytes are generally dif-
fusely dispersed at the interface of epithelium and fibrous tissue; the epithe-
lium is hyperplastic and thrown into papillary folds (Fig 11.85). Pooling of
plasma on the surface of the mucosa indicates trauma. Osseous and chon-
droid metaplasia are seen in approximately 5% of cases, particularly in the
Fig. 11.82 anterior maxilla.6 Salivary glands are present in 43% of cases.
Denture-induced fibrous hyperplasia: there is an elongated mass of soft tissue in
the mandibular sulcus with a fissure running through it.
Fig. 11.85
Denture-induced fibrous hyperplasia: there is papillomatosis and hyperplasia of
Fig. 11.83 epithelium and fibrous tissue. A cartilaginous rest is present in this lesion from the
Denture-induced fibrous hyperplasia: the denture flange (edge) fits into the fissure. anterior maxillary sulcus.
Gingival fibroma 389
Fig. 11.86 Fig. 11.87

Denture-induced papillary hyperplasia: curettage specimens yield these fibrous Gingival nodule: note how the nodule arises from the gingival margin and hangs
nodules with chronic inflammation. down onto the tooth.
In palatal lesions, the histology is that of multiple small nodules of fibro-

vascular tissue containing chronic inflammatory cells that are typically
removed piecemeal (Fig. 11.86).4 If spongiotic pustules are present, Candida
superinfection should be excluded.7
Gingival nodules
Clinical features
The term ‘epulis’ refers to any mass or nodule on the gingiva or alveolar ridge
and should be confined to clinical usage only. The two exceptions are epu-
lis fissuratum and congenital granular cell epulis, referring to two particular
clinical and histological entities.
Most solitary gingival nodules represent one of the following conditions:
reactive tumor-like proliferations, odontogenic cysts, primary odontogenic
and nonodontogenic neoplasms, and metastatic neoplasms. The first are by
far the most common and consist of the following entities:
• fibroma or fibrous hyperplasia with or without inflammation,
• giant cell fibroma, Fig. 11.88
• pyogenic granuloma, Gingival nodule: such nodules may be located on the palatal aspect of the gingiva.
• peripheral ossifying fibroma,
• peripheral giant cell granuloma.
These lesions are located on the attached or marginal gingiva adjacent to
teeth. Depending on the degree of vascularity, inflammation, and/or ulcer-
ation present, they may be mucosal-colored, erythematous or ulcerated and Gingival fibroma
painful (Figs 11.87, 11.88).
It is thought that these fibrous and vascular reactive nodules develop Clinical features
as a response to irritation from dental plaque and calculus, often exacer- Some fibromas represent the scarred remnants of pyogenic granulomas. One
bated by the presence of defective restorations or other dental hardware. form of fibroma, the gingival fibrous nodule (also known as fibrous hyper-
Undifferentiated mesenchymal cells in the connective tissue proliferate and plasia, fibrovascular polyp, inflammatory fibrous hyperplasia, fibrous epu-
differentiate into cells that form native tissues in the area such as fibroblasts lis) occurs not on the free or marginal gingiva but on the attached gingiva as
(fibroma), endothelial cells (pyogenic granuloma), bone- and cementum- multiple mucosal-colored papules.1 Another variant is the giant cell fibroma,
producing cells (peripheral ossifying fibroma), or osteoclasts (peripheral which often has a papillary surface and may be clinically mistaken for a
giant cell granuloma). It is therefore not uncommon to see features of all papilloma.
four entities present to varying degrees within any one lesion. Unless the
source of irritation is removed completely, it is not unusual for these lesions
to recur. Histological features
Dental plaque is often present as clumps of Gram-positive filamentous Gingival fibroma is composed of a mass of densely or delicately collagenized
bacteria that morphologically resemble actinomycotic colonies. Unless sur- tissue with variable vascularity (Fig. 11.89).2 If there is significant chronic
rounded by a mantle of neutrophils, such colonies are surface colonizers and inflammation, the stroma may be edematous. The overlying epithelium is
do not represent Actinomycosis infection. sometimes hyperkeratotic and there may be continuity with crevicular epi-
Other gingival nodules and masses include the gingival and periodontal thelium, which generally shows spongiosis, neutrophilic exocytosis, and an
abscess and the parulis. underlying plasmacytic infiltrate (Fig. 11.90).
Fig. 11.89 Fig. 11.91

Inflammatory fibrous hyperplasia of the gingiva: the surface keratinized epithelium Granuloma gravidarum: this nodule occurred in an edentulous part of the
is in continuity with the nonkeratinized crevicular epithelium, where inflammatory mandible.
cells are present.
Fig. 11.90
Inflammatory fibrous hyperplasia of the gingiva: note the crevicular epithelium with
spongiosis and the piece of dental plaque that morphologically resembles a mass
of actinomycotic organisms. Fig. 11.92
Pyogenic granuloma:
there is a typical lobular
proliferation of endothelial
cells and capillaries.
Pyogenic granuloma
Clinical features
These nodules tend to be dark red and bleed readily. One variant of this cells, many of which form canalized and congested capillaries (Figs 11.92,
lesion, the granuloma gravidarum, occurs during pregnancy, usually in the 11.93).5 Dilated, branching vessels are usually present in the center of
second and third trimesters, probably as a consequence of the neovasculariz- lobules.3 The overlying epithelium is ulcerated in 75% of cases and there
ing effects of estrogen (Fig. 11.91).1 The recurrence rate is 16%.2 is a variable neutrophilic, lymphocytic, and plasmacytic infiltrate.2 Some
Although the majority of intraoral pyogenic granulomas occur on the gingiva, pyogenic granulomas become increasingly sclerotic and may eventuate in
other sites including the lips, buccal mucosa, and tongue may be affected.3–5 gingival fibrous hyperplasias after the bulk of the vasculature is replaced by
fibrous tissue (Figs 11.94, 11.95).
There is no increase in the number of estrogen receptors on the endothelial
Histological features cells of such lesions compared with controls although they may express more
Gingival pyogenic granuloma is characterized by a diffuse (very common) vascular endothelial growth factor and other angiogenesis-enhancing factors
or lobular (more common on nongingival sites) proliferation of endothelial and fewer inhibitory factors.6,7
Peripheral ossifying fibroma 391
A B
Fig. 11.93
Pyogenic granuloma: (A) note benign-appearing endothelial cells and dilated capillaries; (B) normal mitoses are not uncommonly seen.
Peripheral ossifying fibroma

Clinical features
This tumor, also known as calcifying fibrous epulis or calcifying fibroblastic
granuloma, occurs in the second and third decades and women are affected
up to two times more often than men (1.5–2:1). Up to two-thirds occur in the
maxilla.1,2 The recurrence rate is 8–16%.1,2
The lesion presents as a nonencapsulated cellular proliferation of plump,
fibroblast-like cells with fusiform-to-ovoid vesicular nuclei and indistinct
cell borders (Figs 11.96, and 11.97). Admixed are varying amounts of
osteoid, and woven and lamellar bone (Fig. 11.98). The more mature
the bone, the less cellular the stroma. The bone may be focally rimmed
by osteoblast-like cells. Droplet calcifications and (less commonly) broad
Fig. 11.94
Sclerosing pyogenic granuloma: note the break-up of the lobular architecture by
fibrous tissue.
Fig. 11.96
Peripheral ossifying
fibroma: there is a mass
Fig. 11.95 of cellular fibrous tissue
Sclerosing pyogenic granuloma: note marked sclerosis and corresponding reduction with calcifications and
in the number of vessels. overlying ulceration.
Fig. 11.97 Fig. 11.99

Peripheral ossifying fibroma: note the plump fibroblasts and the marked cellularity. Peripheral ossifying fibroma: it is not uncommon to see clusters of osteoclast-like
giant cells in these lesions.
Peripheral giant cell granuloma is characterized by a discrete but unencap-
sulated diffuse proliferation of osteoclast-like multinucleate giant cells and
mononuclear cells in a vascular stroma with abundant fresh hemorrhage and
hemosiderin deposition (Figs 11.100, 11.101). The giant cells may have
vesicular or hyperchromatic nuclei.7 The mononuclear cells have large vesicu-
lar nuclei with prominent nucleoli (Fig. 11.102). Mitoses are common.8
A Grenz zone often separates the giant cells from an overlying intact or ulcer-
ated epithelium.2 Chronic inflammation may be present. Myofibroblasts have
been demonstrated, supporting the reactive nature of this lesion.9 Foci of
peripheral ossifying fibroma are present in one-third of cases.8,10,11
The giant cells and mononuclear cells express vimentin, muramidase,
α1-antitrypsin, α1-,antichymotrypsin and CD68, suggesting that they are of
monocyte–phagocyte lineage.7,12 Other studies have shown that the multinucle
ated giant cells stain for MBI, an osteoclast marker.13 Estrogen but not proges-
terone receptors have been identified in both mononuclear and giant cells.14
Fig. 11.98
Peripheral ossifying fibroma: the bone may take the form of osteoid, woven and/or
lamellar bone, or calcified spherules.
anastomosing globular masses of cementum are sometimes seen.1,3 This

lesion is not a true neoplasm but rather a fibrous hyperplasia that forms
metaplastic bone and cementum. Even if calcifications are not clearly
identified, the cellular proliferation of such fibroblast-like cells should
raise the suspicion of this entity, and deeper sections will usually reveal the
presence of osteoid. Foci of osteoclast-like multinucleated giant cells are
occasionally present in addition to areas resembling pyogenic granuloma
(Fig. 11.99).1,2
Peripheral giant cell granuloma

Clinical features
This lesion usually occurs in the fourth and fifth decades of life and the
mandible may be two to three times more often involved than the maxilla.
Fig. 11.100
It often resides in a cup-shaped depression within the underlying bone.1–3 Peripheral giant cell
Some 19–22% occur in edentulous areas.4 The recurrence rate is up to granuloma: there is
22%.3 Examples of such peripheral lesions associated with hyperpara- generally a Grenz zone
thyroidism most likely represent gingival extension of central giant cell that separates the giant
granulomata.5,6 cells from the epithelium.
Peripheral odontogenic fibroma 393
Fig. 11.101 Fig. 11.103

Peripheral giant cell granuloma: note the marked vascularity of the lesion. Parulis: note the small papule located on the non-attached gingiva, at some distance
from the gingival margin.
Fig. 11.102 Fig. 11.104

Peripheral giant cell granuloma: giant cells, mononuclear cells and many siderophages
Parulis: the papule is composed of edematous granulation tissue; a tract leads from
are present.
deep in the tissues to the surface.
Parulis
Peripheral odontogenic fibroma
Clinical features
The parulis (or gum-boil) is a red or pink, painless papule, sometimes with a Clinical features
central punctum. It is located away from the gingival margin, usually overly- The preferred site for this tumor is the mandibular premolar/cuspid and ante-
ing the apex of a tooth, and represents the opening of a draining sinus from rior maxillary region.1 It mainly occurs in adults in the third decade with an
an intraosseous odontogenic infection (Fig 11.103). equal sex predilection. Recurrence varies from 3% to 39%.1,2
The nodule consists of a proliferation of edematous granulation tissue contain-
ing many acute and chronic inflammatory cells and, in particular, microab- The nodule consists of a proliferation of fibrous tissue that may be densely
scesses in a linear array – the sinus tract (Figs 11.104, 11.105). or loosely collagenized and variably hypercellular or hypocellular. More typi-
cally, the stroma has a whorled, streaming or fasciculated pattern.2–4 Islands,
strands, and nests of odontogenic epithelium are present to a variable extent
Differential diagnosis (Figs 11.106, 11.107). Epithelial cells may appear clear or, rarely, squamous
Although this lesion bears a superficial resemblance to a mucocele, no mucin and hyaline cuffs are sometimes seen around the epithelium (the so-called
or muciphages are present. Mucoceles almost never occur on the gingiva since ‘inductive effect’). Calcifications are present in 33–50% of cases and take two
salivary gland tissue is absent at this site. forms: as dentinoid or as dystrophic globular calcifications in the stroma.1,2,4,5
Fig. 11.107
Peripheral odontogenic fibroma: strands of squamous epithelium show a hint of
palisading of the peripheral nuclei, typical for odontogenic epithelium.
Fig. 11.105
Parulis: note the natural
space formed by
neutrophils in a linear
array.
Fig. 11.108
Peripheral odontogenic fibroma: note the abundance of epithelium in this lesion.
By courtesy of T. Daley, DDS, Winnipeg, Ontario, Canada.
Fig. 11.106
Peripheral odontogenic fibroma: strands of odontogenic epithelium are present in a
fibrous stroma.
When epithelium is abundant, the term odontogenic gingival epithelial hama-

rtoma may be applied (Fig. 11.108).6 One variant contains stromal granular
cells.1,7 The presence of giant cells has also been reported.8
Lack of significant atypia distinguishes this lesion from metastatic carcinoma
although it must be borne in mind that many malignant glandular and/or
adnexal tumors can sometimes show minimal pleomorphism.
Peripheral odontogenic fibroma is the most common peripheral odonto-
genic tumor and should also be distinguished from other odontogenic tumors
that may present on the gingiva.9 The peripheral ameloblastoma contains
many large islands of odontogenic epithelium with distinct palisading and Fig. 11.109
reverse polarization of the basal cell nuclei, resembling a basal cell carcinoma Peripheral ameloblastoma: islands of epithelium grow into the stroma from the
(Figs 11.109, 11.110).10 surface. By courtesy of C. Allen, DDS, Columbus, USA.
Gingival cyst of the adult 395
Fig. 11.110 Fig. 11.113

Peripheral ameloblastoma: note the typical palisading of the basal cell nuclei. Calcifying epithelial odontogenic tumor: note the presence of epithelial cells and
By courtesy of C. Allen, DDS, Columbus, USA. amyloid.
Peripheral calcifying odontogenic tumor is lined by basaloid cells con-

taining ghost cells, sometimes with dystrophic calcification (Figs 11.111,
11.112).11 The counterpart of this lesion on the skin is the calcifying epi-
thelioma of Malherbe (pilomatrixoma). A solid variant called the odonto-
genic ghost cell tumor has a predominance of ghost cells and dentinoid or
osteoid.12
Peripheral calcifying odontogenic tumor consists of large polyhedral cells
with eosinophilic cytoplasm associated with amyloid deposits and ringlike
dystrophic calcification (Fig. 11.113).13
Gingival cyst of the adult

Clinical findings
This lesion occurs in the fifth decade with a roughly equal sex distribution.
Fig. 11.111 Three-quarters occur in the mandible, mainly in the cuspid/ bicuspid buccal
Odontogenic ghost cell tumor: note the basaloid cells and calcified material gingiva. It presents as a bluish nodule, usually measuring less than 1 cm in
adjacent to the epithelium. diameter.1–3

A variety of origins have been postulated. The gingival cyst may arise from
stimulated rests of dental lamina (a residuum of odontogenesis) or be derived
from epithelium in the gingival sulcus 2,4,5
The cyst is usually lined by nonkeratinized epithelium, either low cuboidal
or squamous, 1–3 cells thick (Figs 11.114, 11.115). Focal epithelial plaques
are present in approximately one-third of cases, some of which contain clear
cells.1–3 Occasional lesions resemble an intraosseous odontogenic keratocyst
with a thin epithelial lining, corrugated parakeratosis, and palisading of the
basal cells.6 This variant is sometimes referred to as a peripheral odontogenic
keratocyst.
In children, dental lamina cysts of the newborn occur on the alveolar ridge
(especially maxillary) and are almost always filled with keratin, resembling
milia.7 If the cyst contains oncocytic cells, it is much more likely to be a sali-
Fig. 11.112 vary duct cyst. Salivary gland lesions do not occur in the gingiva (which does
Odontogenic ghost cell tumor: note the ghost cells and the foreign body reaction to not contain salivary gland tissue) although it may extend onto the gingiva
them. from the maxillary or mandibular sulcus.
Fig. 11.114 Fig. 11.116

Gingival cyst: note thinly lined cyst in the lamina propria. Generalized gingival hyperplasia: this overgrowth of gingiva was caused by poor oral
hygiene.
Fig. 11.115 Fig. 11.117

Gingival cyst: the cyst is lined by three to six layers of squamous or low cuboidal Cyclosporin-induced gingival hyperplasia: this patient was taking cyclosporin to
cells. prevent rejection of a renal allograft; he was also taking nifedipine, a calcium-
channel blocker.
Gingival hyperplasia occurs in approximately 50% of patients tak-

ing phenytoin,4,5 15–40% of patients taking nifedipine,3,6 and 25–70%
of patients on cyclosporin.7–9 Renal transplant patients taking both
Generalized gingival hyperplasia cyclosporin and nifedipine show greater gingival overgrowth than those
taking cyclosporin alone.10 Of all calcium channel blockers, nifedipine and
Clinical features those of the hydropyridine class are most likely to cause gingival hyperpla-
In this condition, multiple and usually all quadrants of the upper and sia. Verapamil causes hyperplasia in 4% and amlodipine in 3% of cases,
lower gingiva are involved, initially by nodular hyperplasia in the inter- which is probably not significantly different from patients not taking these
dental areas, which then become coalescent to form diffuse nodular/papil- medications.11,12
lary masses. The gingiva may be edematous and boggy, or it can be firm, Several cases of cyclosporin-induced fibrous hyperplasias/pyogenic gran-
fibrotic, and so proliferative as to reach the biting surfaces. Provoking fac- ulomas of extragingival sites have been reported in patients treated for
tors include: chronic GVHD (Fig 11.118).13–15 It is, however, unusual to see significant
• poor oral hygiene (Fig 11.116), gingival hyperplasia in patients taking cyclosporin for treatment of chronic
• hormonal influences (during puberty and pregnancy), GVHD.
• ingestion of medications, in particular phenytoin, valproic acid, calcium One unusual form of gingival hyperplasia is associated with ligneous con-
channel blockers, and ciclosporin (Fig. 11.117). junctivitis, an autosomal recessive disorder leading to functional plasminogen
Such overgrowths are rare in edentulous patients and if the teeth are deficiency and characteristic histological features in the conjunctiva and gin-
extracted, the lesions do not recur, pointing to plaque bacteria as playing an giva.16,17 The gingiva develops painless coalescent waxy nodules similar to those
important role in their pathogenesis.1–3 In general, good oral hygiene mea- on the conjunctiva.18,19 Other mucosal surfaces may also be involved.20 One case
sures reduce the severity of disease. occurred after systemic tranexamic acid (an antifibrinolytic agent) therapy.21
Generalized gingival hyperplasia 397
In cyclosporin-induced nongingival lesions, the tumors are essentially

inflammatory fibrovascular polyps that are extensively ulcerated and composed
of edematous granulation tissue with a varying degrees of inflammation; some
resemble pyogenic granuloma (Figs 11.120, 11.121).13–15
Ultrastructural studies show an increase in cytoplasmic volume of fibro-
blasts with more extensive rough endoplasmic reticulum and Golgi com-
plexes, reflecting increased synthetic activity and concomitant reduction
in phagocytic activity of fibroblasts.27,28 Increased numbers of fibroblasts
exhibiting secretory granules filled with sulfated mucopolysaccharides have
been noted.29 Myofibroblasts are present in increased numbers.30
Fig. 11.118
Cyclosporin-induced nongingival hyperplasia: this patient was taking ciclosporin
for treatment of chronic graft-versus-host disease after allogeneic bone marrow
transplantation

Gingival hyperplasia caused by cyclosporin (the most widely studied of all
the drugs) may result from accumulation of collagen and extracellular matrix
as a consequence of either increased production from susceptible subpopula-
tions of fibroblasts in the gingiva, or else, decreased degradation.22,23 Calcium
homeostasis is an important pharmacodynamic feature of these drugs and it
has been postulated that impairment of calcium-dependent mechanisms (such Fig. 11.120
as collagenase and metalloproteinase activity) may play an important etiolog- Cyclosporin-induced
ical role. Cyclosporin up-regulates the activity of TGF-β1, a potent cytokine nongingival hyperplasia:
involved in collagen homeostasis.24,25 these are essentially
Histologically, there is proliferation of fibrous tissue and ground substance polypoid masses of
granulation tissue similar
with variable hyperplasia of fibroblasts. The epithelium, which is paraker-
to pyogenic granuloma.
atinized, may also be hyperplastic and there is often a lymphoplasmacytic
infiltrate and vascular ectasia (Fig. 11.119). Straight-sided ‘test tube’ rete
ridges have been reported in such drug-induced gingival hyperplasias but
this is not a specific finding.6,7,26 There may also be foci that appear myxoid/
mucinous.
Fig. 11.121
Cyclosporin-induced
nongingival hyperplasia:
Fig. 11.119 note the edematous
Inflammatory fibrous hyperplasia: the histology is similar to that of the solitary granulation tissue and
gingival nodules of similar etiology. inflammation.
Fig. 11.123
Varix: note the blue bleb on the lower labial mucosa.
Fig. 11.122
Ligneous gingivitis: there
is abundant fibrinous
eosinophilic material that
fills the lamina propria.
In ligneous gingival hyperplasia, the lamina propria is filled with eosino-

philic, PAS-positive amorphous material that stains with MSB phosphotung-
stic acid–hematoxylin and consists of fibrin (Fig. 11.122).17,18 Stains for
amyloid are negative. There may be associated epithelial hyperplasia with
acute and chronic inflammation and apoptosis. Early lesions show fibrin
deposits around blood vessels.
Accumulations of eosinophilic material in the gingiva may be seen in lipoid
proteinosis (hyalinosis cutis et mucosae); these deposits do not stain for fibrin-
Fig. 11.124
ogen or fibrin and there is usually involvement of the skin and other sites.31,32
Varix: note the blue bleb on the buccal mucosa.
Amyloid deposits should also be excluded. Similar amyloid-like material may
sometimes be seen in the buccal mucosa (but not usually in the gingiva) of
patients who use snuff.
Varix
Clinical features
Varices (or venous lakes) are most common on the ventral surfaces of the
tongue (sublingual varicosities) and on the lower lip and buccal mucosa, usu-
ally in older individuals (Figs 11.123, 11.124).1,2 They are bluish-purple
blebs that may become firm if thrombosed.
A varix represents a dilatation of an endothelium-lined blood vessel/venule
with a very thin muscular wall (Figs 11.125, 11.126).3 Some develop
thrombi, which on organization and canalization may present as a Masson
tumor (intravascular papillary endothelial hyperplasia) (Fig. 11.127).4
The caliber-persistent labial artery (a pulsatile lesion of the lower lip) consists
of an artery that lies close to the surface epithelium with an artery diameter/ Fig. 11.125
depth ratio of less than 1.6 (Fig. 11.128).5,6 These putatively represent arterial Varix: there are grossly
branches from a main supplying labial artery that penetrate the superficial dilated venules in the
mucosa without loss of caliber.6 lamina propria.
Hairy leukoplakia 399
Fig. 11.126
Varix: the grossly dilated venule has a very thin wall.
Fig. 11.128
Caliber-persistent artery:
this small artery is
typically superficially
located.
Fig. 11.127
Varix: there is intravascular papillary endothelial hyperplasia within this organizing
thrombus.
Infections
vertical fissures running perpendicular to the long axis of the tongue (Figs
Hairy leukoplakia 11.129, 11.130).5,6 Its appearance is associated with the development of
acquired immunodeficiency syndrome (AIDS) within 3 years in one-third of
Clinical features patients.7
Hairy leukoplakia is an Epstein-Barr virus infection of the oral epithelium
that was first described in the HIV-infected population.1 It may also be seen Pathogenesis and histological features
in other immunocompromised patients who are susceptible to opportunistic The oropharyngeal epithelia and lymphoid tissue are sites of persistent latent
viral infections or reactivations, such as organ transplant recipients.2,3 Cases Epstein-Barr virus infection.8 Reactivation of latent infected tongue mucosa
have been reported in apparently healthy individuals.3,4 Although the term is may be the cause of hairy leukoplakia.9
now entrenched in the scientific literature, ‘hairy leukoplakia’ as used in this Oral hairy leukoplakia is characterized by hyperparakeratosis with a slightly
condition does not ever connote an increased incidence of cytological atypia shaggy surface. Candida hyphae are present in 80% of cases, usually unassoci-
or propensity for development of squamous cell carcinoma such as is often a ated with spongiotic pustules.5,6,10,11 Beneath the keratin is a distinct band of
feature of ‘leukoplakia’. vacuolated and ballooned cells (Fig. 11.131). Pale cells contain Cowdry Type
The majority of cases (> 70%) occur bilaterally on the lateral border of the A eosinophilic inclusions and characteristically exhibit condensation of chro-
tongue as a white, corrugated (hence ‘hairy’) plaque that in early lesions has matin against the nuclear membrane (‘beaded effect’) (Figs 11.132, 11.133).12
Fig. 11.129
Hairy leukoplakia: the thick white plaque on the lateral border of the tongue has
vertical fissures. Fig. 11.131
Hairy leukoplakia: note
the thick parakeratin
and, importantly, the
vacuolated virally infected
cells just beneath.
Fig. 11.130
Hairy leukoplakia: this white plaque does not have the vertical fissures.
Fig. 11.132
This morphology is readily seen even on exfoliative cytology.13,14 In situ
Hairy leukoplakia: note condensation of chromatin in a beaded pattern against the
hybridization localizes Epstein-Barr virus within keratinocyte nuclei (Fig. nuclear membrane.
11.134).
PCR-in situ hybridization studies demonstrated proteins that disrupt
Epstein-Barr virus latency in all layers of the epithelium including basal cells,
supporting the concept of reactivation of latent Epstein-Barr virus infection.
HIV has also been identified within the keratinocytes.9 Focal epithelial hyperplasia
Although HPV was identified in hairy leukoplakia in earlier studies, more
recent studies have disputed this observation.5,9,15 Clinical features
Although any racial group may be affected, there is a predilection for focal epi-
thelial hyperplasia (Heck's disease, multifocal papillomavirus epithelial hyper-
Differential diagnosis plasia) in Native Americans of Central and South America, Inuits, and Africans.
Sometimes chronic bite injury is misdiagnosed as hairy leukoplakia. The Over 90% of cases occur in the first two decades of life and there is a prevalence
two conditions share in common shaggy hyperparakeratosis and cytoplas- of 7–13% in predisposed populations.1–3 The condition tends to regress over
mic vacuolation. However, true hairy leukoplakia usually does not have the time. Focal epithelial hyperplasia also occurs in patients infected with HIV.4
fissures and clefts rimmed by bacteria seen in bite injury unless, of course, Lesions are almost always multiple and multifocal, favoring the labial
there is concomitant secondary bite injury. The vacuolated cells in bite injury mucosa, lips, buccal mucosa, and lateral tongue (Figs 11.135, 11.136).
represent keratinocyte edema and not viral cytopathic effect. Identification of They are mucosal-colored papules or nodules that sometimes may appear
Epstein-Barr virus establishes the diagnosis. papillary.2
Focal epithelial hyperplasia 401
Fig. 11.133 Fig. 11.136

Hairy leukoplakia: ultrastructural confirmation of chromatin condensation; the center Heck's disease: typical multiple coalescent papules on the lateral tongue in this
of the nucleus is filled with herpes virus. native of East Africa.
Fig. 11.134 Fig. 11.137

Hairy leukoplakia: in situ hybridization reveals the presence of intranuclear Epstein– Heck's disease: there is epithelial hyperplasia with the formation of broad rete
Barr virus. ridges, somewhat similar to a condyloma.
There is benign epithelial hyperplasia with slight keratinization and
broad anastomosing rete ridges (Fig. 11.137). Koilocytes are usually
present superficially (Fig. 11.138). ‘Mitosoid’ figures are a characteris-
tic finding in the mid and lower third of the epithelium (Fig. 11.139).
These represent degenerate and karyorrhectic nuclei showing aggregates
of coarsely clumped chromatin resembling mitoses. They may be identified
in up to 50% of original sections and are almost always present in further
levels.2,5,6
HPV-13 has been identified in 50–100% of cases while HPV-32 was found
in 60% of cases.3,6,7
Condyloma acuminatum may appear similar clinically and histologically
but generally this lesion does not contain HPV-13 and HPV-32. Bowenoid
Fig. 11.135 papulosis may also exhibit similar ‘mitosoid’ figures, usually in a more florid
Heck's disease: the lesions are pale, fleshy papules. fashion and with more epithelial atypia.
Fig. 11.139
Heck's disease: ‘mitosoid’ bodies represent human papillomavirus-induced nuclear
changes.
Fig. 11.138
Heck's disease: koilocytes
are readily identified.
Lichenoid and hypersensitivity reactions
Oral lichen planus and lichenoid stomatitis

Clinical features
Oral lichen planus is a chronic inflammatory condition of the mouth that occurs
in 1–2% of the population (range 0.08–4.0%).1 There is a 1.5 to 3-fold predilec-
tion for women and most patients are in the sixth decade.2,3 The buccal mucosa
is affected in 80–90% of cases, followed by the tongue and the gingiva.
While the older literature described between five and six different clinical
variants, they can be grouped simply into three main categories:
• Reticular and/or papular oral lichen planus presenting with classic lacy
white keratotic striations (Wickham's striae). Annular, papular, and
linear variants may also be seen. This variant tends to be non- or only
mildly symptomatic (Fig. 11.140).
• Erythematous (or erosive) oral lichen planus presenting as variably
symptomatic reddened mucosa. Because the mouth is a trauma-intense
environment, bullae or vesicles of bullous lichen planus are rarely seen.
Any blisters that develop soon rupture, giving rise to erythematous and
ulcerative lesions. Another erythematous variant presents clinically as
‘desquamative gingivitis’ (Fig. 11.141).4–6 Fig. 11.140
Oral lichen planus: Wickham's striae of reticular lichen planus with mild erythema.
• Ulcerative lichen planus, which presents with a yellow fibrinous exudate
on the surface and is almost always painful (Fig. 11.142).
Oral lichen planus often presents with a combination of the above clinical Plaque-type lesions resembling leukoplakia should be considered as con-
manifestations and may also change from one to another over time.7 From ventional leukoplakia arising in association with oral lichen planus. The rate
epidemiological studies, reticular lesions are the most common, especially on for malignant transformation varies from 0% to 12.5% but many reports
the buccal mucosa, whereas in studies from referral centers, the erythema- with the higher rate did not correct for tobacco usage as a confounding fac-
tous and ulcerative forms predominate because they tend to be symptomatic. tor.2,3,13,14 The true risk is probably in the order of 0.1–1%. Some authors
Similarly, the skin is reportedly involved in approximately 5% of cases in epi- believe that plaque-type disease has a higher association with malignancy
demiological studies and 20–40% at referral centers.2,3,8 Concurrent involve- while others believe erosive lesions are particularly susceptible. One reason
ment of the gingiva with erosive oral lichen planus and lesions affecting the for the confusion is that clinicians sometimes diagnose any red and white
female genitalia is known as the vulvovaginal-gingival syndrome although lesion as lichen planus while erythro-leukoplakia, also a red and white
men may also experience penile lesions. Other mucosal sites such as the lesion (see below), has a very high malignant transformation rate. Lesions of
esophagus may also be affected.9–12 Spontaneous remission occurs in approxi- proliferative leukoplakia and proliferative erythroleukoplakia have also been
mately 7% of cases.2 misdiagnosed clinically as lichen planus.
Oral lichen planus and lichenoid stomatitis 403
Fig. 11.141 Fig. 11.143

Oral lichen planus: desquamative gingivitis may be a form of erythematous lichen planus. Oral lesions of discoid erythematosus: lichenoid reticulations in a patient with
systemic lupus erythematosus.
Fig. 11.142
Oral lichen planus: note the presence of some white papular areas, erythema, and
Fig. 11.144
ulcers.
Chronic oral graft-versus-host disease: lichenoid reticulations in a patient with
chronic oral graft-versus-host disease.
Local factors that may induce oral lichen planus or oral lichenoid lesions
include contact lichenoid reactions to mercury in amalgam restorations.
Between 16% and 91% of patients have a positive patch test to mercury,
especially those with lesions in direct contact with the restoration.15–17 These
lesions regress when the restorations are replaced. Similar reactions have been
reported to composite restorations, possibly representing a reaction to form-
aldehyde.18,19 In the Saudi Arabian population, chewing of deram has been
reported to cause oral lichen planus.20
Oral lichenoid drug eruptions and oral lichen planus are clinically and
histologically indistinguishable. The classes of drugs that have been impli-
cated include antihypertensive agents (in particular thiazides), antimalari-
als, gold, nonsteroidal antiinflammatory drugs (NSAIDs), hypoglycemic
agents, penicillamine and allopurinol.21,22 Patients previously diagnosed with
Grinspan syndrome (oral lichen planus, diabetes mellitus, and hyperten-
sion) were probably exhibiting a lichenoid mucosal reaction to their medica-
tions. Patients with autoimmune conditions such as lupus erythematosus and
chronic GVHD may present with oral lesions that are clinically and histologi-
cally indistinguishable from lichen planus (Figs 11.143, 11.144).23–25 There
is also an increased prevalence of oral lichen planus in patients with hepatitis,
in particular hepatitis C, and especially in Southern European and Japanese Fig. 11.145
populations associated with an increase in HLA-B6 (Fig. 11.145).26–28 Oral lichen planus: lichenoid reticulations in a patient with hepatitis C.
Patients with oral lichen planus show an increased incidence of HLA-Bw57

in the white British population, HLA-DR9 in the Chinese and Japanese, and
HLA-DR3 in the Swedish, with a decrease in incidence of HLA-DQ1 in the
white British population.29–32 The Israeli population showed a significant
association with HLA-DR2 and a decrease in DR4.33 IFN-γ and IL-4 gene
polymorphisms influence disease susceptibility and progression of oral lichen
planus in a Chinese cohort.34
Because so many different conditions can lead to the clinical appearances
of oral lichen planus – contact phenomena, hypersensitivity to medications,
and autoimmune diseases – it is more appropriate to view oral lesions as the
final common pathway of expression of the mucosa to local or systemic anti-
gens. It represents a delayed-type hypersensitivity reaction characterized by a
T-cell reaction to altered epithelium and leading ultimately to basal cell lysis.
The pathogenesis of oral disease has been reviewed in several publi-
cations and only a summary, albeit somewhat simplistic, is presented
here.22,35,36 The initiating event is alteration of the keratinocyte either from
antigen bound or unmasked on the cell surface (e.g., drugs, major his-
tocompatibility complex (MHC) or viral antigens). Keratinocytes and
antigen-presenting cells secrete chemokines that attract lymphocytes.
Fig. 11.147
Antigen-presenting cells in the epithelium present antigens via MHC II mol-
Oral lichen planus: high-power view emphasizing the interface stomatitis; note the
ecules to CD4 cells while basal cells present antigens via MHC I molecules presence of colloid bodies.
to CD8 cells. A Th1 response mediated by CD4 cells results in secretion of
IL-2 and IFN-γ that bind receptors on CD8 cells that become activated and
trigger basal keratinocyte apoptosis.36 In the meantime, local mast cells
are activated and secrete TNF-α, which induces endothelial cell adhesion
molecule expression, priming the vasculature for lymphocyte adhesion and
transmigration.37
The reticular/papular type exhibits either hyperparakeratosis or hyper-
orthokeratosis with hypergranulosis, and variable acanthosis (Figs 11.146,
11.147). The erythematous form is non- or thinly keratinized and exhibits
epithelial atrophy or erosion (Fig. 11.148). In both cases, there is lympho-
cyte exocytosis, mild spongiosis, and increased numbers of Langerhans cells.
Common to all variants is destruction of the basal cell layer with blurring of
the epithelial–connective tissue interface, and a superficial bandlike lympho-
cytic infiltrate.35 Early lymphocytic infiltrates contain mainly CD4 cells while
older lesions consist predominantly of CD8 cells. Saw-toothed rete ridges and
apoptotic cells (cytoid or Civatte bodies) may be present, and the basement
membrane zone is sometimes thickly eosinophilic due to fibrinogen deposi-
tion. Subepithelial separation is occasionally present but may be artifactual
(albeit a reliable one) (Fig. 11.149). Although lymphocytes predominate,
plasma cells may be seen, particularly in hypersensitivity lichenoid reactions,
or if an ulcer or erosion is present. The term ‘lichenoid stomatitis/mucosi- Fig. 11.148
tis’ is sometimes used when a lesion has only some of the above features, in Oral lichen planus: erosive and ulcerative lichen planus without hyperkeratosis.
Fig. 11.146 Fig. 11.149

Oral lichen planus: typical features of hyperkeratosis, acanthosis, squamatization of Oral lichen planus: subepithelial separation occurs to varying degrees and is well
basal cells, and a lymphocytic band at the interface. demonstrated in this case.
Oral lichen planus and lichenoid stomatitis 405
articular, only focal basal cell degeneration or a sparse lymphocytic band at

p true dysplasia is the presence of basal cell hyperplasia and atypia rather than
the interface. Lesions of amalgam-induced oral lichen planus and banal lichen degeneration. In one report, dysplastic lesions with a lichenoid histologic
planus are histologically indistinguishable.38 character were seen more commonly in clinically ‘lichenoid’ lesions rather
The chemokine RANTES and the adhesion molecule ICAM-1 are both than reticulated oral lichen planus.42 Such lichenoid histologic and clinical
expressed in lesions of oral lichen planus and amalgam-induced lichenoid lesions (rather than typical histologic and clinical lesions of lichen planus)
reactions, but not IL-8.39 also showed a higher rate of malignant transformation.43
Although reactive epithelial atypia may be present, unequivocal epithelial Contact lichenoid hypersensitivity reactions to cinnamic aldehyde
dysplasia should be reported as such. The term ‘lichenoid dysplasia’ was orig- show peri- and paravascular nodular lymphocytic infiltrates (Figs 11.152,
inally coined to denote dysplasia arising within histologic lichenoid stomati- 11.153).44,45 The absence of eosinophils does not rule out an oral hypersen-
tis, which subsequently progressed to squamous cell carcinoma.40,41 These are sitivity reaction.
lesions that exhibit hyperparakeratosis or hyperorthokeratosis, epithelial dys- Direct immunofluorescence demonstrates fibrinogen at the basement mem-
plasia, and a bandlike lymphocytic infiltrate (Figs 11.150, 11.151). They are brane zone, often in a fibrillar, shaggy ‘stalactite’ pattern with occasional C3
no different from any other oral epithelial dysplasia and should not be classi- and IgM. Cytoid bodies also stain with IgM or C3.46 Indirect immunofluo-
fied separately. Rather, a diagnosis of ‘mild/moderate/severe dysplasia with a rescence studies have shown that there may be circulating antibodies directed
lichenoid infiltrate’ is more appropriate. An important histological feature in against basal cells.47–49
Patients with chronic ulcerative stomatitis (an erosive–ulcerative condition
of the mouth that clinically resembles erosive oral lichen planus) have strati-
fied epithelium-specific antinuclear IgG in a speckled pattern primarily affect-
ing the lower epithelium (Fig. 11.154).50–52 Indirect immunofluorescence
Fig. 11.150
Epithelial dysplasia with Fig. 11.152
lichenoid inflammatory Cinnamaldehyde-associated contact stomatitis: erythematous area on the tongue
infiltrate: note the caused by cinnamon gum contact hypersensitivity reaction.
atypical cells and bandlike
Fig. 11.153
Fig. 11.151 Cinnamaldehyde-associated contact stomatitis: there is a lichenoid inflammatory
Epithelial dysplasia with lichenoid inflammatory infiltrate: note that there is basal infiltrate at the interface with peri- and paravascular nodular lymphocytic aggregates;
cell prominence and maturation disarray. in this case, the basal cells are intact.
Plasma cell gingivostomatitis

Clinical features
In the 1960s and early 1970s, patients presented with symptoms of soreness
and burning of the oral mucosa following the use of chewing gum. There was
angular cheilitis with fissuring, dry atrophic lips, and occasional desquama-
tion. The tongue was often fissured, edematous, and crenated (with scalloped
borders) and the gingiva (free and attached) was fiery red, often with exten-
sion onto the palatal mucosa.1,2 Some patients had drug allergies while others
had atopic states. The gingiva was sometimes the only site of involvement.3
Discontinuation of gum chewing led to resolution of lesions in most but
not all cases and it was postulated that this condition represented a hypersen-
sitivity reaction to some component of chewing gum or some other unidenti-
fied antigen.1,2 Since that cluster of cases and reformulation of chewing gum,
only occasional cases occur now in response to a variety of putative topical
irritants such as cinnamicaldehyde-flavored toothpastes and khat.4,5
Subsequent to these reports, patients were identified who not only pre-
sented with oral symptoms of pain but also with hoarseness, dysphagia, and
Fig. 11.154
airway obstruction. On endoscopy, the larynx showed thickened, red, velvety,
Chronic ulcerative stomatitis: this presents with a vaguely reticulated mucosa.
By courtesy of L. Solomon, MD, SUNY, Buffalo, NY, USA.
and edematous mucosa; the lips were thickened and fissured with angular
cheilitis and fissured tongue.6–9 The soft palate and gingiva were sometimes
concurrently involved. Equivalent lesions have since been noted on the penis
(Zoon's balanitis) and the vulva.
using guinea pig esophagus demonstrates nuclear reactivity particularly well.
It is unclear whether this widespread involvement of the mucosa of the
The putative antigen is deltaNp63alpha, an isoform of p63.53 Histologically,
upper respiratory tract indicates a more severe and extensive form of plasma
chronic ulcerative stomatitis also resembles oral lichen planus and it is still
cell gingivostomatitis. No obvious allergen has been identified.
unclear what the relationship is between these two conditions.54
Loss of heterozygosity on chromosome arms 3p, 9p, and 17p is not a Histological features
feature of oral lichen planus, a finding that supports the hypothesis that this
disease is not intrinsically premalignant; however, a high frequency of loss Plasma cell orificial mucositis and plasma cell gingivostomatitis have simi-
was found in dysplastic lesions with a lichenoid infiltrate.55 Telomerase activ- lar histology. There is psoriasiform epithelial hyperplasia with spongiosis,
ity has been detected in up to 70% of patients.56 A high rate of TP53 muta- spongiform pustules, and leukocyte exocytosis (Fig. 11.156). The suprapap-
tions has also been reported in oral lichen planus.57 The role of p53 in the illary epithelium is severely thinned.1,3 Dyskeratosis is often present in more
development of malignancy is still unclear.58 severe cases.6,8 Characteristically, the lamina propria is filled with sheets of
plasma cells with expression of both kappa and lambda light chains (Fig.
Differential diagnosis 11.157). Russell bodies may be present but Dutcher bodies are not seen.
Occasional lymphocytes are also present.1,3
Lesions of discoid lupus erythematosus may also show a lichenoid lympho-
cytic band at the interface and peri- and paravascular nodular lymphocytic Differential diagnosis
infiltrates (Fig. 11.155). Direct immunofluorescence studies are usually
positive for the lupus band test in lesional tissue. An intense plasma cell infiltrate is characteristic of banal chronic gingivitis and
An intense chronic inflammatory infiltrate at the interface may also be periodontal disease. However, in these lesions, the plasma cells are not generally
seen in plasma cell gingivitis although the cells in this condition are, of course, present in uninterrupted sheets but have a compartmentalized, slightly lobular
predominantly plasmacytic. Rare cases of lichen planus pemphigoides have character (Fig. 11.158). Clinically, even though the gingiva may be hyperplastic
been reported.59 and edematous, gingivitis/periodontitis responds well to local therapy.
Fig. 11.156
Fig. 11.155 Plasma cell gingivitis: there is a prominent inflammatory infiltrate at the interface
Oral lupus erythematosus: note the lichenoid inflammatory infiltrate. with epithelial hyperplasia and atrophy.
Orofacial granulomatosis 407
Fig. 11.159
Orofacial granulomatosis: there is diffuse rubbery swelling of the lower lip.
Fig. 11.157
Plasma cell gingivitis: the Orofacial granulomatosis
lamina propria is packed
with plasma cells. Clinical features
Orofacial granulomatosis (cheilitis granulomatosa, granulomatous cheili-
tis) is a chronic, non-necrotizing, granulomatous and inflammatory condi-
tion, likely a delayed-type hypersensitivity reaction. It is characterized by
nontender swelling and edema of the lips and/or face, often but not always
accompanied by swelling of the gingiva (usually around the anterior teeth),
and cobblestoning, folding, and erythema of the buccal mucosa. There may
be angular cheilitis, ulcerations, and prominent vertical fissures in established
lesions.1
In the Melkersson-Rosenthal syndrome, facial nerve palsy and fissured
tongue are additional findings.2,3
In general, the swelling of the lips is the most important clinical sign, and
is initially soft and relapsing (Fig. 11.159). However, swelling may involve
other sites such as the periorbital, zygomatic, or mental regions.4 Over the
years, it becomes persistent and rubbery. The gingiva is affected in 20–30%
of cases.5,6 Gingival swellings extend onto the alveolar mucosa and become
increasingly fibrotic over time (Fig. 11.160).6 Facial nerve palsy is pres-
ent in 13–47% of cases and may be due to either direct granulomatous
involvement of the nerve or edema leading to nerve compression. It predates
Fig. 11.158
Chronic periodontitis: note
the pockets of plasma
cells separated by bands
of collagen.
Plasma cell granuloma, a rare lesion in the oral cavity, is histologically

similar to plasma cell orificial mucositis except that the lesions are clinically
tumorous masses or nodules.10–13 Cases of plasma cell granuloma reported
from the periodontal space most likely represent chronic periodontitis or
banal inflammatory fibrovascular hyperplasias with the usual intense plasma
cell infiltrate.14 Fig. 11.160
Lack of light chain restriction excludes plasmacytoma. Orofacial granulomatosis: note the thickened anterior maxillary gingiva.
facial/lip swelling in 57–100% of cases.3,5,6 Fissured tongue is present in

40–50% of cases although its significance is uncertain since this is a relatively
common oral finding.3,5 Spontaneous improvement or resolution occurs in
approximately one-third of patients.5
Ten percent of patients have associated Crohn's disease while only 3%
have associated sarcoidosis.7 Vulval and eye lesions have been reported in
addition to more extensive neurological involvement. Of interest, patients
with orofacial granulomatosis but no gastrointestinal symptoms were found
on ileocolonoscopy and biopsy to have intestinal pathology and granulomata
in 54% of cases.8

Hypersensitivity to foods (such as eggs, chocolate, and dairy products),
flavorings, antioxidants (such as octyl butylated hydroxyanisol and cinnam-
aldehyde), preservatives (such as benzoate and metabisulfites), and fragrances
have been demonstrated in up to 20% of cases; there is often a strong his-
tory of atopy.1,9–11 Elimination diet may result in significant improvement of
symptoms.12 Investigations targeting an infectious etiology with emphasis on
Saccharomyces cerevisiae, Mycobacterium tuberculosis, and Borrelia burg-
Fig. 11.162
dorferi have yielded variable results.13–15 Orofacial granulomatosis: typical subtle non-necrotizing granulomatous inflammation.
Orofacial granulomatosis is associated with increased HLA-A3, B7 and
DR2 expression.16 The cytokine profile (such as increased production of
interferon-gamma) suggesting a predominantly Th1 response, similar to that be larger and more conspicuous. Angioedema and hypersensitivity reactions
seen in gut lesions of Crohn's disease.17 may present with edema and vascular ectasia in the absence of granulomata.
Non-necrotizing granulomata are present in the lamina propria, sometimes Oral Wegener's granulomatosis is accompanied by pseudoepitheliomatous
adjacent to lymphatic vessels with associated lymphocytes and plasma cells hyperplasia and a mixed acute and chronic inflammatory infiltrate with
(Figs 11.161, 11.162).2,6 The granulomata may be subtle and poorly formed abscesses, necrosis, and eosinophils.
and often require serial sectioning to be identified with certainty. They may
bulge into and obstruct vessels.18 Edema and vascular dilatation has also been
reported but such features in isolation are insufficient for a diagnosis of oro-
facial granulomatosis. Foreign material within the granulomata effectively Oral Crohn's disease
excludes a diagnosis of orofacial granulomatosis. As with any granulomatous
infiltrate, special stains for microorganisms should always be performed. Clinical features
Crohn's disease usually presents in the second decade, with a male predomi-
Differential diagnosis nance.1,2 In one study, 37% of patients had asymptomatic gastrointestinal
Granulomata in this clinical setting are histologically indistinguishable from disease.3 There is usually swelling of the face or lips; additionally, there may
those of extragastrointestinal Crohn's disease; clinical differences help to dif- be linear vestibular aphtheiform ulcers, angular cheilitis, papulous and poly-
ferentiate between the two. In general, the granulomata of sarcoidosis tend to poid masses, mucosal tags, lip and gingival swelling, gingival erythema, and
cobblestoning of the mucosa (Figs 11.163, 11.164).1,3 Some patients present
with pyostomatitis vegetans and ‘snail-track ulcers’.4 In 22–60% of cases, oral
symptoms precede intestinal symptoms.1–3 Adhesions may lead to limitation
in mouth opening.2
Fig. 11.161
Orofacial granulomatosis:
this was the only
granuloma present in Fig. 11.163
the multiple sections Oral Crohn's disease: there is swelling of the lips and a reddened, indurated area of
examined. skin adjacent to the lower vermilion typical for skin involvement by Crohn's disease.
Mucous membrane pemphigoid 409
Fig. 11.164 Fig. 11.165

Oral Crohn's disease: note the fissures and cobblestoning of the lower labial Oral Crohn's disease: there is involvement of the minor salivary glands of the lower
mucosa. labial mucosa by non-necrotizing granulomata.
Pathogenesis and histological features papulous folds, mucosal tags, and even ulcers. Salivary glands may also be
It is believed that patients with the NOD2/CARD15 genes are predis- involved (Fig. 11.165).
posed to Crohn's disease and that the disease represents a dysfunctional
immune response and impaired defense to intracellular microbes such as
Mycobacterium avium subspecies paratuberculosis and/or adherent-invasive Differential diagnosis
Escherichia coli.5 Granulomatous diseases associated with specific infections or for-
Granulomata, which are seen in up to 88% of mucosal lesions, are typi- eign material must always be excluded. The histological features of oral
cally noncaseating, often subtle, and usually located in the superficial lamina Crohn's disease are indistinguishable from those of idiopathic orofacial
propria, similar to orofacial granulomatosis.1–4 They are found within the granulomatosis.
Autoimmune conditions
Mucous membrane pemphigoid usually occurs in the sixth decade and

Desquamative gingivitis upward with a female predilection.1,4–11 The oral cavity is affected in 84–96%
of cases, and the conjunctiva in 52–81%.4–6,12 Other sites of involvement
Desquamative gingivitis is a chronic condition of adults, usually women (4:1),
in order of frequency are the upper airway (40–50%), skin (20–25%), and
affecting either the gingiva diffusely or multifocally. It presents as friable, fiery
(less frequently) genitalia (9–17%), anorectal area (3–4%), and esophagus
red, painful, eroded, denuded attached gingiva, primarily on the facial or buccal
(3–4%).4–6,12 ‘High-risk’ patients are those showing involvement of eyes,
aspect, with occasional areas of ulceration.1,2 In approximately half the cases of
genitalia, nasopharynx, esophagus, and the larynx because of life-threatening
desquamative gingivitis, the gingiva is the only site affected by disease.
airway obstruction, and morbidity due to stricture and scarring. ‘Low-risk’
Desquamative gingivitis represents a distinct clinical manifestation of auto-
patients are those showing involvement of oral mucosa only or oral mucosa
immune blistering diseases, hypersensitivity reactions or oral lichen planus.2,3,4
and skin.3
Large studies of desquamative gingivitis have shown that mucous membrane
The oral cavity is the only site involved in approximately 60% of cases
pemphigoid and lichen planus together accounts for approximately 80%
and is the first manifestation of the disease in 48–96% of patients.4,13,14
of cases, with the rest representing pemphigus vulgaris and cases with non-
The gingiva is the most frequent site of involvement affecting from 64% to
specific findings, some of which may represent hypersensitivity reactions.5–7
94% of cases; this often takes the form of desquamative gingivitis.1,6,8,9,14
Occasional cases of epidermolysis bullosa acquisita present as desquamative
Desquamative gingivitis may be the sole manifestation of cicatricial pem-
gingivitis. Cases of linear IgA confined to the mouth likely represent IgA type
phigoid in 60% of cases (Fig. 11.166).10 The buccal mucosa, labial mucosa,
mucous m embrane pemphigoid.8
and tongue are less often affected (Fig. 11.167). Lesions present as painful
areas of erosion, erythema, and ulceration. Intact blisters are rarely seen.
Mucous membrane pemphigoid The collapsed blister roof may take the form of a yellow-white membrane
that readily peels off the mucosa. Unlike cases with ocular involvement,
Clinical features cicatrization is an uncommon finding and was noted in only 9% of cases
Mucous membrane pemphigoid is the most common autoimmune subepi- in one series.4
thelial blistering disease presenting in the mouth. Several subsets of mucous Paraneoplastic pemphigoid has been reported in association with lym-
membrane pemphigoid exist, with variable antigenic characteristics but all phoma and lung cancer and may represent paraneoplastic autoimmune mul-
are characterized by predominant involvement of the mucous membranes by tiorgan syndrome (see below).15,16
a subepithelial blistering disorder. Cicatrization, however, is not a feature of Oral and ocular pemphigoid is associated with increased frequency of
oral mucosal disease.1–3 HLA-DQB1*0301.17–19
Fig. 11.166 Fig. 11.168

Mucosal pemphigoid: this typical case presented with erythematous gingiva and Mucosal pemphigoid: there is epithelial separation and preservation of the basal cells.
white epithelial sloughs.
Fig. 11.167 Fig. 11.169

Mucosal pemphigoid: there are large oral ulcers on the buccal mucosa. Mucosal pemphigoid: the lamina propria contains many dilated small capillaries and
a lymphocytic infiltrate with scattered plasma cells.

Mucous membrane pemphigoid is characterized by separation of the mucosal
squamous epithelium from the underlying connective tissue with preservation Mucous membrane pemphigoid is now recognized to be a heterogeneous
of the basal keratinocytes (Figs 11.168, 11.169 ).8–10 A variable lymphop- condition. Thus a number of antigens have been implicated in immunoblotting
lasmacytic infiltrate is usually present in the lamina propria. Unlike bullous and immunoprecipitation studies. These include BPAg2 and to a lesser extent
pemphigoid, eosinophils are rarely seen. BPAg1, laminin-332, beta4 subunit of alpha6 beta 1 integrin, and other less
Direct immunofluorescence studies reveal basement membrane zone anti- well characterized molecules.3,12–33
bodies in a smooth, continuous linear fluorescence pattern in 67–96% of
cases.12,20,21 IgG is present in 39–96% of cases, C3 in 43–97% of cases, and
IgA in 20–30% of cases.3,7,9,20,22 Differential diagnosis
Indirect immunofluorescence studies for circulating autoantibodies (usu- Oral lesions in mucous membrane pemphigoid must be distinguished
ally IgG) are present in approximately 20% of cases.9,12 However, one study from other subepithelial and autoimmune bullous dermatosis and bullous
using oral mucosa as a substrate elicited a 36% positivity rate.20 There is no lichen planus. The latter, however, typically shows destruction of basal
consistent correlation between antibody titer and disease activity. cells and colloid body formation. In addition, the lymphocytic infiltrate
Indirect immunofluorescence studies in salt-split skin reveal circulating is usually denser.
IgG or IgA in 84–100% of cases.21,23,24 The majority (57–82%) show epi- Direct immunofluorescence studies are essential in helping to differentiate
dermal binding with 9–22% showing dermal or both epidermal and dermal between lichen planus and interface autoimmune stomatitides. Cases previ-
localization. Those with both circulating IgG and IgA are virtually certain to ously referred to as pure oral linear IgA disease should probably be reclassi-
need systemic immunosuppressive therapy.21 fied as mucous membrane pemphigoid, IgA type.
Lupus erythematosus 411
Direct immunofluorescence shows deposition of IgG and/or complement in the

Pemphigus intercellular space, and along the basement membrane zone.1,4 Indirect immuno-
fluorescence is positive in a large number of cases if rat bladder is used.3 Antibodies
Clinical features against envoplakin and periplakin are consistently present, although antibodies
Oral pemphigus vulgaris typically begins in the sixth decade of life with a against desmoglein and basement membrane zone antigens are also present.3,5
female predilection. The mouth is involved in up to 87% of cases.1–4 Lesions in
the oral cavity precede those at other sites in up to 80% of cases.5 The mouth
is the only site of involvement in 25% of cases and the buccal mucosa, tongue, Linear IgA disease
palate, and floor of mouth are most often affected (Fig. 11.170).5 Pemphigus
vulgaris may present as desquamative gingivitis. Patients with pemphigus vege- Clinical features
tans often show oral involvement.6 Mucous membrane involvement in pemphi- Oral mucosal lesions associated with linear IgA disease occur in 26–100% of
gus foliaceus and pemphigus erythematosus is exceedingly rare. Paraneoplastic cases and present as vesicles, bullae, erosions or ulcerations.1–3 They may be
pemphigus characteristically involves the oral cavity (see below). located on the palate, buccal or labial mucosa, and oropharynx.3–6
Histological features Histological features

Biopsies of lesional tissue of pemphigus vulgaris reveal suprabasilar acantho- In linear IgA disease, there is a subepithelial vesicle or bulla with neutrophil
lysis and clefting.4,7 Pemphigus vegetans in addition shows papillary epithelial or eosinophil predominance.4,5 In many lesions, the infiltrate is mixed neutro-
hyperplasia and eosinophilic abscesses.6 philic and eosinophilic.
Direct immunofluorescence studies in pemphigus vulgaris and vegetans Direct immunofluorescence studies reveal homogeneous linear deposits of
reveal characteristic staining of the epithelial intercellular space with IgG in IgA along the basement membrane zone.1,4,5 Currently, it is thought that cases
all cases with active untreated disease.4,7 This differentiates pemphigus from of desquamative gingivitis alone (without skin lesions) that are positive for
pyostomatitis vegetans which also shows suprabasilar acantholysis. linear deposition of IgA represent mucous membrane pemphigoid.7
Paraneoplastic pemphigus Dermatitis herpetiformis

Clinical features Clinical features
In paraneoplastic pemphigus, the oral mucosa is involved in all cases with Oral involvement in dermatitis herpetiformis, a condition associated with gluten-
persistent, painful, treatment-resistant erosions of the oropharynx and sensitive enteropathy, presents as erythematous, pseudovesicular, purpuric or ero-
lips; the crusting vermilion lesions are reminiscent of Stevens-Johnson sive lesions in 70% of patients.1,2 Aphthous-like ulcers accompanied by mucosal
syndrome.1,2 More recently, the concept of paraneoplastic autoimmune erythema and atrophic glossitis have been described in up to 22% of patients.3
multiorgan syndrome has been proposed.3 This syndrome is characterized by
an autoimmune blistering mucocutaneous disease with positive immunofluo- Histological features
rescence findings, characteristic immunoprecipitation findings, presence of
Mucosal biopsies may sometimes reveal neutrophil microabscesses at the
malignancy (most often lymphoproliferative in nature), and involvement of
epithelial–connective tissue interface, occasional evidence of subepithelial
other organ systems such as the lungs and kidneys. The mucocutaneous disor-
blistering, and eosinophils and lymphocytes in the lamina propria.1,2
der may resemble pemphigus vulgaris, erythema multiforme or be lichenoid.
Extravasated erythrocytes are often conspicuous.
It is believed that either dysregulation of the immune system caused by the
Direct immunofluorescence studies reveal granular deposits of IgA in the
neoplasm leads to production of autoantibodies or host antitumor response
basement membrane, particularly at the tips of the papillae.1,2,4
produces antibodies that cross-react with native antigens.3
Pathogenesis and histological features Epidermolysis bullosa acquisita

Histologically, there is suprabasilar acantholysis identical to pemphigus, in
addition to individual keratinocyte necrosis and vacuolar interface change, Clinical features
suggestive of a lichenoid inflammatory process.1,3
The oral mucosa is involved in from 53% to 64% of cases, although in many
reports the nature of the lesions is not documented.1,2 However, all 11 cases
of epidermolysis bullosa acquisita in children in one series had involvement of
the buccal mucosa, some taking the form of desquamative gingivitis.3
The histological features are variable. In some lesions, there is a cell-free
subepithelial blister (classic variant) whereas in others, a neutrophil-rich or
eosinophil-rich lesion is seen.
Direct immunofluorescence studies show linear deposits of IgG and C3 at the
basement membrane zone similar to lesions of pemphigoid.4 Circulating anti-
basement membrane antibodies localize exclusively to the floor of the blister
in salt-split skin.5 Cases of paraneoplastic epidermolysis bullosa acquisita likely
represent paraneoplastic autoimmune multiorgan syndrome (see above).6
Lupus erythematosus
Clinical features
Oral involvement – mainly in the form of ulcers, erythema with or without
Fig. 11.170 white striations, exfoliative areas, and discoid plaques – is seen in 26–45% of
Pemphigus vulgaris: this presented as an ulcer on the lower labial mucosa. patients with systemic lupus erythematosus, presenting primarily on the hard
palate, buccal mucosa, and lips. Some lesions cause burning or soreness while
others are asymptomatic.1–4 Not surprisingly in bullous lupus erythematosus,
oral ulcers are occasionally seen.5,6
In patients with discoid lupus erythematosus, oral lesions in the form
of white plaques, papules, and striations associated with erosions and
ulcers are seen in 5–50% of cases.1,7,8 These often have a lichen planus-like
appearance.
Oral lesions of both systemic and discoid lupus erythematosus exhibit hyper-
parakeratosis or hyperorthokeratosis, epithelial hyperplasia or atrophy,
liquefactive degeneration of the basal cells, subepithelial PAS-positive depos-
its, perivascular inflammatory infiltrates (with some cases showing a bandlike
lichenoid infiltrate), and collagen degeneration.2,8–10
Direct immunofluorescence studies show deposition of IgG, lgM, IgA and/
or C3 in a band at the basement membrane zone; cytoid bodies stain for
IgM.8 As expected, T lymphocytes (CD4) predominate.11
Fig. 11.171
Wegener's granulomatosis Oral Wegener's granulomatosis: note the typical ‘strawberry gingivitis’. By courtesy
of S. Zunt, DDS, Indianapolis, USA.
Clinical features
Wegener's granulomatosis (one of the ANC vasculitides) in its complete form Oral mucosal biopsies show marked pseudoepitheliomatous hyperplasia
is characterized by necrotizing vasculitis of small- and medium-sized vessels, with edema, a mixed acute and chronic inflammatory cell infiltrate, hem-
noninfectious granulomatous inflammation of the upper and lower respira- orrhage, and vascular dilatation; many eosinophils may also be present.
tory tract, and glomerulonephritis. Approximately 5% of patients have oral Granulomata are usually poorly formed or absent although scattered multi-
involvement. Although almost all patients show upper and/or lower airway nucleated giant cells are sometimes present.2 Vasculitis with fibrinoid necrosis
disease, some cases with isolated skin and mucosal disease have been reported is sometimes a feature.3,8 The typical geographic necrosis with palisaded gran-
(limited Wegener's granulomatosis). In some patients, the disease runs a ulomata is not usually a feature in the oral mucosa, although it is occasionally
protracted course limited to the upper airways before progressing to mul- evident in the major salivary glands.9
tiorgan involvement.1 The gingiva is hyperplastic, often with a friable, gran- Direct immunofluorescence studies may show immune deposits of IgG or
ular, erythematous-to-magenta appearance, so-called ‘strawberry gingivitis’ IgA around blood vessels in skin biopsies.10
(Fig. 11.171). Ulcerated and necrotic masses may be present.2,3 The dentition
in the affected sites becomes mobile and extraction sockets heal poorly.
Pathogenesis and histological features Infectious processes must be excluded in the setting of a mixed inflamma-
Patients' sera demonstrate the presence of antineutrophil cytoplasmic antibodies tory infiltrate. The presence of pseudoepitheliomatous hyperplasia with
(ANCA). There are two main immunofluorescent staining patterns for ANCA: eosinophils and scattered giant cells raises the possibility of a fungal infec-
• cytoplasmic or c-ANCA staining (which is more specific for Wegener's tion, such as blastomycosis. Other vasculitides should also be considered
granulomatosis) targets proteinase-3, a 29-kD serine protease found in although sole presentation in the oral cavity is rare. Microscopic polyarteritis
the azurophilic granules of neutrophils, is indistinguishable from lesions of Wegener's granulomatosis but this does
• perinuclear or p-ANCA staining targets myeloperoxidase, another not show immune deposition within vessel walls.11,12 Pyostomatitis vegetans
constituent of neutrophilic granules.4,5 Other targets include lactoferrin and pemphigus vegetans do not show vasculitis or granulomata and typi-
and human neutrophil elastase. cally show acantholysis, although both may exhibit pseudoepitheliomatous
However, disease limited to the upper airway may be negative for such hyperplasia and eosinophils.
antibodies.6 Proinflammatory cytokines prime neutrophils causing them to Cocaine-induced midline destructive disease may resemble Wegener's granu-
express proteinase-3 and myeloperoxidase on the cell surface. ANCAs are lomatosis, particularly if obvious granulomas are not seen, and they can also be
then able to activate such cells, leading to degranulation and the secretion of ANCA positive.13 Wegener's granulomatosis is differentiated from nasal natural
additional cytokines, thus damaging endothelial cells and recruiting further killer (NK)/T-cell lymphomas of the palate and nasal cavity (‘midline destructive
inflammatory cells to the region.7 disease’) by the absence of an atypical lymphocytic infiltrate (see below).
Salivary gland disease
Reactive conditions (59–73%), buccal mucosa (11–17%), floor of mouth (7–12%; referred to as
ranula), and ventral tongue (4%) (Fig. 11.172).1–3 It presents as a dome-shaped,
fluctuant, bluish, and sessile lesion, which often increases and decreases in size.
Mucocele Salivary duct cyst or sialocyst results from dilatation of the excretory duct,
caused by a distal obstruction. Salivary duct cyst or sialocyst results from
Clinical features dilatation of the excretory duct, caused by a distal obstruction and is there-
A mucocele (mucous escape phenomenon) caused by a tear in the excretory duct fore a retention cyst. The patients are older and the most common sites are the
and spillage of mucin into the connective tissue. This usually arises in children floor of mouth (50%), buccal mucosa, and upper lip where the obstruction
and young adults and the most common locations are the lower labial mucosa is often a sialolith.2
Reactive conditions 413
Fig. 11.172
Mucocele: note the bluish sessile nodule on the lower labial mucosa, a typical site.
Fig. 11.174
Mucocele: there is
no epithelium in the
lining, just condensed
granulation tissue.
Fig. 11.173
Mucocele: the cyst-like
cavity filled with mucin
Fig. 11.175
lies in the lamina propria.
Mucocele: in areas of organization, there are sheets of muciphages with variable
amounts of granulation tissue.
Superficial mucoceles are distinctly vesicular or dewdrop-like, raising the
suspicion of a herpetic infection or autoimmune vesiculobullous disease and Superficial mucoceles exhibit pools of mucin that are bordered superiorly
occur in older adults, particularly on the palate, retromolar pad, and buccal by surface squamous epithelium only that is often thinned.5,8
mucosa.4,5 Salivary duct cysts are lined by cuboidal or columnar epithelium, often
Floor of mouth mucoceles, when large, are also called ranulas, and these with mucous cells or foci of squamous metaplasia; more than half may be
may extend below the mylohyoid muscle presenting extraorally as a ‘plung- lined by oncocytic cells, sometimes with papillary projections (Figs 11.176,
ing ranula’.6 There is recurrence in approximately 2% of cases.1 11.177).4 These may also be referred to as oncocytic sialocysts.
The least common variant is the mucopapillary cyst,which is frequently
Histological features multiloculated and lined by stratified squamous or columnar epithelium with
Mucous escape mucoceles consist of pools of mucin containing muciphages pronounced mucous cell metaplasia and luminal papillary projections.4 The
and often many neutrophils surrounded by condensed granulation tissue with associated minor salivary glands often exhibit varying degrees of acinar atro-
associated muciphages (Figs 11.173, 11.174).1,2 Some specimens consist only phy, ductal dilatation, and interstitial chronic inflammation with fibrosis.
of the collapsed wall of granulation tissue or even a solid mass of granulation
tissue containing muciphages (Fig. 11.175). Mucin may be dispersed in the Differential diagnosis
inter- and intralobular connective tissue. Portions of a metaplastic duct are Parulides (gum-boils) of the gingiva can sometimes be mistaken for extrava-
seen in 20% of cases.2 Occasionally, eosinophilic globular masses are present sation mucoceles. However, neither pools of mucin nor muciphages is present
within the mucin pools.7 and microabscesses and sinus tracts are almost always evident.
and periductal inflammation (Fig. 11.178). Bacteria and inflammatory cells

may be present between the calculus and the duct lining, or between lamella-
tions. Rupture can lead to acute and chronic inflammation and/or a foreign
body reaction. Approximately one-quarter of calculi are unmineralized.1
Phleboliths and calcified thrombi are generally not lamellated and occur
within vascular lumina lined by endothelial cells.
Necrotizing sialometaplasia
Clinical features
This is a self-healing inflammatory condition of salivary glands that may be
clinically and histologically mistaken for a malignancy because of its rapidly
progressive ulcerative nature and the lack of associated pain in a significant
proportion of cases.
Adults (2M:1F) are mainly affected with a mean age of onset in the fifth
decade. It usually presents as a painful or painless ulcer or (less often) as a
Fig. 11.176 mass, with the majority (approximately 80%) occurring on the hard palate
Oncocytic sialocyst: this retention cyst consists of a grossly ectatic excretory (Fig. 11.179). Approximately 10% of cases affect the major glands and (less
salivary duct; intraluminal papillary projections are evident. often) the mucous glands of the nose, maxillary sinus, and larynx.1 One-third
Fig. 11.177 Fig. 11.178

Oncocytic sialocyst: the lining cells are oncocytic. Sialolith: the sialolith is present within an ectatic salivary duct, the lining of which
exhibits squamous metaplasia.
The mucopapillary retention cyst is distinguished from mucoepidermoid

carcinoma by the lack of infiltration of the stroma and absence of discrete,
solid islands of neoplastic epidermoid and mucous cells.
Papillary cystadenomas are true tumors consisting of a proliferation of
salivary ductal cells in a cystic configuration (see below). In the major salivary
glands, papillary cystadenoma lymphomatosum (Warthin's tumor) shows a
prominent lymphoid component in addition to oncocytic lining cells.9
Sialolithiasis
Clinical features
In sialoliths (salivary gland calculi), affected patients are in their sixth or seventh
decade. The most common sites are the upper lip and buccal mucosa which
together account for 75–90% of all minor salivary gland lithiasis.1,2 They present
as deep masses, nodules, and swellings, sometimes associated with drainage.
The calculi have a lamellated appearance with alternating eosinophilic and
basophilic bands and a generally homogeneous center.1,2 Globular and granu- Fig. 11.179
lar areas and cellular inclusions may be present. Such calculi generally reside Necrotizing sialometaplasia: there is punched-out ulcer on the hard palate.
within a cystically dilated excretory duct that exhibits squamous metaplasia By courtesy of C. Allen, DDS, Columbus, USA.
of patients give a history of recent surgery at the site. Other predisposing

factors include a history of trauma, injection of local anesthetics, or alcohol
and tobacco use, and there is sometimes an association with tumors.1 Cases
have been reported in bulimic patients and cocaine use.2,3, Generally, healing
occurs within several weeks of diagnosis.

The etiology is vascular compromise leading to infarction of the gland and
reactive squamous metaplasia of the ducts and acini. This has been experi-
mentally produced by ligation of salivary ducts and injection with local anes-
thetics.4,5 This hypothesis is supported by the development of necrotizing
sialometaplasia in a patient with Buerger's disease.6
One of the most important features in establishing this diagnosis and distin-
guishing it from a malignancy is preservation of the lobular architecture of the
gland with minimal distortion. Early lesions show infarction of acini resulting
in outlines of acinar units without viable acinar cells; more advanced lesions
show metaplastic changes with pseudoinvasive islands of benign-appearing
squamous epithelium (Figs 11.180, 11.181). There is generally a prominent
inflammatory infiltrate with granulation tissue formation in later stages.1,7,8
Fig. 11.181
Variable features include pseudoepitheliomatous hyperplasia, reactive epi- Necrotizing sialometaplasia: the squamous cells are benign and represent
thelial atypia, and vascular occlusion. Serous and mucoserous glands are less metaplastic ducts.
likely to show the necrosis and infarctive changes.1 Very early lesions may
show predominantly mucus spillage.
Nicotinic stomatitis
The preservation of lobular architecture, lack of infiltration of the surround-
ing tissues by the epithelial elements, infarction necrosis, and generally bland
nuclear morphology of the metaplastic islands distinguish this condition from
Clinical features
squamous cell carcinoma. Mucoepidermoid carcinoma tends to have a sub- Nicotinic stomatitis (stomatitis nicotina) is associated with pipe smoking and
stantial number of mucous cells and will often show obvious infiltration of its severity is proportional to the duration of the habit. It is reversible after
surrounding structures. The use of CK7 and myoepithelial markers may help cessation of pipe smoking.1–3 It is caused by the heat from the pipe smoke,
to differentiate between these three conditions.9 and not the nicotine itself. The condition has also been noted in a patient who
Subacute necrotizing sialadenitis characteristically develops in younger consumed hot beverages.4
patients (third decade), with an almost exclusive location on the palate. Early lesions appear as small red punctate areas sometimes associated with
Presentation, which is typically acute and over a matter of days, is character- whitening of the surrounding mucosa on the posterior half of the palate, a site
ized by a painful, nonulcerated mass, with rapid resolution within 2 weeks.10 where many salivary glands are present. Involvement is usually symmetrical.
Since most cases have been reported in the military, there is speculation that As the lesions progress, the palate may take on a cobblestone appearance
this may represent a viral infection that is transmitted between individuals with raised white papules having slightly umbilicated central puncta (Fig.
living in close quarters. There is only focal necrosis with little ductal metapla- 11.182).1,3 The red puncta represent the inflamed ostia of the excretory
sia. The glands are diffusely infiltrated by a mixed inflammatory infiltrate of salivary ducts.
neutrophils, lymphocytes, histiocytes, and occasionally eosinophils.11,12 Some Similar changes have been described in patients who practice reverse
contend that subacute necrotizing sialadenitis may fall within the spectrum smoking (smoking with the lighted end of the cigarette in the mouth as is
of necrotizing sialometaplasia but, in general, there are sufficient clinical and common in parts of Asia).5,6
histological differences to warrant treating them as two distinct entities.
Fig. 11.180 Fig. 11.182

Necrotizing sialometaplasia: there are islands of squamous cells that are organized Nicotinic stomatitis: cobblestone, nodular appearance of the hard palate in a patient
in the usual salivary gland lobules, with inflammation. who reverse smokes. By courtesy of L. Lee, DDS, Toronto, Ontario, Canada.
s uppurative condition of the minor salivary glands, usually of the lower lip.
Because salivary glands at other mucosal sites may be affected, the alternative
term ‘stomatitis glandularis’ has been proposed.1
Patients present with a painless or painful swelling and eversion of the lip,
often with a mucous or mucopurulent discharge through the duct ostia.1,2 The
lip may be dry, scaly, and nodular. Simple, deep, and deep suppurative forms
have been identified.

The etiology is unknown but the condition is likely to represent an inflamma-
tory response to a variety of local irritants. Cases of carcinomatous transfor-
mation have occurred in older male patients with outdoor occupations and
tobacco smoking; eversion of the lower lip increases its exposure to actinic
damage.3 Factitial injury such as repeated wetting and drying of the lips may
also play a role.4 Familial examples have been reported.5,6
There is dilatation and metaplasia (squamous, mucous cell or oncocytic)
of the excretory ducts with variable surrounding acute and chronic inflamma-
tion. Intraluminal suppuration may be present.1,2,7,8 The minor salivary glands
exhibit non-specific inflammatory changes of acinar atrophy, ductal ectasia,
Fig. 11.183
Nicotinic stomatitis: the nodule consists of metaplastic excretory salivary ducts and
interstitial fibrosis, and interstitial inflammation (Fig. 11.185).2,8
surrounding chronic inflammation.
Histological features Similar histological changes are seen in glandular obstruction such as occurs
in glands draining into a mucocele and, in particular, in glands that have
There is hyperparakeratosis or hyperorthokeratosis and acanthosis. The pap- been plugged by thick mucinous secretions or by small calculi, a common
ules represent openings of the excretory salivary ducts that have undergone phenomenon in the upper lip. The clinical presentation separates this condi-
squamous metaplasia and are usually surrounded by plasma cells and lym- tion from mucocele or sialolithiasis, both of which are localized and discrete
phocytes in an edematous stroma (Figs 11.183, 11.184).2,7 Lymphocytes are phenomena.
often seen within the metaplastic ducts. Lobules of minor salivary gland may
be present depending on the depth of the biopsy.
Dysplasia or even invasive squamous cell carcinoma may be present in Salivary gland neoplasms
patients who reverse smoke but in general malignant change is not a feature
in pipe smokers.3 Clinical features
Any salivary gland neoplasm of epithelial differentiation, benign or malig-
Cheilitis glandularis (stomatitis glandularis) nant, that occurs in the major salivary glands may also occur in the intraoral
minor glands (which are predominantly mucous secreting). Here, only the
Clinical features more common salivary gland neoplasms affecting the minor glands will be dis-
cussed. Approximately half of intraoral salivary gland neoplasms are benign
Cheilitis glandularis (stomatitis glandularis, cheilitis glandularis apos- and half are malignant and there is a female predilection.1–4 The most com-
tematosa) is a rare chronic, recurrent, inflammatory and, in some cases, mon sites are the hard and soft palate, lips, and buccal mucosa, although
any site may be involved. As expected, lesions present as a swelling at the
site. Benign lesions tend to have a long history of gradual enlargement while
malignant lesions tend to grow more rapidly and ulcerate.
Fig. 11.184
Nicotinic stomatitis: there
is chronic inflammation in
the surrounding fibrous
tissue and lymphocyte Fig. 11.185
exocytosis through the Cheilitis glandularis: there are grossly dilated excretory ducts with mucous cell
duct epithelium. metaplasia, intraluminal suppuration, and surrounding chronic inflammation.
The ensuing discussion will focus on the histopathology of only five lesions
which present with some frequency in the oral cavity:
• pleomorphic adenoma
• canalicular adenoma
• mucoepidermoid carcinoma.
• polymorphous low-grade adenocarcinoma
• adenoid cystic carcinoma.
There may be some variation in prevalence of some tumors over others
based on racial differences.3,4
Pleomorphic adenoma (together with its variant, myoepithelioma) and
canalicular adenoma comprise the two most common benign neoplasms.1,3,4
The canalicular adenoma has a particular predilection for the upper lip in
females and lesions are often multifocal.
The most common malignant neoplasm is mucoepidermoid carcinoma
(the second most common tumor overall after pleomorphic adenoma).1,3,4
The polymorphous low-grade adenocarcinoma (originally referred to as lob-
ular carcinoma because of its resemblance to lobular carcinoma of the breast,
and terminal duct adenocarcinoma) was recognized as a distinct entity only in
the 1980s.5–7 Prior to that, it was likely diagnosed as pleomorphic adenoma,
adenoid cystic carcinoma or adenocarcinoma, not otherwise specified, and Fig. 11.186
Pleomorphic adenoma.
is even today a challenging diagnosis for many. Genetic markers for these
tumors have been reviewed recently.8
A condition known as adenomatoid hyperplasia of the minor glands con-
sists of proliferation of normal-appearing mucous acini. This condition is
often seen adjacent to, and possibly as a reaction to, an adjacent salivary
gland neoplasm and should prompt a search for the primary tumor.
Pleomorphic adenoma
This term is preferable to the old term of ‘benign mixed tumor’. It is believed
to arise from intercalated duct reserve cells that can be differentiated into
ducts, acini or myoepithelial cells. In its classic presentation, it comprises a
discrete although not usually entirely encapsulated proliferation of ductal,
myoepithelial, and mesenchymal elements forming ducts and cysts, as well as
sheets, strands, and trabeculae of tumor cells.9 Ducts are lined by eosinophilic
cuboidal cells and surrounded by a cuff of epithelioid myoepithelial cells
(Figs 11.186, 11.187). From these periductal locations, they may blend
into spindled or stellate myoepithelial cells in the stroma which is hyalinized
and/or myxochondroid, sometimes with bone or adipose tissue formation
(Fig. 11.188).10 Keratin pearl formation, although unusual, should not be
misinterpreted as a sign of malignancy and neither should focal capsular inva-
sion. Many variations of this classic histology may be seen including cellular
Fig. 11.187
and myxoid variants and, importantly, the myoepithelial predominant vari- Pleomorphic adenoma: the ducts are lined by uniform cuboidal cells and there is a
ant, or myoepithelioma.2–4 surrounding myoepithelial layer.
Myoepitheliomas are believed to be a variant of pleomorphic adenoma
where the myoepithelial element predominates and where ductal structures
may be minimal or altogether absent. Most lesions occur on the palate
and consist of spindled cells, plasmacytoid or ‘hyaline’ cells (large cells
with abundant eosinophil cytoplasm and eccentric nuclei) or a combina-
tion of both (Fig 11.189).11 Clear and epitheloid myoepithelial cells may
also be present. Plasmacytoid myoepithelial cells can exhibit variation
in shape and size of the nuclei but mitoses are not seen. Pockets of such
plasmacytoid myoepithelial cells may be seen in banal pleomorphic ade-
noma. Differentiation of myoepitheliomas from plasmacytoma is based
on the myoepithelial cells not exhibiting a zone of Hopf, the lack of a
clumped chromatin pattern, and negative staining for B-cell markers or
monoclonality.
Myoepithelial cells stain consistently for cytokeratin, S-100 protein, and
vimentin. They also stain for calponin, p63, and glial fibrillary acidic pro-
tein while staining for muscle-specific actin and smooth muscle actin are less
consistent.9,12,13
Malignant transformation in intraoral pleomorphic adenomas occurs but
it is uncommon.9
Adenomatoid hyperplasia of the salivary glands, a benign lobu-
lar proliferation of acini and ducts resembling normal glands is often
seen adjacent to both benign and malignant salivary gland tumors (Fig Fig. 11.188
11.190).14,15 Pleomorphic adenoma: in this example there is a focal chondroid stroma.
Fig. 11.189 Fig. 11.191

Myoepithelioma: high-power view showing plasmacytoid myoepithelial cells. Canalicular adenoma: the tumor is encapsulated and composed of well-defined
trabeculae and interlacing strands of basaloid cells.
Fig. 11.190
Salivary gland adenomatoid hyperplasia: note the lobular growth pattern. The acini Fig. 11.192
resemble those seen in normal salivary gland. Canalicular adenoma: the trabecular are two cells thick and form small ductal
structures; stroma is myxoid with little collagen and dilated capillaries.
Canalicular adenoma
The canalicular adenoma generally has a thick capsule. There is a prolif-
eration of strands and anastomosing trabeculae of basaloid cells, often in a
double layer. Solid and trabecular forms are also recognized.16 The nuclei are
fusiform with inconspicuous nucleoli and no atypia. The stroma is generally
myxoid and contains small blood vessels but is not particularly collagenized.
Multifocality is not uncommon and should not be mistaken for infiltra-
tion (Figs 11.191, 11.192). Tumors stain for S-100 protein but not smooth
muscle actin, calponin or c-kit.9,17
Mucoepidermoid carcinoma
The mucoepidermoid carcinoma, as its name suggests, consists of a proliferation
of mucous, epidermoid cell, and intermediate cells with variable duct and cyst
formation (Figs 11.193, 11.194).9,18 The epidermoid cells have ample, palely
eosinophilic cytoplasm and medium-sized nuclei with dispersed chromatin while
intermediate cells have less cytoplasm. Cystic structures are often lined by all
three cell types, often with luminal proliferation of the same cells forming ducts
and complex architecture. Some tumors have a preponderance of clear cells. Fig. 11.193
Invasion of the stroma occurs as small islands of cells and these may not always Mucoepidermoid carcinoma: medium-power view showing ducts and cystic spaces
be readily identified. lined by mucous cells with stroma infiltration.
isomorphism of the cells themselves (Figs.11.195, 11.196).7,9,25 The cells are

ovoid to spindled with medium-sized nuclei with finely dispersed chroma-
tin, small nucleoli, and pale cytoplasm. There may be clear or oxyphilic cells.
Mitotic activity and necrosis are infrequent. A helpful feature is the presence of
cells ‘in single file’ at the periphery or near the mucosal surface of the tumor.
The stroma is hyalinized and/or myxoid but cartilaginous and osseous elements
are not seen. Perineural invasion is common in spite of the tumor being of low
grade. It may be difficult to identify areas of true stromal invasion in curet-
ted specimens. Immunohistochemistry studies for glial fibrillary acidic protein,
S-100, actin, bcl2, and p53 have shown variable results and do not distinguish
between this tumor and pleomorphic adenoma or adenoid cystic carcinoma.25
Differentiation of this tumor from a pleomorphic adenoma can be difficult
if there is no evidence of perineural invasion since it shares many features with
pleomorphic adenoma such as variable pattern, bland cytology, and myxoid
stroma. The presence of plasmacytoid myoepithelial cells in clusters and the cuff-
ing of ductal structures by a layer of myoepithelial cells are features of pleomor-
phic adenoma and not seen in polymorphous low-grade adenocarcinoma. Cells
A positive for glial fibrillary acidic protein are seen often in stromal cells in pleo-
morphic adenomas but not in polymorphous low-grade adenocarcinomas.26
The tumor may also resemble adenoid cystic carcinoma although the
latter tends to have more nuclear pleomorphism, hyperchromatism, and atypia.
Both stain for p63 but CD43 may be less often expressed in polymorphous
low-grade adenocarcinoma than in adenoid cystic carcinoma.27,28
Adenoid cystic carcinoma

This tumor takes three forms: the classic type that has a prominent cribriform
pattern, the tubular type, and the solid type which forms few ductal or cribri-
form structures and carries the worst prognosis.9,16,29
Adenoid cystic carcinoma is an invasive tumor and consists of a prolif-
eration of basaloid cells that have large, oval or irregularly shaped, angu-
lar, hyperchromatic nuclei (Figs 11.197 to 11.199). Cells have less cytoplasm
than is seen in polymorphous low-grade adenocarcinoma. A cribriform pat-
tern (so-called ‘swiss cheese’ appearance) is the most reliable feature seen usu-
ally in combination with a tubular pattern. The stroma is variable myxoid or
hyalinized and perineural invasion is a frequent finding. Perineural invasion
B of major nerves is associated with higher local recurrence and lower survival
rates as are tumors with >30% solid component.30
Fig. 11.194 It may be difficult to differentiate this tumor from a polymorphous low-
Mucoepidermoid carcinoma: high-power views of (A) mucous and epidermoid cells;
grade adenocarcinoma that may also have focal areas with a cribriform
(B) focal squamous differentiation.
configuration although this tumor tends to stain with c-kit and CD43 more
strongly.28 In general, the cells in an adenoid cystic carcinoma exhibit more
nuclear atypia, hyperchromatism, and mitotic activity.
For many decades, grading into low, intermediate, and high grades was
based on the presence of cystic spaces and the proportion of mucous to epi-
dermoid cells. However, more recently, two studies have proposed grad-
ing schemas using point systems based on the presence of cystic structures,
mucous cell population, anaplasia, stromal and bone invasion, neural and
vascular invasion, and mitotic activity.19,20 Grade I to III in both systems cor-
relate with recurrence and prognosis. Expression of p27 and high Ki-67 index
may impact prognosis.21,22
Acinic cell carcinomas may look similar but they lack significant numbers of
mucous cells and more than 90% of them contain zymogen granules that are
PAS positive and diastase resistant. Cystic lesions are easily mistaken for pap-
illary cystadenomas (which do not generally contain mucous cells), especially
since the cytology of these tumors is bland with little evidence of mitotic activ-
ity.9,23 Luminal proliferation of mucous and epidermoid cells, complex ductal
architecture, and invasion of the surrounding stroma are important features.
It may also share similarities with a papillary cystadenocarcinoma which
has prominent luminal papillae, shows hobnailing of cells in the lumen and
more cytologic atypia and mitotic activity.24
Polymorphous low-grade adenocarcinoma

Fig. 11.195
This unencapsulated but often well-circumscribed tumor is characterized by Polymorphous low-grade adenocarcinoma: at low power, this tumor can be readily
two features: a marked variation in the pattern of the tumor cells with solid, confused with pleomorphic adenoma. Note the solid areas, ductal differentiation,
ductal, cribriform, cordlike, trabecular, cystic or fascicular patterns; and bland and focal myxoid stroma.
Fig. 11.198
Adenoid cystic carcinoma: myoepithelial cells surrounding myxoid stroma forming
cribriform pattern.
Fig. 11.196
Polymorphous low-grade adenocarcinoma: (A) the tumor cells appear uniform with
vesicular nuclei and prominent nucleoli. Clear cell forms are evident. There is a
myxoid stroma, (B) in this field, cystic spaces are evident.
Fig. 11.199
Adenoid cystic carcinoma: tubular structures with ductal and myoepithelial cells in
hyalinized stroma.
Papillary ductal lesions

Three conditions deserve mention: intraductal papilloma, inverted papil-
loma, and sialadenoma papilliferum.1 They are all likely reactive papillary
and metaplastic lesions and not true neoplasms.
The intraductal papilloma and inverted papilloma present as mucosal nod-
ules or masses. The intraductal papilloma occurs within a cystically dilated
salivary duct as a result of papillary proliferation of columnar epithelium,
usually with many mucous cells overlying fibrovascular cores.1 The inverted
papilloma presents as an endophytic papillary proliferation of epithelium
forming large lobular structures with crypts.2 The epithelium is columnar on
the luminal aspect and basaloid within the lobules. Mucous cells and micro-
cysts are present. There is minimal mitotic activity and usually no atypia.
Human papillomavirus 6/11 have been identified in rare cases.3
Sialadenoma papilliferum is the mucosal counterpart of syringocystade-
noma papilliferum.4,5 These lesions are usually located on the palate and clini-
cally present as an exophytic papillary growth. Microscopically, there is an
exophytic proliferation of squamous cells and an endophytic proliferation of
ductal and cystic structures with a complex branching architecture and also
Fig. 11.197 luminal papillary projections of columnar and mucous cells. Positive staining
Adenoid cystic carcinoma: low-power view showing characteristic cribriform growth for cytokeratin, S-100, glial fibrillary acidic protein, vimentin, and smooth
pattern. muscle actin suggests that myoepithelial cells play a role in these tumors.4
Leukoplakia, erythroplakia and epithelial dysplasia 421
Premalignant conditions
Leukoplakia, erythroplakia and carcinoma – so-called ‘high-risk’ sites – are the floor of mouth, tongue, and
soft palate (Fig 11.202).8,9,11
epithelial dysplasia Dysplasia, carcinoma-in-situ or invasive squamous cell carcinoma is
present in 20–34% of leukoplakias overall.6,10 However, in subcontinental
Clinical features Indians, the rate is generally less than 1%, suggesting alternative factors or
Leukoplakia, a clinical term, is defined as a white plaque that does not wipe that different diagnostic criteria may be at play.8 The malignant transforma-
off and cannot be characterized clinically or pathologically as any other dis- tion rate of leukoplakia is 3–5%.12 If epithelial dysplasia is present, the rate
ease and is not associated with any physical or chemical agent except tobacco; increases to 12–19%;13–15 one study had a rate of 37%.6
it excludes all frictional keratoses.1,2 Its prevalence is 1.5%.3 There is a strong Verrucous leukoplakia most likely represents a precursor lesion of ver-
association between the appearance of leukoplakia and the use of tobacco rucous carcinoma or papillary squamous carcinoma. Clinically, this variant
products.4,5 Conversely, of all patients who have leukoplakia, 70–90% have presents as a rough white plaque on the gingiva or alveolar mucosa in patients
a tobacco history.6,7 Prevalence increases with age.6 Clinically, lesions may more than 50 years old, with a roughly equal sex distribution.16 More exten-
appear homogeneous (in color and texture) or nonhomogeneous; if the lat- sive lesions are referred to as proliferative verrucous leukoplakia. This is a per-
ter, they may be referred to as erythroleukoplakia (or speckled leukoplakia), sistent and progressive form of leukoplakia that tends to affect women (3:1),
verrucous leukoplakia or nodular leukoplakia (Figs 11.200 and 11.201).1,2,8 with a tobacco habit present in approximately one-third of cases.17–20 It starts
The most common sites are the buccal mucosa, commissure, tongue, gingiva/ as an innocuous leukoplakia that subsequently spreads or develops multifo-
alveolar mucosa, and the palate, although the nature of oral habits may affect cally, becoming increasingly verrucous and sometimes erythematous over the
the location of leukoplakia.4,8–10 However, sites associated with dysplasia and roughly two decades that it often takes to be recognized (Figs 11.203, 11.204).
Fig. 11.202
Fig. 11.200
Leukoplakia: this red and white plaque exhibited severe epithelial dysplasia.
Leukoplakia: nonhomogeneous sharply demarcated and fissured white plaque on
the buccal mucosa. This exhibited moderate dysplasia.
Fig. 11.203
Fig. 11.201 Proliferative verrucous leukoplakia: this patient had been aware of this progressive
Leukoplakia: erythroleukoplakia on the lateral tongue. This exhibited moderate lesion for approximately 10 years. This was a verrucous carcinoma arising from
dysplasia. proliferative verrucous leukoplakia.
These lesions, although clinically extensive, are often cytologically bland

and patients have had multiple biopsies without a diagnosis of dysplasia
or carcinoma. Malignant transformation to squamous cell or verrucous
carcinoma occurs in 60–100% of cases.20
Erythroplakia (similar to erythroplasia) presents as a velvety red papule
or plaque that is usually painless. It is much less common than leukoplakia
(Fig. 11.205). Dysplasia, carcinoma-in-situ or invasive carcinoma is present
in 69–91% of cases at the time of biopsy.21–23

All leukoplakias are characterized by hyperparakeratosis or hyperorthok-
eratosis with varying degrees of acanthosis and chronic inflammation.
Unlike in other mucosae, architectural features of dysplasia are particu-
larly important, especially for evaluating lesions of proliferative verrucous
leukoplakia. Architectural features of dysplasia include marked papilloma-
tosis and exophytic growth, such as is seen in verrucous hyperplasia, and
endophytic growth;24 these are often bulky lesions. Rete ridges are frequently
bulbous if there is prominent epithelial hyperplasia, or tear-drop or drop
shaped. Cytological features are similar to those used for other epithelia: loss of
Fig. 11.206
normal stratification and polarity, dyscohesion, dyskeratosis, basal cell hyper- Epithelial dysplasia: there is budding of the rete ridges; dysplastic cells involve less
plasia, increased nuclear-to-cytoplasmic ratio, mitoses in the mid and upper than one-third of the thickness of epithelium.
epithelium, and anaplasia.2,13,25 By convention, the terms mild, moderate, and

severe dysplasia are applied if less than one-third, between one- and two-
thirds, and greater than two-thirds of the epithelium is affected (Figs 11.206–
11.208). Full- thickness involvement represents carcinoma-in-situ.
Extension and spread of dysplastic cells from the surface epithelium down
excretory salivary ducts (particularly in floor of mouth dysplasias) without
evidence of stromal invasion is accompanied by the same recurrence rate
as for invasive squamous cell carcinoma (Fig. 11.209).26 This may, in part,
explain recurrences in the floor of mouth after superficial excision or laser
ablation.
Squamous intraepithelial neoplasia is a term used for dysplasia and car-
cinoma-in-situ of the upper aerodigestive tract, analogous to the concept of
cervical intraepithelial neoplasia.27 Squamous intraepithelial neoplasia con-
notes not only histomorphological features of malignant change (albeit of
a noninvasive lesion) but also molecular and genetic changes of neoplastic
transformation.
Fig. 11.204
Proliferative verrucous leukoplakia: this is the same patient depicted in Figure
11.203, showing palatal involvement.
Fig. 11.207
Epithelial dysplasia:
dysplastic cells involve
Fig. 11.205 greater than one-third but
Erythroplakia: this innocuous-appearing red macule on the lateral tongue was an less than two-thirds of the
invasive squamous cell carcinoma histologically. epithelium.
Leukoplakia, erythroplakia and epithelial dysplasia 423
Fig. 11.210
Verrucous hyperplasia: note the exo- and endophytic squamous proliferation with
marked hyperkeratosis; normal epithelium is present at one edge.
Fig. 11.208
Carcinoma-in-situ:
dysplastic cells involve
the full thickness of the
epithelium.
Fig. 11.211
Verrucous hyperplasia:
there is hyperorthokera-
tosis, normal-sized rete
Fig. 11.209 ridges, and minimal
Carcinoma-in-situ: dysplastic cells involve the excretory salivary duct, also in an in cytological atypia.
situ pattern; this has important prognostic implications.
with the blunt ones being usually non- to thinly keratinized and the sharp
The use of molecular markers to help predict malignant transformation is ones being markedly hyperkeratotic (Figs 11.210, 11.211).12 Cytological aty-
rapidly evolving.28 Loss of heterozygosity in 3p, 9p, and 17p are associated pia may be minimal. If there is hyperparakeratosis and the papillary folds of
with dysplasia but not consistently so.29,30 There is increased expression of epithelium push endophytically and assume frondlike rete ridges, a diagnosis
p53 in moderate and severe dysplasia and carcinoma-in-situ.31,32 The presence of verrucous carcinoma should be made (Figs 11.212, 11.213).24,35 Between
of p53 in suprabasal cells correlates with the development of oral squamous 20% and 30% of verrucous hyperplasias have been found to harbor human
cell carcinoma even when clear evidence of dysplasia is not present.33 The use papillomavirus.36,37
of microarrays for the identification of specific gene expression products may The histological features of proliferative verrucous leukoplakia are vari-
prove important in further defining the progression potential of dysplastic able and usually those of verrucous hyperplasia. They all show hyperorthok-
lesions.34 Other studies include those that have investigated ploidy status, and eratosis or hyperparakeratosis and papillomatosis. Epithelial dysplasia may be
proliferation and differentiation markers. However, the current ‘gold stan- absent to mild in early lesions. As they spread relentlessly over the mucosa,
dard’ for the evaluation of dysplasia is still routine histology. lesions may show increasing cytological evidence of dysplasia, more marked
A histological diagnosis of verrucous hyperplasia is made for those lesions exophytic papillomatosis and, finally, an endophytic and/or frankly invasive
exhibiting marked hyperorthokeratosis or hyperparakeratosis with the epi- growth pattern of conventional squamous cell or verrucous carcinoma.20 In
thelium thrown into exophytic papillary projections, sometimes bulbous rete one series, 77% of cases were positive for HPV-16.38 DNA aneuploidy has also
ridges and an endophytic growth pattern.24 This corresponds clinically to ver- been reported.39 Cases may also develop aneuploidy as the lesions progress and
rucous leukoplakia. ‘Blunt’ and ‘sharp’ papillary projections are identified, become dysplastic.40
Fig. 11.212 Fig. 11.214

Verrucous hyperplasia/early verrucous carcinoma: note the exo- and endophytic Sanguinaria-induced leukoplakia: the maxillary gingiva and sulcus is a typical
squamous proliferation with bulbous pushing rete ridges. location for these sharply demarcated, rough plaques.
Fig. 11.213 Fig. 11.215

Verrucous hyperplasia/ Koilocytic dysplasia: there is carcinoma-in-situ.
early verrucous carcinoma:
there is parakeratin
plugging, minimal atypia, The term ‘lichenoid dysplasia’ has been used to denote epithelial dyspla-
and a broad endophytic
sia associated with a band of lymphocytes at the interface. In such instances,
front.
it may be less confusing to use the term ‘epithelial dysplasia with lichenoid
inflammatory infiltrate’ because the lymphocytic band is likely a host response
to dysplastic cells.
The use of a sanguinaria-containing dentrifice may lead to a leukoplakia in
the maxillary vestibule that exhibits hyperorthokeratosis, atrophy, papillo-
matosis, and usually mild cytological atypia/dysplasia (Fig. 11.214).41,42 No Submucous fibrosis
cases have resulted in carcinomatous transformation although discontinua-
tion of the dentifrice has not always led to resolution. Clinical features
Bowenoid papulosis, a condition of young adults, occurs uncommonly on This condition affects adults of usually Asian descent (subcontinental
the lips, tongue, and buccal mucosa. In addition to koilocytes, there are atypi- Indians in particular) who chew areca nut as a component of betel quid or
cal, dyskeratotic, apoptotic cells with peculiar fragmented chromatin simulat- paan.1 Patients develop progressive pallor, fibrosis, and a marble-like rigid-
ing arrested mitoses involving the full thickness of the epithelium, while the ity of the tissues usually beginning in the soft palate and fauces, and then
surrounding epithelium exhibits varying degrees of epithelial dysplasia (Figs involving the buccal mucosa, lips, and tongue, not dissimilar to progressive
11.215, 11.216).43–46 Seventy percent of cases may be HPV positive by in situ systemic sclerosis. Palpable fibrous bands run vertically down the buccal
hybridization and most are positive for high-risk HPV-16/18.42 The authors of mucosa in advanced lesions and lead to reduction in mouth opening. Ulcers,
another series consider that the term bowenoid papulosis should not be used areas of erythema, and symptoms of burning are common.2 This is a prema-
if dysplasia is present, and recommend that the term ‘koilocytic dysplasia’ be lignant condition, as squamous cell carcinomas develop in a large number
used instead. In their series, 68% of cases were positive for HPV-16/18.45 of cases.3,4
Squamous cell carcinoma 425
Fig. 11.217
Fig. 11.216 Submucous fibrosis:
Koilocytic dysplasia: there is epithelial atrophy
nuclear fragmentation is and dense fibrosis that
a characteristic feature of surrounds skeletal muscle
this condition. fibers.
Pathogenesis and histological features Early ultrastructural studies showed abnormal collagen fibrils that were
fragmented, angulated, and degenerate.12 Other studies have shown the pres-
Arecoline (areca nut alkaloid) and areca nut flavonoids stimulate collagen
ence of type I and type III collagen in a normal distribution with normal fiber
synthesis and are carcinogenic. Increased collagen synthesis and reduced
morphology but with increased density.13 A further study has shown reduced
matrix degradation mediated through transforming growth factor-beta leads
amounts of type III procollagen and type VI collagen in fibrotic areas.14
to fibrosis and this condition may be considered a collagen metabolic dis-
ease.5,6 Destabilized chromosome loci and loss of heterozygosity at loci asso-
ciated with oral squamous cell carcinoma have been identified in almost half
of cases of submucous fibrosis in one study, as well as inhibition of p53 and The eosinophilic bands of collagen do not stain for amyloid. Smokeless tobacco
DNA repair and impairment of T-cell function.7–9 keratosis may exhibit similar eosinophilic bands of altered collagen but, in
The epithelium is hyperkeratotic and atrophic with loss of rete ridges. addition, there is surface coagulation and keratin chevrons, as well as epithe-
The subepithelial connective tissue first shows edema, vascular dilatation, lial hyperplasia rather than atrophy as is typically seen in submucous fibrosis.
and chronic inflammation. Progressive thickening of the collagen bundles Involvement of the oral mucosa by systemic sclerosis is an important differential
occurs with increasing degrees of hyalinization (Fig. 11.217). In severe diagnosis that can be excluded on clinical grounds and with serological tests.
cases, hyalinized bands of collagen are devoid of cells.2,10,11 Half of cases Lichen sclerosus is a rare oral condition. In addition to the hyalinized
may show a lichenoid pattern of inflammation.11 Epithelial dysplasia was eosinophilic subepithelial band, there is basal cell degeneration and a
noted in 8% of cases.11 lymphocytic band beneath the area of hyalinization.15–17
Malignant lesions
different etiology (sunlight) and its better prognosis. HPV is identified infre-
Squamous cell carcinoma quently in carcinomas of the oral cavity proper but is found in approximately
25% of squamous cell carcinomas of mucosa associated with the tonsils and
Clinical features Waldeyer's ring and carries a better prognosis; the vast majority are of HPV-
Squamous cell carcinoma is the most common malignancy in the oral cavity, 16 subtype.8,9
accounting for more than 90% of all oral cancers. In the USA, it constitutes The tumor may present initially as plaque lesions of leukoplakia,
approximately 3% of all malignancies and accounts for 20 000–25 000 cancer erythroplakia, and proliferative verrucous leukoplakia, or as nonheal-
cases diagnosed annually.1,2 The two most significant risk factors are cigarette ing ulcers, masses or nodules (Fig. 11.218). As with leukoplakia, the
smoking (by far the most important) and excessive alcohol consumption.3–5 In premalignant condition, the most common sites are tongue and floor of
Asian countries, tobacco use and areca nut chewing in its various forms are mouth.1,2 Patients are usually in the sixth decade of life or older, although
a major cause of oral cancer.5 Oral cancer is the most common form of can- more recent data reveal a rise in these tumors in younger patients, often
cer among men in India where such habits are prevalent;5 these tumors often unassociated with tobacco use. Up to 25% of patients present with syn-
develop within submucous fibrosis. Other risk factors include a history of a chronous or metachronous tumors of the upper aerodigestive or digestive
previous oral squamous carcinoma, history of cancer elsewhere in the body, tract.10 Overall 5-year survival is 58% with stage I and II tumors showing
history of immunosuppression, family history of cancer and age.6,7 Lip carci- 85% survival and stage III and IV tumors with distant metastases, 25%
noma is generally not included in the discussion on oral lesions because of its survival.1
Fig. 11.218
Squamous cell carcinoma: there is a fungating mass on the buccal mucosa.

Squamous cell carcinoma:
The development of oral squamous cell carcinoma is a multistep process invasive well-differentiated
involving allelic imbalance and loss of heterozygosity involving chromosomes tumor.
3p, 9p, and 17p especially, as well as 11q, 13q, and 17p; although these are
the most common, genetic aberrations involving practically every gene have
More recently, sentinel node biopsy in patients without clinical evidence
been identified.11,12 A history of tobacco and alcohol use is associated with a
of cervical metastases has disclosed metastatic disease in approximately
high frequency of p53 mutations.5 With molecular techniques, p53 overex-
25–50% of cases.23
pression has been found in histopathologically benign margins. Local recur-
An important variant is the papillary squamous cell carcinoma, which pre-
rence has been noted in 38% of patients with such p53-positive margins and
dominantly occurs on the alveolar ridge, buccal mucosa, larynx, pharynx, floor
metastatic nodal disease identified in 21% of clinically negative lymph nodes.
of mouth, and tongue. The literature regarding this entity is somewhat confus-
Diploid tumors are associated with lower incidences of recurrence and lymph
ing. There are two subtypes, both characterized by a papillary growth pattern:
node metastasis.13
Histologically, these tumors are similar to squamous cell carcinoma aris-
• One occurs in the larynx and upper respiratory tract and consists of an
invasive papillary proliferation of minimally to nonkeratinizing epithelium
ing at other sites (Fig 11.219). The overlying epithelium shows varying
with highly atypical epithelial cells and numerous mitoses overlying a
degrees of dysplasia. Tumor cells exhibit dyskeratosis and keratin pearl for-
fibrovascular core (Figs 11.220, 11.221).24–26 The in situ portion of
mation and vary in degree of pleomorphism and mitotic activity. The cells
the tumor resembles a squamous papilloma with carcinoma-in-situ.
are usually large with abundant eosinophilic cytoplasm, and intercellular
bridges are often readily identified. Tumors in the nasopharyngeal and ton-
sillar areas that are minimally keratinizing with basaloid morphology are
generally positive for high risk HPV and p16 is a reliable marker for that.8
The tumor may invade the stroma as large islands and fronds of epithe-
lium on a pushing front (bluntly invasive type), often connected to the sur-
face epithelium, or it may infiltrate the stroma as smaller irregular islands
and nests of tumor cells or as single cells. Keratin pearl formation associ-
ated with microabscesses at the tips of rete ridges are often seen in bluntly
invasive lesions. Immunolocalization of type IV collagen and laminin reveals
that basement membrane is generally preserved in bluntly invasive patterns of
growth and lost in infiltrative tumors.14 The infiltrative pattern is associated
with a significantly higher incidence of lymph node metastasis compared to
bluntly invasive tumors.15,16 Thicker tumors such as those 5 mm or greater are
more likely to metastasize; however, a figure as low as 1.5–2 mm is quoted for
lesions of the tongue and floor of the mouth, both being high-risk sites.17–21 A
recent tumor scoring system is based on seven parameters:22
• vascular invasion,
• tumor size,
• grade of differentiation,
• tumor thickness,
• degree of inflammation,
Fig. 11.220
• shape of invasion, Papillary squamous cell
• perineural spread. carcinoma: the papillary
This has shown good correlation for prediction of cervical lymph node projections of malignant
metastasis. Although tumors are often graded well, moderately, or poorly dif- epithelial cells are
ferentiated depending on the amount of keratin produced, the degree of kera- nonkeratinized and there
tinization is unlikely to be related to prognosis. is stromal invasion.
Sarcomatoid carcinoma 427
Fig. 11.221 Fig. 11.222 Fig. 11.223

Papillary squamous cell carcinoma: there is marked Papillary well-differentiated squamous cell carcinoma: Papillary well-differentiated squamous cell carcinoma:
pleomorphism and koilocyte-like cells. note the abundant keratin formation and papillary and the cells in this tumor are keratinizing.
crypt-like formations.
These tumors are HPV positive in approximately one-third of cases and the main body of the tumor.1 Tumor cells are seen to ‘drop off’ or stream
the presence of p53 correlates with poor survival.26 from the surface epithelium as spindled cells into the underlying stroma.
• In contrast, oral papillary squamous cell carcinomas are well keratinized The spindled cells may form streaming fascicles and storiform patterns, and
and generally well differentiated, although they usually show varying have a prominent myxoid stroma (reminiscent of granulation tissue) (Fig.
degrees of dysplasia in contrast to the bland histology typical of 11.224).1,2,5 The cells sometimes have bipolar processes or appear stellate-
verrucous carcinoma (see below) (Figs 11.222, 11.223).27 shaped and epithelioid; nuclei may be pleomorphic with prominent nucle-
Intraoral so-called keratoacanthomas are rare and may resemble verru- oli (Fig. 11.225). There are usually abundant mitoses, and pleomorphic
cous carcinoma.28,29 They typically have a crateriform architecture with the tumor giant cells as well as osteoclast-like giant cells are sometimes pres-
cup-shaped depression filled with keratin. Cells have ‘glassy’ cytoplasm and ent. Osteoid is present in 7% of cases and malignant cartilage has been
the underlying stroma is usually infiltrated by cells exhibiting cytological aty- reported.1,4,6
pia. Keratoacanthoma is best regarded (and treated) as a variant of well- Cytokeratins such as AE1/AE3 and CAM 5.2 are present in the spin-
differentiated squamous cell carcinoma. dled cells in 50–62% of cases; spindled cells may also coexpress vimentin
Sarcomatoid carcinoma
Clinical features
Sarcomatoid carcinoma (carcinosarcoma, sarcomatoid squamous carci-
noma, spindle cell carcinoma, metaplastic carcinoma) is a tumor of the sixth
to eighth decades with an equal sex distribution.1 The most common sites to
be affected are the lower lip, tongue, and alveolar ridge. A polypoid, exo-
phytic configuration is the most common presentation.1,2 A history of radia-
tion to the site has been noted in 13–67% of cases.1–3 Oral cavity tumors
tend to be deeply invasive and associated with low survival rates; polypoid
lesions may have a better prognosis.2,4
The tumor, which is typically ulcerated, is biphasic with a malignant epi-
thelial component (squamous cell carcinoma) usually present at the base or Fig. 11.224
peduncle of the polypoid lesions, and a malignant spindle cell component in Sarcomatoid carcinoma: note the streaming, fasciculated pattern.
Fig. 11.225 Fig. 11.226

Sarcomatoid carcinoma: note the large, pleomorphic spindled cells. Basaloid squamous cell carcinoma: there is comedo-necrosis and lobules of
malignant basaloid cells.
iffusely.4,7 Epithelial membrane antigen (EMA) is seen in less than 10% of

d
cases. S-100 protein and GFAP are typically negative.3,7
Ultrastructurally, desmosomes may be well or poorly developed and kera-
tin filaments are variably present. Dilated rough endoplasmic reticulum and
the presence of tropocollagen suggest secretory activity.3–5
Sarcomatoid carcinoma is the most common spindle cell malignancy in
the oral cavity.8 The diagnosis is not usually difficult when a spindle cell
malignancy is present in association with typical squamous cell carcinoma
although the latter may be only evident focally at the base of polypoid lesions.
Important differential diagnoses include nodular fasciitis, spindle cell mela-
noma, sarcoma, and malignant myoepithelioma. In difficult cases, immunep-
eroxidase studies will usually enable distinction.
Basaloid squamous cell carcinoma

Clinical features
Fig. 11.227
This is an aggressive variant of squamous cell carcinoma that primarily Basaloid squamous cell carcinoma: there are many mitotic figures and trabeculae of
affects men (M:F = 7:1) in the sixth and seventh decades with a predilec- hyalinized material.
tion for the tongue and floor of mouth; 60–80% develop local and/or distant
metastases.1–3
Histological features s ynaptophysin are absent.2,3 Approximately 50% of tumors are aneuploid
although this may not have prognostic significance.7,8 These tumors show
This unusual tumor is characterized by well to moderately differentiated marked proliferative activity (PCNA studies) and expression of p53 protein
squamous cell carcinoma coexisting with a malignant lobular proliferation and Bax.9,10,11
of basaloid cells. The tumor lobules often exhibit comedo-like necrosis and
microcystic spaces filled with PAS-positive material (Fig. 11.226). A cribri-
form pattern is evident and hyalinized material surrounding tumor islands Differential diagnosis
is an occasional feature; there may be peripheral palisading of tumor cells Nonkeratinizing HPV-associated squamous cell carcinoma of the oropharynx
(Fig. 11.227).1,4 True ductal differentiation or a focal spindle cell morphol- appears very similar but does not have an associated conventional squamous
ogy is sometimes seen.5 The basaloid cells have dark hyperchromatic nuclei cell carcinoma.12 Salivary gland carcinomas such as adenoid cystic carcinoma
and indistinct nucleoli. Mitoses are often abundant and perineural invasion and basal cell adenocarcinoma (uncommon in minor salivary glands) con-
is frequently conspicuous.3 tain basaloid cells but do not contain a recognizable conventional squamous
Recognizable squamous cell carcinoma must be identified to establish this cell carcinoma. Adenoid cystic carcinoma also exhibits diffuse cytoplasmic
diagnosis. Dysplasia of overlying epithelium is present in 85% of cases and vimentin expression, whereas in the basaloid squamous carcinoma it is peri-
transition between the squamous and basaloid patterns may be subtle or even nuclear when present. One study showed that basaloid cell carcinoma almost
absent.2,4 always stains for 34betaE12 keratin while small cell undifferentiated carci-
The cells express cytokeratin (in particular AE1/AE3, CAM 5.2, and nomas are negative.13 Merkel cell carcinoma has a trabecular or solid growth
34betaE12), EMA, and NSE (weakly). Carcinoembryonic antigen (CEA) pattern and is generally NSE positive. Keratin expression is characterized by
and S-100 protein are present in approximately 50% of cases.2 Others paranuclear punctate dots and the tumor cells contain typical neurosecre-
report vimentin in a perinuclear rim in the basaloid cells, the absence of NSE tory granules.14 Adenosquamous carcinoma has true ductlike structures and
and S-100 (and present only within dendritic cells).3,4,6 Chromogranin and produces epithelial mucin.
Verrucous carcinoma 429
One variant of this tumor is the pseudovascular adenoid squamous cell

Adenoid squamous cell carcinoma carcinoma that exhibits anastomosing pseudovascular spaces lined by epi-
thelioid cells, mimicking angiosarcoma.9 The lining cells exhibit cytokeratin
Clinical features staining and do not express vascular antigens.
In adenoid squamous cell carcinoma (acantholytic squamous cell carcinoma,
pseudoglandular squamous cell carcinoma, adenoacanthoma) the major- Differential diagnosis
ity of tumors present on the lower lip with a fivefold male predilection.1,2 These lesions must be differentiated from adenosquamous carcinoma in
Approximately 21% occur on the upper lip, an unusual site for conventional which true glandular differentiation occurs. See below.
usual squamous cell carcinoma.3 While lip lesions generally have a good prog-
nosis, intraoral tumors have a mortality of up to 75% for stage 4 lesions.2–4
Adenosquamous carcinoma
Clinical features
Conventional squamous cell carcinoma must be identified. Pseudoglandular
structures with central ‘lumina’ lined by two to three layers of atypi- Only a few cases have been reported in the oral cavity although the larynx
cal squamous epithelium are seen within the tumor islands (Fig 11.228). and paranasal sinuses are common sites for this tumor.1,2 It occurs in older
Typically, these contain rounded acantholytic tumor cells within the ‘lumina’ men with a predilection for the tongue and floor of mouth. At least half the
(Fig 11.229).1–5 In most lesions, the acantholysis appears to begin in the cases show metastasis to regional and distal sites.1,3,4
immediate suprabasal cells.6 In lip lesions, there is typically a background
of solar elastosis, and sometimes acantholytic solar keratosis is present,
supporting the association with sun damage.7 Clear cell change may also Two distinct components are present: there is a moderately to poorly differentiated
be seen.8 The epithelial cells stain for cytokeratins and EMA but not for squamous cell carcinoma, a mucin-secreting adenocarcinoma, and transitional
mucin.2,3,8 areas (Figs 11.230, 11.231). Mucin is present within lumina or intracellularly.1,3
Ductal carcinoma-in-situ may be present and the adenocarcinoma may show
tubular, alveolar, and ductal structures.1,5 High molecular weight keratins are
present in the squamous cell carcinoma component and low molecular weight
keratins in the adenocarcinoma.3 Carcinoembryonic antigen and CAM 5.2 are
often present in glandular areas but not in the squamous areas.6
High-grade mucoepidermoid carcinomas tend to have a prominent malig-
nant epidermoid component and inconspicuous cystic and mucous cell com-
ponent and may be mistaken for adenosquamous carcinoma. In general, the
malignant epidermoid component does not show the degree of pleomorphism,
atypia, and keratinization of a conventional squamous cell carcinoma.
Verrucous carcinoma
Clinical features
Verrucous carcinoma presents in older individuals (usually seventh decade)
with a predilection for the buccal mucosa and gingiva (more than 70% of cases)
and is strongly associated with the use of smokeless tobacco or cigarettes.1–4
Fig. 11.228 The tumors are white, fungating, cauliflower-like masses, generally several cen-
Acantholytic squamous cell carcinoma: note the pseudoglandular structures. timeters in size, and have usually been present for several years before patients
Fig. 11.230
Fig. 11.229 Adenosquamous carcinoma: low-power view of a poorly differentiated tumor with
Acantholytic squamous cell carcinoma: note the atypical acantholytic cells. intracytoplasmic lumina.
A B
Fig. 11.231
Adenosquamous carcinoma: (A) note the atypical squamous cells; (B) there are intracytoplasmic lumina resembling signet-ring cells.
are finally diagnosed (Fig. 11.232). There may be destruction of underlying

bone and other structures on a broad advancing front. Reactive lymphade-
nopathy is often present and nodal metastases are distinctly unusual except in
irradiated tumors.1,4 Between 17% and 20% of patients may have associated
leukoplakia (most likely verrucous leukoplakia or proliferative verrucous leu-
koplakia) and up to 38% have a second primary carcinoma.1,4
Verrucous carcinoma is characterized by marked hyperparakeratosis with
keratin plugs between papillary projections of benign-appearing epithelium.
The epithelium forms large, bulbous, frond-like rete ridges that are bluntly
invasive on a broad advancing front (Fig. 11.233). Although there may be
slight epithelial atypia, pleomorphism or anaplasia is lacking (Fig. 11.234).
Some of the rete ridges exhibit central degeneration and abscess formation.
Foreign body granulomas may develop secondary to keratin spillage.1,2,4
Lymph node dissection does not usually reveal metastatic disease.5
Foci of more typical infiltrative squamous cell carcinoma may be seen in
one-fifth of tumors, the so-called ‘hybrid tumor’. These foci may be respon-
sible for a higher recurrence rate (approximately 30%) and subsequent Fig. 11.233
anaplastic transformation, independent of radiation treatment.4 Strictly, Verrucous carcinoma: there is an endophytic proliferation of squamous epithelium
such tumors probably should be diagnosed as papillary well-differentiated with a broadly invasive front; note the normal gingival epithelium at the periphery.
squamous cell carcinoma rather than verrucous carcinoma.
Strict criteria must be adhered to for the diagnosis of verrucous carcinoma.
Papillary squamous cell carcinoma usually seen in the larynx, which is gen-
erally minimally if at all keratinized, is composed of convoluted ribbons of
highly atypical squamous cells, with dysplastic cells involving the full thickness
of the epithelium.6 These are distinct from the papillary well-differentiated
squamous cell carcinoma that resemble verrucous carcinoma but can be dis-
tinguished by the presence of significant atypia, pleomorphism, dyskeratosis,
keratin pearl formation, and infiltration of the stroma (even if the invasion is
of the ‘blunt’ type). Cases of verrucous carcinoma exhibiting perineural inva-
sion by ‘nests of well-differentiated squamous epithelium’ may also actually
represent papillary well-differentiated squamous cell carcinoma.7
Midline destructive disease

Clinical features
Midline destructive disease (also known as midline lethal granuloma, cen-
trofacial malignant granuloma, polymorphic reticulosis) presents with deep
Fig. 11.232 ulceration and necrosis of the midline of the face, nasal septum, and palate.
Verrucous carcinoma: there is a warty mass in the mandibular buccal mucosa and sulcus. Although once thought to represent a distinct entity, it is now recognized that
Amalgam tattoo 431
Fig. 11.234
A B Verrucous carcinoma (A, B): there is minimal cytological
atypia and no single cell infiltration.
the features may be caused by a wide range of conditions, including infections istiocytosis and angiocentric lymphoma) consist of small, cleaved, and large
h
(particularly deep fungal, treponemal, and mycobacterial), chronic cocaine atypical lymphocytes dispersed in a polymorphic infiltrate of neutrophils, reac-
use, Wegener's granulomatosis, malignancy and, in particular, NK/T-cell lym- tive lymphocytes, histiocytes, and plasma cells, and showing invasion of vessels
phoma of the sinonasal tract.1–4 T-cell lymphomas constitute 60% of all such with consequent necrosis.4–7 There is a strong association with Epstein-Barr
midline lesions.1 These lymphomas (also previously referred to as malignant virus and presentation in native South Americans and Asians.5,8,9
Pigmented lesions
Amalgam tattoo
Clinical features
These are asymptomatic gray, bluish, black or slate-colored macules that gen-
erally occur on the gingiva/alveolar ridge (approximately 50%), the buccal
mucosa (approximately 25%) or the floor of mouth (approximately 10%)
(Figs 11.235, 11.236). However, they can occur anywhere in the oral c avity
of adults.1

Particles of amalgam restorations may be traumatically implanted into the
mucosa by the dentist during placement or removal of a restoration, by
the patient from bite injury, from leakage and disintegration of a restora-
tion (or root canal filling material), from a restoration falling into a tooth
socket after extraction or after endodontics surgery and an amalgam retro-
fill. Dental amalgam is a mixture of mostly silver and tin and other metals in
smaller amounts, and mercury. The silver stains agryrophilic fibers within the Fig. 11.235
connective tissue. It is believed that metallothioneins (low molecular weight Amalgam tattoo: there are slate-gray macules on the left buccal mucosa
proteins that bind metals) are also present within tattoos and bind metals, corresponding to some large amalgam restorations.
preventing local and systemic toxicity.2
Amalgam in the tissues takes two main forms: as large dense dark-brown
to black fragments that are often macroscopic, and as fine golden- or dark- itself may sometimes be stained a golden color. In approximately 50% of
brown dusty granules (Fig. 11.237).1 The fine granules characteristically are cases, a lymphocytic and/or histiocytic and foreign body granulomatous reac-
dispersed along connective tissue fibers since the silver deposits on reticu- tion is seen around the larger particles, some of which are present within the
lin. They particularly outline the basement membrane of the epithelium and cytoplasm of macrophages and giant cells.1 Scarring is generally present, con-
blood vessels and stain nerve and muscle sheaths (Fig. 11.238). The collagen firming its traumatic etiology in many cases.
Ultrastructurally, the metal particles are located in the lamina densa of the
basal lamina beneath the epithelium and around blood vessels, and on elastic
fibers.3 They contain silver, copper, and other metals typical for amalgam.
Graphite (pencil lead) can present as clumps of black particles. These tend to
be coarse and they do not localize to the connective tissue fibers (Fig.11.239).
Aluminum and silicon (hardeners for graphite) may be identified using dis-
persive X-ray microanalysis.4
Silver tattoos of nonamalgam derivation have been reported in patients
following silver nitrate cautery.5
Oral melanocytic lesions

Four conditions are of particular importance: melanotic macule, melanoacan-
thosis, melanocytic nevus, and melanoma.
Oral melanotic macule

Fig. 11.236
Amalgam tattoo: there is a blue-black macule on the attached gingiva superior to a
semilunar scar; this tattoo is caused by a root canal-related surgical procedure. Clinical features
These are the most common melanocytic lesions in the oral cavity. Originally,
these were labeled ‘labial melanotic macule’ since most of them are found on
the lips (Fig. 11.240).1,2 However, subsequent reports identified similar-appearing
Fig. 11.237
Amalgam tattoo: there are coarse and fine granules of amalgam associated with
foreign body granulomata; there is also a golden stain to the collagen fibers. Fig. 11.239
Graphite tattoo: there are large deposits of black granular material.
Fig. 11.238 Fig. 11.240

Amalgam tattoo: note the typical staining of the vessel basement membrane. Oral melanotic macule: note the typical dark brown-to-black macule on the vermilion.
Oral melanocytic lesions 433
lesions intraorally (especially on the palate) and at other mucosal sites such as on
the genitalia. The preferred term for such oral lesions is ‘oral melanotic macule’.3
These are often solitary (two-thirds solitary, one-third multiple), well-
defined, brown-to-black macules measuring less than 1.5 cm and occurring
on the lips (usually lower), palate, gingiva or buccal mucosa in adults, with a
female predilection (2:1).1,4,5 The intensity of pigmentation is usually constant
unlike in ephelides, which tend to darken with sun exposure. The lesion has
often been present for months to years and 14–25% give a history of increase
in size.1,4,6 Biopsy is usually performed to exclude a melanoma. Oral melan-
otic macules tend not to recur except in those associated with HIV infection.7
This may because these particular lesions are medication-induced or repre-
sent post-inflammatory hyperpigmentation.

The melanocytes may be functionally hyperactive as suggested by melanin incon-
tinence and the presence of heavily melanized melanosomes seen ultrastructur-
ally although the cause for such activity is unclear.8 Since 14% of patients with
labial melanotic macules give a family history, there may be a genetic predisposi-
tion. Some melanotic macules may represent a drug-induced hypermelanosis, an Fig. 11.242
unusual distribution of physiologic/racial pigmentation, a manifestation of endo- Postinflammatory
hypermelanosis: there is
crine disorder, a postinflammatory hypermelanosis, or represent an idiopathic con-
increased melanization
dition. Oral melanotic macules are also associated with longitudinal pigmented
of the basal cells,
bands in the nails (melanonychia striata), pigmentation of the genitalia and other vascular ectasia, chronic
skin and mucosal sites in the Laugier-Hunziker syndrome.9,10 Correlation with inflammation, and many
clinical data is essential in helping to arrive at a definitive diagnosis. melanophages in the
The oral melanotic macule is characterized by increased melanin pigmen- lamina propria.
tation in the basal cell layer of the epithelium, usually localized to the tips
of the rete ridges with no or only minimal melanocytic hyperplasia (Fig.
11.241).1,3,8 One study, however, found that melanocytic hyperplasia is a a more intense lymphoplasmacytic infiltrate and vascular ectasia (Fig. 11.242).
constant feature.11 There are usually increased numbers of melanophages in These features are particularly prominent in resolving lesions, such as may be
the lamina propria that correlate with the degree of chronic inflammation seen in lichenoid mucositis and oral lichen planus, and in smokers.12
present. There may be associated mild hyperkeratosis and acanthosis. Ephelides occur on sun-exposed areas and the darkness of pigmentation
Ultrastructurally, stage III and stage IV heavily melanized melanosomes are increases with sun exposure. Lentigo shows epithelial and melanocytic hyper-
clustered in complexes within melanocytes, keratinocytes, and melanophages.8 plasia in addition to increased melanin pigmentation. Rare cases of oral len-
tigo simplex have been reported where epithelial and melanocytic hyperplasia
Differential diagnosis have been identified.13
Postinflammatory hypermelanosis exhibits increased melanin in the basal kera- Syndromes associated with melanotic macules such as Peutz-Jegher's
tinocytes without concentration at the rete ridges. In addition, there is melanin syndrome, Albright's disease, neurofibromatosis, and Laugier-Hunziker
deposition within the lamina propria, with increased numbers of melanophages, syndrome are differentiated primarily by clinical features since they are his-
tologically identical. Minocycline-induced pigmentation usually shows a
combination of melanin and iron deposits in the lamina propria.
Melanoacanthosis
Clinical features
Melanoacanthosis (oral melanoacanthoma, mucosal melanotic macule)
should not be confused with cutaneous melanoacanthoma. It occurs in young
black females (greater than 70%), and typically presents in areas that are
susceptible to trauma such as the buccal mucosa, lower lip, palate, and gin-
giva.1–4 The macules have a slightly rough surface and are brown, black or
bluish (Fig. 11.243). The lesion may be well or poorly demarcated. Most
lesions are solitary although rare cases are multifocal.5 A history of trauma is
present in only 50% of cases. Lesions may grow rapidly to several centimeters
in size. Complete resolution occurs within weeks to months.

It is likely that oral melanoacanthosis is a reactive lesion, most probably pre-
cipitated by trauma with subsequent inflammation resulting in stimulation of
dendritic melanocytes and transepithelial elimination of melanocytes.
There is slight parakeratosis and acanthosis; spongiosis is also usually evi-
Fig. 11.241
dent (Fig. 11.244). Numerous dendritic melanocytes and their melanin-laden
Oral melanotic macule:
there is increased
processes are found insinuating between keratinocytes throughout the full
melanization of the basal thickness of the epithelium (Fig. 11.245).1–6 Such transmigration of melano-
cells in the absence of cytes should not be overdiagnosed as melanoma since there is no cytologic
melanocytic hyperplasia or atypia. Melanophages, a mild lymphocytic infiltrate, and vascular ectasia
inflammation. may also be seen in the lamina propria. Sometimes the spongiosis may be so
Fig. 11.243
Melanoacanthosis: there is a blue-black macule on the buccal mucosa that enlarged
rapidly over a few weeks. Fig. 11.245
Melanoacanthosis: benign
dendritic melanocytes
are present throughout
epithelium.
most common (63–66%), followed by the blue nevus and compound nevus
(3–5%).1,3,4 Epithelial hyperplasia is seen in association with intramucosal
nevi in approximately 50% of cases, sometimes associated with benign len-
tiginous melanocytic hyperplasia. Approximately 13% may be histologically
nonpigmented. Nevus cells are also sometimes seen within the underlying adi-
pose tissue and muscle.1 The spindled cells of blue nevi are usually separated
from the overlying epithelium by a Grenz zone. Intramucosal and oral blue
nevi stain for S-100 protein and HMB-45.5
Combined nevi (blue and intramucosal) have been reported.3 Spitz and
congenital nevi have also been described, albeit rarely.6,7
Oral melanoma
Fig. 11.244
Melanoacanthosis: there is parakeratosis, acanthosis, and spongiosis. Clinical features
Primary oral melanomas comprise up to 20–40% of mucosal head and neck
severe as to form spongiform vesicles. Stains for melanocytes such as S-100,
7 melanomas.1–3 It is particularly common in the Japanese.4 Tumors are most
Melan-A, and HMB-45 are positive.3,8 often seen in older adults, with an equal sex distribution. The hard palate
mucosa and maxillary gingiva are affected in more than 70% of cases. The
Differential diagnosis lesions are usually pigmented and macular and, less commonly, nodular with
surrounding macular melanosis.2,4–6 Between 20% and 40% of patients pres-
Melanoacanthosis differs from a nevus by the absence of any junctional activity.
ent with lymph node metastases.1–3
The benign cytology readily distinguishes this lesion from oral melanoma.
Overall, the prognosis for oral tumors is much worse than for cutane-
ous melanoma, the 5-year survival rate being varying from 8% to 10%,1,2
Oral melanocytic nevus although rates of 40% have been reported.3,7 A high rate of nodal metastasis,
thick tumor at presentation, extensive tumor spread, and the complicated
Clinical features anatomy of the maxillary complex make it difficult to completely excise the
Oral melanocytic nevi are generally diagnosed and biopsied in the third and majority of these lesions.
fourth decades of life, with a female predilection (2:1). Approximately 85%
are clinically pigmented (gray, brown, blue or black, or a combination thereof) Histological features
and almost all are raised, being nodular or papular lesions.1,2 The hard pal- Most oral melanomas arise from pre-existing intraepithelial melanocytic dys-
ate and buccal mucosa are the favored sites, followed by the labial mucosa, plasia that is either lentiginous or pagetoid, similar to cases of acral lentiginous
gingiva, and vermilion. Seventy-five percent of all intraoral blue nevi occur as melanoma.8 Invasive tumors consist of malignant epithelioid and spindled mela-
macules on the palate followed by the labial mucosa, whereas intramucosal noma cells, which are only rarely amelanotic. High clinical stage, tumor thick-
banal nevi occur on the palate and buccal mucosa equally.3 ness greater than 5 mm, presence of vascular invasion, absence of melanin in
histological sections and the development of nodal and distant metastases pre-
Histological features dict a worse prognosis.3,9 Furthermore, survival of patients with stage I disease
Melanocytic nevi in the oral cavity are histologically identical to those found correlates with depth of invasion, as would be expected.9 Desmoplastic mela-
on the skin. The intramucosal nevus (counterpart of the dermal nevus) is the noma has been reported in the oral cavity;10,11 cartilaginous metaplasia has been
Granular cell tumor 435
reported (metaplastic melanoma).12 Results of immunohistochemistry studies Pathogenesis and histopathological features
are identical to those for cutaneous melanomas.
The metabolites of these medications are either themselves pigmented or chelate
One other intraoral tumor that presents with melanotic pigmentation
to hemosiderin and melanin to form these discernible granules of pigment.
is the melanotic neuroectodermal tumor of infancy. This occurs as an
There is deposition of small, 1–3 micron, brown spherical granules in the
intraosseous lesion that usually breaks through the cortical bone into the
superficial lamina propria that are disposed often in a linear fashion along
soft tissues.13
connective tissue fibers. Some granules are present within macrophages.
Importantly, there is usually no increased melanin deposition within the
Medication-induced oral pigmentation basal keratinocytes. However, the granules often stain for melanin (Fantama
Massan) and iron (Prussian blue).
Clinical features
These present as slate-blue macular pigmentation usually of the hard palate Differential diagnosis
and gingiva. The cutaneous tissues may or may not be involved. The medica- Many medication-induced hyperpigmentary states are not caused by metabo-
tions involved include minocycline, antimalarial agents, clofazamine, birth lites of the medication, but rather represent postinflammatory hypermelani-
control medications, amiodarone, and drugs that contain heavy metals.1–6 nosis. This is particularly common if the medications cause a lichenoid or
Tetracycline becomes incorporated into hydroxyapatite crystals of bone and interface stomatitis. In such cases, the lesions almost always show increased
teeth. It is common for the pigmented bone to show through the mucosa as melanin pigment within the basal keratinocytes (even if a lymphocytic band
grey macular areas.7 Extracted teeth also have a grayish-green cast. at the interface is not present), and the stain for iron will be negative.
Other tumors
The overlying epithelium exhibits pseudoepitheliomatous hyperplasia in
Granular cell tumor one-third to two-thirds of cases, which in some tumors is so marked as to
result in a misdiagnosis of invasive squamous cell carcinoma.3,4,6,7 The tumor
Clinical features is unencapsulated and presents as nests, cords, and sheets of granular cells
The granular cell tumor presents at a variety of sites, most commonly the that commonly abut the epithelium, often but not invariably filling the entire
skin (38% of cases), the tongue (23–28%), the breast (16%), and the larynx, lamina propria and infiltrating into the underlying muscle (Fig. 11.247).4
especially the true cord (8%).1–3 Females are affected twice as often as males There is usually close association between the tumor cells and skeletal muscle,
and the mean age at presentation is in the fourth decade. However, cases have nerves, and blood vessels.4,7,8 Cells are large and polygonal with either distinct
also been reported in the first two decades of life.4 In the mouth, the major- or indistinct cell borders and a small nucleus (Fig. 11.248).4 The cytoplasm
ity of cases (> 80%) occur in the tongue, with the lips, buccal mucosa, and contains granules that are PAS positive and diastase resistant, although this is
floor of mouth being other sites of involvement.5 Approximately 8% of cases far from an invariable finding and is of limited diagnostic value.
are multiple.1 The lesions are yellowish-white, firm and indurated, painless S-100 protein is invariably positive and immunohistochemistry for muscle
masses or plaques generally measuring less than 2 cm in greatest dimension and histiocytic markers is consistently negative.7–9 Stains for CD68 and PGP
(Fig. 11.246). There is little tendency to recur even after incomplete excision. 9.5 are often positive.10–13

Although many theories of histogenesis have been proposed over the years,
including myoblastic, neural, fibroblastic, and undifferentiated mesenchymal
cells, the consistent staining of the tumor cells with S-100 protein supports
schwannian differentiation with degenerative changes.6,7
Fig. 11.247
Granular cell tumor:
granular cells fill the
lamina propria and
insinuate between the
Fig. 11.246 muscle fibers of the
Granular cell tumor: note the yellowish deep mass in the tongue. tongue.
Fig. 11.248
Granular cell tumor: the cells are polyhedral with pale granular cytoplasm and small
nuclei. Fig. 11.249
Ectomesenchymal
chondromyxoid tumor of
the tongue: the tumor is
discrete and myxoid, with
Ultrastructurally, the granular cells contain autophagic granules and vesic- many cleft-like spaces.
ular bodies.14 Membrane-bound angulate bodies represent angular lysosomes.
A basal lamina is sometimes seen around the cells, supporting a schwannian
derivation.
Malignant granular cell tumors are rare and exhibit pleomorphism, mito-
ses, necrosis, and spindling of cells with a similar staining pattern. They may
metastasize.15,16
There is a variant of the granular cell tumor that does not stain with S-100
protein – the ‘primitive polypoid granular cell tumor’. This lesion is poly-
poid with an epithelial collarette, and the granular cells exhibit slight nuclear
atypia.17–19 The congenital granular cell tumor is also S-100 negative and has
a delicate arborizing vasculature. Granular cell change may also be observed
focally in many other tumors.18
Ectomesenchymal chondromyxoid tumor

Clinical features
Fig. 11.250
This unusual nodular tumor of the anterior tongue dorsum occurs in the third Ectomesenchymal chondromyxoid tumor of the tongue: note the epitheloid cells and
to sixth decades of life.1,2 trapping of muscle fibers.
The tumor is a well circumscribed but unencapsulated, lobular proliferation
Ultrastructurally, basal lamina is focally present, but desmosomes and
of tumor cells in the superficial tongue musculature, arranged in sheets,
dense bodies are absent.1
strands, and cords in a chondromyxoid stroma with cleft-like spaces
It is likely that this tumor arises from a pluripotential mesenchymal cell.
(Fig. 11.249).1–3 Cells are polygonal, ovoid, and fusiform with small nuclei
and faintly basophilic cytoplasm. There may be focal nuclear hyperchroma-
tism and bi- or multinucleation. The myxoid nature of the stroma often gives Differential diagnosis
the tumor a reticular appearance and pseudocyst formation is seen in 50% Myoepitheliomas may resemble this tumor because of a similar cytomorphol-
of cases (Fig. 11.250). Muscle fibers are often trapped at the periphery of ogy and immunohistochemistry. The chondromyxoid matrix is also shared by
the tumor.4 both. The distinction can be readily made, however, by the absence of duc-
The tumor cells stain for vimentin, GFAP, and S-100 protein, and often tal differentiation and plasmacytoid cells. In addition, myoepithelioma typi-
cytokeratin.1–3 Staining for CD57, smooth muscle actin, and Leu-7 is variable. cally arises in close proximity to a salivary gland and does not extend into
Tumors are negative for desmin and EMA 1,2 Stains typical for myoepithelial or entrap adjacent skeletal muscle. While the tumor stains for glial fibrillary
cells such as calponin, smooth muscle myosin, and p63 have been reported acidic protein and S-100 protein, it does not stain for other markers of myo-
as negative.5 epithelial cells.
Chapter
See
for references and
additional material
Diseases of the anogenital skin
Eduardo Calonje, Sallie Neill, Chris Bunker,
Nick Francis, Alcides Chaux and Antonio C Cubilla
12
Introduction 438 Penile necrosis 459 Penile horn 489
Spontaneous scrotal ulceration 460 Pseudoepitheliomatous, keratotic and
Normal female anatomy 438 Scrotal fat necrosis 460 micaceous balanitis 489
Labia majora and perianal skin 438
Labia minora and clitoral prepuce 439 Associations with systemic disease 460 Genital intraepithelial neoplasia, and
Glans clitoris 439 Crohn’s disease 460 squamous cell carcinoma 490
Vestibule 439 Acute hemorrhagic edema of Squamous cell carcinoma of the genital
childhood 461 epithelia 492
Normal male anatomy 439 Necrotising vasculitis 461 Verrucous carcinoma 493
Embryology 440 Penile squamous cell carcinoma 494
Infectious diseases 461
Invasive squamous cell carcinoma 498
Pubic hair 441 Erythrasma 461
Usual squamous cell carcinoma 498
Tinea 461
Anogenital ‘sweat’ glands 441 Subtypes of squamous cell carcinoma 499
Trichosporosis 463
Normal variants 443 Condyloma acuminatum 463 Cloacogenic carcinoma 509
Pigmentation 443 Syphilis 465
Adnexal tumors 510
Circumcision 443 Granuloma inguinale 472
Papillary hidradenoma (mammary-like
Acrochordons 443 Chancroid 474
gland adenoma of the vulva) 510
Pearly penile papules 443 Lymphogranuloma venereum 475
Benign tumors of Bartholin’s gland 511
Vestibular papillomatosis 443 Schistosomiasis 476
Adenoma of minor vestibular glands 512
Sebaceous gland hyperplasia 443 Amebiasis cutis 478
Bartholin’s gland carcinoma 512
Demodecidosis 478
Inflammatory dermatoses 444 Malacoplakia 479 Basal cell carcinoma 512
Intertrigo and balanoposthitis 444 Fournier’s gangrene 479
Non-specific balanoposthitis 444 Metastatic tumors 513
Eczema 445 Miscellaneous conditions 479
Vulvodynia 479
Lymphoma and leukemia 513
Infantile gluteal granuloma 445
Lichen simplex chronicus 445 Idiopathic calcinosis 480 Juvenile xanthogranuloma 513
Seborrheic dermatitis 445 Dermatitis artefacta 480
Sclerosing lipogranuloma 480 Langerhans cell histiocytosis 513
Psoriasis 446
Reiter's syndrome 446 Pilonidal sinus 480 Soft tissue tumors 513
Genital lichen planus 449 Pigmented lesions 481 Keloid 513
Lichen nitidus 452 Genital melanosis 481 Fibroepithelial stromal polyp 513
Lichen sclerosus 452 Genital melanocytic nevi 482 Lymphedematous fibroepithelial
Zoon’s balanitis 456 Melanoma 484 polyp of the glans penis
Zoon’s vulvitis 457 and prepuce 514
Granuloma annulare 457 Epithelial lesions 486 Prepubertal vulval fibroma 515
Vesiculobullous conditions 457 Benign mucinous metaplasia and mucinous Angiomyofibroblastoma 515
Genital papular acantholytic syringometaplasia 486 Aggressive angiomyxoma 516
dyskeratosis 457 Endometriosis and endosalpingiosis 486 Cellular angiofibroma 516
Penile acne 457 Median raphe cyst 486 Genital leiomyoma 517
Hidradenitis suppurative 458 Bartholin duct cyst 487 Leiomyosarcoma 518
Aphthe 459 Mucinous cyst 487 Vulvar leiomyomatosis 518
Lipschutz ulcer 459 Mesonephric cyst 488 Myointimoma 518
Sclerosing lymphangitis of the penis 459 Mesothelial cyst 488 Postoperative spindle-cell nodule 519
Pyoderma gangrenosum 459 Periurethral cyst 488
438 Diseases of the anogenital skin
Introduction 4
1
This section concerns itself principally with dermatological disorders specific
to the anogenital skin. Conditions that are properly the preserve of the
gynecologist (or urologist) are not discussed. 5
Many of the dermatological conditions that present in the skin 2
elsewhere sometimes affect the anogenital area although this site may
be one of predilection. Clinical and histological features can be modified
by the chronicity of the problem and the occlusive effect of this natural
6
flexural site.
Over the years, various unsatisfactory classifications have been devised
for vulval disorders.1 Terms such as squamous cell hyperplasia are clinically 3
meaningless and at best histologically descriptive. There is probably no need
1. Glans clitoris
for a separate classification for cutaneous disorders that affect the vulval
2. Labium majus
skin and mucosa. The terminology for vulval intraepithelial neoplasia (VIN) 3. Posterior labial commissure
and penile intraepithelial neoplasia (PIN) are discussed later. Extramammary 4. Prepuce of clitoris Fig. 12.1
Paget’s disease and in situ melanoma are no longer included in the spectrum 5. Labium minus Normal vulva showing the
of VIN. 6. External orifice of urethra major anatomical landmarks.
The anogenital area is covered by both skin and mucous membrane, i.e.,
keratinized and nonkeratinized stratified squamous epithelium. The transi-
tion from skin to mucosa is characterized by a subtle modification in the Labia majora and perianal skin
properties of the epithelia at their junctions. It is therefore critically impor-
tant that the site sampled for histological analysis always be specified so as to Histological features
avoid confusion and misinterpretation. These sites most closely resemble skin from other regions of the body since the
epithelium is keratinized and stratified and adnexal structures are represented.
The epithelium of the labia majora normally contains occasional lymphocytes,
which are found in very small numbers around the superficial dermal vascula-
Normal female anatomy ture. In the labia majora, sebaceous glands are present in association with hair
The vulva comprises the mons pubis, the labia majora and minora, the vesti- follicles and both eccrine and apocrine glands are typically present. On the
bule, the clitoris (including the prepuce and frenulum), the glands of Bartholin medial aspect of the labia majora the hair follicles become modified and there
and Skene, the hymen, posterior commissure, fossa navicularis, introitus and is often no hair seen although sebaceous glands are still present (Fig. 12.2).
the external urethral orifice (Fig. 12.1). Some may open directly onto the epithelium (Fordyce spots, see below). In the
deep dermis, a layer of smooth muscle known as the tunica dartos labialis is
seen. The subcutaneous tissue of the labia majora tends to be prominent in
Histological features women of reproductive age but decreases in amount after the menopause. The
The anogenital region, as with other mucocutaneous sites, is characterized by labia majus contains a long smooth muscle called the cremaster. The skin of
a gradual transition from skin to a mucosal surface. the perianal area shows numerous terminal hairs with sebaceous glands.
Fig. 12.2
(A, B) Normal vulva: medial aspect of labium majus. The
A B epidermis is keratinized. The dermis is richly vascular. Hair
follicles are absent.
Normal male anatomy 439
Labia minora and clitoral prepuce that the penile urethra does possess a true mucosa, while the glans of the
circumcised male does not; the glans and inner prepuce of the uncircumcised
male probably does not display mucosa but the outer prepuce does. There are
Histological features several epithelial transition zones.7 The proximal (pre-prostatic and prostatic)
The labia minora represent the female equivalent of the penile corpus urethra is lined by transitional epithelium, the membranous spongy penile
spongiosum. They are located lateral to the vaginal vestibule, medial to urethra by pseudostratified columnar epithelium. The distal penile urethra is
the labia majora and are covered by stratified, often pigmented, squamous lined by stratified or pseudo-stratified squamous epithelium incorporating a
epithelium. In most females, adnexal structures are absent, as is subcutaneous single layer of columnar cells at the surface and contains Littre’s glands, the
tissue. The stroma is richly vascular and contains abundant erectile tissue and distal 5–6 mm of penile urethra, which includes the navicular fossa manifests a
elastic fibers. 6–10 cell layer of nonkeratinizing squamous epithelium, contains no adnexae
The pilosebaceous unit is incomplete, as the sebaceous gland is not usually and is continuous with the epithelium of the uncircumcised glans (which may
associated with a hair follicle and opens directly onto the surface. Sweat show some thin keratinization, although some accounts state that the glans
glands are sparse and subcutaneous fat is not seen. is not keratinized in the uncircumcised) and inner preputial epithelium; the
outer preputial epithelium is identical to skin.7 Just as there is wide variability
in the size and shape of the navicular fossa, the site of the epithelial transition
Glans clitoris zones and probably the degree of keratinization of the glans and the dispo-
sition of adnexa may vary. Presumed multipotential, mucous secreting cells
Histological features have been described in the perimeatal epithelium8 and mucinous metaplasia
The epithelium is stratified and keratinized. No adnexal structures are of glans and foreskin have also been observed.9,10 Also, the final transition
present. The glans clitoris, unlike its male counterpart, does not contain will depend on the length of the foreskin: it is our experience that male genital
a corpus spongiosum. The frenulum and the prepuce originate from lichen sclerosus has a greater predilection for the male with a longer foreskin
the labia minora and contain abundant sebaceous and mucus-secreting (as does penile cancer11). The wide spectrum of differentiation of the male
glands. urogenital tract is accompanied by changes in the expression of epithelial
cytokeratins, but this is relatively unexplored territory.12 Normal regional
histology is illustrated in Figures 12.4–12.9.
Vestibule
The epithelium is stratified and nonkeratinized, i.e., it is a mucosa (Fig. 12.3).
Both the vagina and the urethra open into the vestibule. Bartholin’s glands
are located deep to the posterior part of the labia majora. They represent the
equivalent of Cowper’s glands or the bulbourethral glands in the male. The
ducts of Bartholin and Skene’s glands and the minor vestibular glands open
into the vestibule
Normal male anatomy

The penis, as well as being essential for sexual intercourse, is also the conduit
for urinary excretion. The scrotum is an extracorporeal sac which contains
the testes at an ideal ambient temperature for spermatogenesis. The natal cleft
and the inguinal (crural) folds are special sites of importance because they are
areas where two layers of skin come into close apposition. They constitute the
flexural junctions between the lower limbs and the trunk and also surround
A
the mucocutaneous junctions of the anus and genitalia. The perineum lies
between the anus and the scrotum and the skin at this site is tightly tethered
to the underlying tissues.
The prepuce has been present in primates for at least 65 million years and
indeed this may be an underestimate, 100 million years having been suggested.
The female counterpart is the clitoral hood. Only 4% of boys have a retractable
foreskin at birth, 15% at six months, 50% at 1 year and 80–90% at 3 years.1
The separation of the mucosa of the prepuce and glans is usually complete by
17 years.2–4 The prepuce is composed of specialized protective and erogenous
tissue. The protection it affords is both physical and immunological.4 Its
structures (e.g., the penile dartos muscle and the corpuscular receptor-rich
ridged band) and secretions are held to be important for normal function. The
foreskin is of variable length and retractability in uncircumcised men.
The anatomical position, when one considers the features of the normal
penis, is that of full penile erection. Thus the dorsal aspect of the penis is the
surface that is in direct contiguity with the abdomen, being the ventral sur-
face of the body.
B
The pattern of keratinization of the epithelium varies throughout the anogen- Fig. 12.3
ital area most markedly in the transition from true urothelium to true skin. Vestibule: (A) the epithelium is nonkeratinizing and rich in glycogen. Cutaneous
There is controversy over the definition of ‘mucosa’ 5,6 but there is no doubt appendages are absent at this site; (B) the epithelium is strongly PAS positive.
F
CC
CC
F
CS
S
Fig. 12.6
Normal histology of the penis, balanopreputial sulcus. Histologic components of
Fig. 12.4 both glans and penile body are present. This specimen from a circumcised person
Penis: This transverse section of the human penis shows the arrangement of the shows the mucosa at top, lamina propria below, then dartos, or smooth muscle
erectile tissues, which exist in the form of three columns. The two dorsal columns layer and Buck’s fascia. H&E. Courtesy of and reproduced with permission from
are called the corpora cavernosa CC and the single ventral column is the corpus Sternberg, SS, ed. Histology for Pathologists, 2nd edition. Philadelphia: Lippincott,
spongiosum CS, through which runs the penile urethra U. At its distal end, the Williams and Wilkins, 1997.
corpus spongiosum expands to form the glans penis. The erectile corpora are
enclosed within, and separated by, a fibrocollagenous capsule F. The erectile
centre of the penis is enclosed in a sheath of skin S to which it is connected by a
loose subcutis containing prominent blood vessels. Reproduced with permission
from Young B. et al., Wheater’s Functional Histology, 5th edition. © Churchill
Livingstone, 2006.
Fig. 12.5
Normal histology of the
penis. Foreskin. Full
thickness of prepuce
shows all five layers:
keratinized stratified
squamous epithelium, Fig. 12.7
dermis with sebaceous Normal histology of the penis. Glans penis. The three layers of glans are noted:
glands, dartos, submucosa nonkeratinized stratified mucosa, lamina propria and corpus spongiosum. H&E.
and squamous mucosa. Reproduced with permission from Sternberg, SS, ed. Histology for Pathologists,
H&E. Courtesy of 2nd edition. Philadelphia: Lippincott, Williams and Wilkins, 1997.
and reproduced with
permission from
Sternberg, SS, ed.
Histology for Pathologists, and cranially and form the genital tubercle. Posteriorly and caudally, they
2nd edition. Philadelphia: are partially joined to form an annulus. The underlying cloacal membrane is
Lippincott, Williams and now subdivided into urogenital and anal membranes craniocaudally by about
Wilkins, 1997. 6 weeks. During the same period, lateral genital swellings develop that will
form either the scrotum or labia majora.
From this point differentiation of the external genitalia occurs in a
Embryology gender-specific manner, driven in the male by fetal testicular androgens. The
genital tubercle lengthens, creating a urethral groove. This eventually becomes
The anatomical position, the arrangement of all of the structures in the area, the urethral canal when the folds fuse at about 12 weeks. The penile urethra
the normal histology and some of the histopathology are explained by the has an epithelium derived therefore from endoderm. It is incomplete cranially
embryology (Figs 12.10, 12.11).1,2 Around the third week of fetal develop- where the glans has developed from the genital tubercle. The glandular urethra,
ment, mesenchymal cells derived from the primitive streak form ridges of tis- the navicular fossa and the meatus are derived from an invading cord of ecto-
sue around the cloacal membrane. These cloacal folds are joined anteriorly derm that eventually becomes canalized. There is wide variability in the size
Anogenital ‘sweat’ glands 441
Allantois Allantois
Future
bladder
Definitive
urogenital
sinus
Cloaca Rectum Future

pelvic urethra
Fig. 12.10
Fig. 12.8 Development of the primitive urogenital sinus. Between 4 and 6 weeks, the
Anal transitional zone (ATZ). Transition from ATZ epithelium (left) to squamous zone
urorectal septum splits the cloaca into an anterior primitive urogenital sinus and
(right). H&E. Reproduced with permission from Sternberg, SS, ed. Histology for
a posterior rectum. The superior part of the primitive urogenital sinus, continuous
Pathologists, 2nd edition. Philadelphia: Lippincott, Williams and Wilkins, 1997.
with the allantois, forms the bladder. The constricted pelvic urethra at the base of
the future bladder forms the membranous urethra in females and the membranous
and prostatic urethra in males. The distal expansion of the primitive urogenital
sinus, the definitive urogenital sinus, forms the vestibule of the vagina in females
and the penile urethra in males. From Bunker C: Male Genital Skin Disease.
Saunders Ltd./Elsevier 2004.
squamous mucosal epithelium, lamina propria, dartos muscle, dermis and

glabrous skin (outer). The preputial fold progressively extends but there is
also an ingrowth of a cellular lamella. It then fuses with the mucosa of the
glans. At birth, the prepuce is still developing histologically and it is usually
incompletely separated from the glans.
Pubic hair
Pubic hair appears during puberty as vellus hair that is focally replaced by
terminal hair. Men have a different pattern of pubic hair than women but
in practice it is one of degree. The distribution of hair and pubic hair varies
widely between men.1 Generally, the abdominal wall, pubic mound, groins,
Fig. 12.9 scrotum and perineum are hairy but the natal cleft, perianal skin, distal penile
Perianal skin. Keratinized shaft, prepuce and glans are hairless.
squamous epithelium and
an underlying apocrine
gland. H&E. Reproduced Anogenital ‘sweat’ glands
with permission from
Sternberg, SS, ed. The anogenital area posseses numerous eccrine and apocrine (some function-
Histology for Pathologists, less) sweat glands. Also plentiful are (holocrine) sebaceous glands, usually
2nd edition. Philadelphia: in association with hair follicles (pilosebaceous units), but also occurring as
Lippincott, Williams and free glands at some sites such as the anal rim or around the coronal sulcus
Wilkins, 1997. (Tyson’s glands). Their secretions lubricate the hinge between limb and torso,
hair, mucocutaneous junctions to assist in the voiding of excreta and protect
the epithelia from irritation and the penis for sexual activity (the retraction
and shape of the navicular fossa in men, testifying to the variable conse- of the foreskin).
quences of this embryological process. The scrotal swellings fuse posteriorly Anogenital ‘sweat’ glands, which were first described by Van der Putte,
at about 14 weeks. They are not occupied by the testes until about the time are found in anogenital skin, mainly in the interlabial sulci.1,2 They share
of birth. The cloacal membrane is where ectodermal and endodermal tissues morphological and histological features of eccrine, apocrine and mammary
are in direct apposition caudally. The separation into urogenital membrane glands, making categorization difficult (Fig. 12.12). Superficially, an excre-
and anal membrane with the formation of the perineum at about 7 weeks is tory duct opens directly onto the skin. A deeper coiled or a long straight
due to the separation of the cloacal portion of the hindgut by the urorectal duct gives rise to several sac-like invaginations forming small glands, which
septum growing caudally between the allantois anteriorly and the hindgut typically extend deeper than the apocrine or eccrine glands. The anogenital
and partitioning the cloaca into the urogenital sinus anteriorly and the ano- sweat glands are lined by simple columnar epithelium surrounded by a layer
rectal canal posteriorly. The anal membrane disintegrates at about 9 weeks to of myoepithelial cells (Fig. 12.12). It has been suggested that adnexal tumors
open into an ectodermal anal pit formed in the posterior cloacal (anal) folds. arising in the genital skin derive from or show differentiation towards the
The prepuce 3,4 is formed by a midline collision of ectoderm, neuroectoderm anogenital glands and, in a number of cases, lesions are very similar to tumors
and mesenchyme, resulting in a pentalaminar structure consisting of (inner) occurring in the breast.3,4
Genital
tubercle
Urogenital Urogenital
fold Urogenital membrane
Cloacal membrane
fold Labioscrotal breaks
Cloacal swelling down
membrane Anal Perineum
membrane Anal fold
A 6th week Early 7th week 7th week
6th to 7th week 14th week
Endoderm
Urethral Urethral Urethral Penile

groove plate fold urethra
3rd month
Fig. 12.11
Formation of the external genitalia in males and females. (A) The external genitalia form
a pair of labioscrotal folds, a pair of urogenital folds and an anterior genital tubercle. Male
and female genitalia are morphologically indistinguishable at this stage. (B) In males, the
urogenital folds fuse and the genital tubercle elongates to form the shaft and glans of the
penis. Fusion of the urogenital folds encloses the definite urogenital sinus to form most
of the penile urethra. A small region of the distal urethra is formed by the invagination
Epithelial of ectoderms covering the glans. The labioscrotal folds give rise to the scrotum. From
B invagination Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
A B
Fig. 12.12
Anogenital mammary-like glands. (A) Medium-power view showing glands with focal cystic dilatation; (B) high-power view showing a double layered cell wall. Focally, there
is a suggestion of apocrine differentiation. By courtesy of D Kazakov, Charles University Medical Faculty Hospital, Pilsen, Czech Republic.
Normal Variants 443
Normal Variants
Pigmentation
The commonest variation is constitutive pigmentation due to race.
Sun-induced facultative pigmentation is rarely relevant in the genital area, but
postinflammatory hyperpigmentation is common. Linear hyperpigmentation
of the ventral penile shaft, along the median raphe, is often seen.
Circumcision
The commonest variation is the presence or absence of the foreskin.
Circumcision is the oldest elective operation, with evidence of its prac-
tice in Ancient Egypt between 2400 and 3000 bc.1 The operation has been
performed for religious, cultural or medical reasons throughout history.2 It
has been estimated that globally 25% of men have been circumcised.3 The
prevalence of circumcision in any population reflects racial, religious, cultural
and medical differences. The risks and benefits of neonatal circumcision have
been the focus of much debate.4–6 Importantly, circumcision protects men from Fig. 12.13
cancer of the penis, urinary tract and sexually transmitted infections includ- Pearly penile papules. Glans penis, coronal rim. From Bunker C: Male Genital Skin
ing HIV and genital dermatoses.7 However, the incidence of penile cancer is Disease. Saunders Ltd./Elsevier 2004.
low in Japan and Denmark where circumcision is rare,8 and therefore other
factors are important in its pathogenesis .
Circumcision is indispensible in the management of diseases of the penis
Vestibular papillomatosis
and foreskin, including dermatological conditions, and is being investigated
for the control of HIV infection. Although the long-held consensus is that Clinical features
there is little evidence of significant adverse effects on health, including Vestibular papillomatosis is not due to human papillomavirus infection and
psychosexual function, circumcision does have side effects and complications is a common finding of no significance.1,2 It is asymptomatic and is the female
including bleeding, postoperative and other infections, adhesions, fistulae and equivalent of penile pearly papules (hirsutoid papillomas). Individual lesions
keloid.5 are dome shaped or filiform and arise on a solitary base. They are found on
the inner aspect of the labia minora and vestibule (Fig. 12.14).
Acrochordons Histological features
There is a normal or thickened epidermis overlying a central fibrovascular core.
Clinical features
Skin tags (acrochordons) are common in the groins, especially in the obese.
They may catch on clothing, bleed and get infected. Fibrosed hemorrhoids
Sebaceous gland hyperplasia
can result in perianal skin tags, but larger, fleshier, more edematous skin
tags should arouse the suspicion of Crohn’s disease: they can predate
Clinical features
gastrointestinal disease by several years.1 These lesions are particularly The sebaceous glands of the inner labia majora, the labia minora and clito-
relevant in young patients with diarrhea, abdominal pain and/or growth ral prepuce do not usually have an associated hair follicle. The glands open
retardation.1 directly onto the surface and may be very prominent and numerous at these
The histology of a skin tag at this site is identical to that of those occurring
elsewhere. The presence of granulomata in anal skin tags is often a clue to the
diagnosis of Crohn’s disease.2
Pearly penile papules

Clinical features
Pearly/pink penile papules1 may be found in 15–50% of men.2–5 They manifest
as flesh-colored, smooth, rounded papules (1–3 mm) occurring predomi-
nantly around the coronal margin of the glans, rarely on the glans. Often
there are rows or rings of papules (Fig. 12.13). Ectopic lesions, for exam-
ple on the penile shaft, have been reported,6 including in children.7 They are
frequently mistaken for warts and Tyson’s or ectopic sebaceous glands. The
lesion is analogous to other acral angiofibromas such as adenoma sebaceum,
subungual and periungual fibromas, fibrous papule of the nose, acquired acral
angiofibroma and oral fibroma. These lesions may regress with circumcision
and old age.8
Fig. 12.14
Vulval papillomatosis: numerous pale papillomata are present in the vestibule and
Histological features on the labia minora. These are a normal finding and are particularly common in
The histology is that of angiofibroma.9 HPV DNA is absent.10,11 pregnancy. By courtesy of the Institute of Dermatology, London, UK.
sites. The yellow uniform papules (Fordyce spots) are often seen best if the Pathogenesis and histological features
skin is stretched (Fig. 12.15). Sebaceous gland hyperplasia may sometime
Generally, dermatologists feel that balanitis, posthitis and balanoposthitis
be associated with pruritus and pain if they enlarge and the contents rupture
are probably more commonly due to inflammatory and precancerous derma-
into the dermis.
toses, while genitourinary physicians teach that most cases are due to infec-
In the male, sebaceous gland prominence, Tyson’s glands, sebaceous
tion, usually with Candida.1 However, Candida is a ready opportunist so
hyperplasia and ectopic sebaceous glands (Fordyce’s condition) are all virtu-
its presence may not always indicate primary infection as the cause of the
ally synonymous and are common, normal variants of the skin of the scrotal
genital inflammation. Bacteria have increasingly been implicated in the eti-
sac and penile shaft (very rarely the glans) but may cause concern to patients
ology of the disease, particularly Staphylococcus aureus.2 In cases in which
even amounting to dysmorphophobia (Fig. 12.16).1, 2
Streptococcus pyogenes is isolated it has been suggested that the disease
may be sexually transmitted by penile–oral intercourse.3 Diabetes may be an
Histological features important predisposing factor to Candida and other infective causes or com-
One or more enlarged sebaceous glands, each composed of numerous plications of balanoposthitis.1
lobules, surround a central duct that opens directly into the epidermis The histological features are non-specific.
(Fig. 12.17).
Non-specific balanoposthitis
Inflammatory dermatoses Clinical experience and histological evidence indicate that non-specific
balanoposthitis is a real entity.1–3 However, in practice it is a diagnosis of
exclusion, because sexually transmitted diseases, eczematous dermatoses,
Intertrigo and balanoposthitis psoriasis, Zoon’s balanitis, lichen planus, lichen sclerosus, mucous membrane
pemphigoid and penile carcinoma in situ must be excluded. Non-specific
Clinical features balanoposthitis is a manifestation of a dysfunctional foreskin. Patients
These are non-specific terms.1 Intertrigo is the name given to any dermato- generally complain of pain during intercourse and may have variable signs,
sis occurring in skin folds: any scale is usually rapidly removed by frictional including eczematous, lichenoid and Zoonoid inflammation, and even
abrasion, and a degree of epithelial loss may result in erosion that renders scarring. Candida and other organisms can be identified, but they probably
the site especially susceptible to secondary infection, e.g., with Candida represent opportunistic infection. Diabetes should be excluded. In severe
(see below). cases, medical treatments fail and the only cure is by circumcision. A prior
Balanitis denotes inflammation of the glans penis while posthitis is inflam- clinical diagnosis may be reversed at this stage by foreskin histology showing
mation of the prepuce. Balanoposthitis means inflammation of the glans and lichen sclerosus, lichen planus or carcinoma in situ. However, experience
prepuce and is regarded as a special form of intertrigo. By definition, there- shows that even where the most thorough histological examination of the
fore, balanoposthitis cannot occur in the circumcised male, but balanitis excised prepuce is undertaken, nothing more than non-specific chronic
might. inflammation is found.
Fig. 12.15 Fig. 12.16 Fig. 12.17

Fordyce spots: hyperplastic sebaceous glands Sebaceous hyperplasia (Fordyce’s condition). Penis, Fordyce spot: this small sebaceous gland can be
presenting as conspicuous yellow papules. Similar prepuce. From Bunker C: Male Genital Skin Disease. seen communicating directly with the epidermis.
lesions may be seen on the inner lip and oral Saunders Ltd./Elsevier 2004.
mucosa. By courtesy of the Institute of Dermatology,
London, UK.
Inflammatory dermatoses 445
Eczema g ranulomata and numerous lymphocytes and plasma cells. Hemorrhage and
hemosiderin deposition can sometimes be present.
Clinical features Differential diagnosis
Seborrheic dermatitis is the commonest form of eczema affecting anogenital
In the elderly variant and, when appropriate, Crohn’s disease and infective
skin, followed by irritant contact eczema. Eczema, particularly seborrheic
granulomatous conditions may have to be excluded
dermatitis, is more common than many other inflammatory dermatoses in
uncircumcised males.1 Allergic contact eczema is rare at genital sites and
occurs more typically in a perianal distribution. Involvement of genital skin Lichen simplex chronicus
with atopic eczema is very uncommon.
In infants, eczematous reactions are often seen in the napkin area. Most Clinical features
of these represent a primary irritant dermatitis. Seborrheic dermatitis and a
The clinical features of lichen simplex chronicus presenting on genital and
psoriasiform napkin rash can also occur. Some but not all of the patients with
anal skin are identical to those seen at other sites of the body. The mons pubis
the latter condition develop psoriasis later in life.2
or labium majus, scrotum and perianal skin are the usual sites affected. Giant
forms (of Pautrier) occur, e.g., on the scrotum, giving a pineapple appearance
Histological features (Fig. 12.19).
The histological features are identical to those seen in eczema affecting other
areas of the skin. Psoriasiform napkin rash shows histological features that Histological features
overlap with psoriasis.
The histological features are discussed in detail elsewhere but lichenifica-
tion is characterized by hyperkeratosis, hypergranulosis, uniform acanthosis,
Infantile gluteal granuloma fibrosis of the papillary dermis and an unremarkable low-grade perivascular
infiltrate of mononuclear leukocytes in the superficial dermis. At mucosal
Clinical features sites hyper- and orthokeratosis create a cornified layer, resulting in the clinical
Infantile gluteal granuloma (papuloerosive dermatitis of Jacquet and Sevestre) appearances of leukoplakia.
is a rare condition that has been described mainly in the newborn and infants
in the napkin area. It frequently develops in a background of an irritant nap- Seborrheic dermatitis
kin rash.1–4 A similar condition has been described in incontinent elderly
women with lesions developing on the labia majora (Fig. 12.18).5–7 Oval or
round papulonodular lesions present on the convex areas of the perineum,
Clinical features
which are in direct contact with the napkin or incontinence pad. They tend to Seborrheic dermatitis is a very common pattern of eczematous disease
regress spontaneously over a few weeks and occasionally leave scars. a ssociated with an abnormal hypersensitivity to the normal commensal
cutaneous yeast, Pityrosporum ovale. It is discussed elsewhere. In addition
Pathogenesis and histological features to the classical sites, e.g., scalp (pityriasis capitis, dandruff), ears, glabella
and brows, nasolabial folds, axillae, chest and back, the groin and penis
The etiology of the process is unclear but occlusion, Candida infection and
can be involved. Indeed, this may be the sole site, leading to the patient
fluorinated corticosteroids have been implicated. The last, however, does not
presenting, with pruritus ani or balanoposthitis, to a dermatologist. Some
seem to be of importance in the incontinent elderly patient.
patients may also have a tendency to psoriasis (‘sebopsoriasis,’ ‘seboriasis’).
The histology is fairly non-specific and includes superficial ulceration,
On the scalp, on the face, in the flexures and at anogenital sites, seborrheic
focal necrosis and a prominent mixed inflammatory cell infiltrate with
dermatitis and psoriasis may be indistinguishable. Seborrheic dermatitis is
very common in HIV infection. Diagnosis is achieved on clinical grounds
and it is not usually necessary to do a biopsy. Pityrosporum spp will be seen
in large numbers.
Histology is identical to seborrheic dermatitis occurring elsewhere.
However, spongiosis can be more prominent.
Fig. 12.18
Papuloerosive dermatitis:
there are multiple
ulcerated papules and
nodules predominantly
affecting the labia majora.
By courtesy of the Fig. 12.19
Institute of Dermatology, Lichen simplex chronicus. Scrotum. Giant ‘pineapple’ lesion. From Bunker C: Male
London, UK. Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Psoriasis
Clinical features
Flexural psoriasis is the most common pattern seen in the anogenital region,
with extension into the genitocrural folds and natal cleft (Figs 12.20–12.23).
There are often difficulties clinically in distinguishing between psoriasis
and seborrheic dermatitis. Genital and flexural disease may reflect koeb-
nerization and is relatively common.1 In the circumcised male the signs
on the glans and distal penile shaft are similar to those of psoriasis at
extragenital sites, whereas the appearances in the uncircumcised male are
of balanoposthitis similar to flexural psoriasis.2
Histology is often unhelpful, as the changes can be quite non-specific. The
typical features of psoriasis are rarely evident and the presence of secondary
spongiosis may be very misleading.
Fig. 12.22
Psoriasis: in this example a slight scale is apparent. By courtesy of the Institute of
Fig. 12.20
Psoriasis: note the symmetrical, intensely erythematous eruption involving the
groins, vulva and perineum. Scaling is typically absent in flexural disease. The sharply
demarcated border is characteristic. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 12.23
Psoriasis: note the
erythematous and slightly
scaly plaque affecting the
perineum. By courtesy
of the Institute of
Reiter’s syndrome
Clinical features
Reiter’s disease or syndrome is part of the same continuum as psoriasis in
genetically predisposed individuals.1 Reiter’s syndrome is defined by the triad
of arthritis, urethritis and conjunctivitis. The eponym is gradually losing favor
in the face of more descriptive nomenclature and the term reactive arthritis is
frequently used. It is precipitated by non-specific urethritis, bacillary or amebic
dysentery and associated with HIV infection and the immunogenotype HLA
B27.2–6 The classical triad may occur together or develop in sequence, and a
range of other symptoms may also be present. It has a worldwide distribution.
Fig. 12.21 Reiter’s syndrome most commonly affects men 20–30 years of age; the male
Psoriasis: there are erythematous plaques on the glans penis. By courtesy of the to female sex ratio is approximately 10:1.1 The syndrome is characterized by
Institute of Dermatology, London, UK. a relapsing course.4
The condition may follow an enteric or a urogenital infection.7,8 Shigella changes include osteoporosis, erosions and loss of joint space, with multiple
dysentery was the first associated enteric infection to be recognized and the joints usually affected.4,30 Periostitis often affects the metatarsals, the pha-
causative organisms were either Shigella flexneri or S. dysenteriae.9 Recently, langes of the feet and the tarsal bones; occasionally, ankylosis develops in
Salmonella, Yersinia and Campylobacter have been reported preceding the small bones of the hands and feet. Ankylosing spondylitis, which is an
Reiter’s syndrome.10–14 important manifestation, correlates with a high erythrocyte sedimentation
Sexually transmitted Reiter’s syndrome may occur with a nongonococ- rate (ESR).30
cal or ‘non-specific’ urethritis.7 Chlamydia trachomatis is isolated from the In the initial stages of the arthritis the clinical picture resembles that of an
genitourinary tract in 40–60% of male cases; isolation is variable, however, acute joint infection, settling to subacute involvement. Although the arthritis
and an indirect immunofluorescence test detects chlamydial infection in in Reiter’s syndrome usually recovers completely, chronic manifestations can
90% of patients.15,16 Mycoplasma infection and Streptococcus viridans sometimes occur; it is important to remember that arthritis may be the only
have also been implicated.17–19 The condition has also been linked to the symptom in recurrent episodes.
acquired immunodeficiency syndrome (AIDS).20–22 Rare associations include Skin lesions in Reiter’s syndrome may be similar to those of psoriasis.
Cyclospora, Cryptosporidium, intravesical bacillus Calmette-Guérin (BCG) Cutaneous manifestations include hyperkeratotic cobblestone lesions on
immunotherapy, Gardnerella vaginalis, hepatitis B immunization and systemic the palms and soles and occasionally affecting the trunk and extremities
interferon-alpha (IFN-α) treatment.23–28 (Fig. 12.24). The lesions initially present as erythematous macules; over the
Reiter’s syndrome is more likely to occur in predisposed individuals. course of several days these become hyperkeratotic waxy papules, with an
Human leukocyte antigen (HLA)-B27, which is thought to occur in up to erythematous halo covered by dry hyperkeratotic material. The papules are
90% of patients, increases the risk of developing Reiter’s syndrome by 25 numerous and eventually coalesce to form thickened horny plaques. Pustular
times; the disease is also more severe in HLA-B27-positive individuals.4,29 lesions of the palms and soles may also be evident (keratoderma blenorrhagi-
HLA-B27 in patients with Reiter’s syndrome correlates with ankylosing spon- cum) (Fig. 12.25).
dylitis.4 Reiter’s syndrome develops in 20% of HLA-B27-positive individuals Circinate balanitis, presenting as a moist superficial erosion, 2–4 mm
after a specific infective episode.30 HLA-B27 is found in approximately 10% across, may affect the glans penis and meatus (Figs 12.26–12.28). Superficial
of the normal population. Recently, an association with HLA-B51 has been ulceration of the oral mucosa may also occur, together with reddening and a
reported.31 Rarely, familial instances have been documented.30 Therefore it granular appearance of the surrounding mucous membrane.4,5
appears that the disease is triggered in genetically predisposed individuals by Stomatitis and nail dystrophy (indistinguishable from that of psoriasis)
an unknown mechanism precipitated by infection. may be additional features.4 Weight loss is common.20 Aortic incompetence is
The genitourinary tract is virtually always involved in the form of urethri- an important late complication and IgA nephropathy has been described in a
tis, prostatitis, seminal vesiculitis and hemorrhagic cystitis. Urethral strictures number of patients.4,33
also sometimes occur and females may develop cervicitis. As stated before, Reiter’s syndrome is very rarely reported in females, and
Bilateral mucopurulent conjunctivitis is the usual form of eye involvement the majority of cases recognized are in males.34–38 Vulvitis has been described
occurring in up to 35% of patients, but occasionally iritis, iridocyclitis, kera- in a small number of case reports.34–38 and in one case cervical lesions were
titis or blindness occurs.32 seen.37 The vulval lesions are erythematous and may be ulcerative, eroded or
Weight-bearing joints and the larger ones (knees, ankles, feet and wrists) scaly, and often resemble mucocutaneous candidiasis. The cervical lesions
are involved by the arthritis, often together with sacroiliitis. Radiological were recorded as white papules.37 There may be accompanying oral lesions.
Fig. 12.24 Fig. 12.25 Fig. 12.26

Reiter’s syndrome: there are bilateral keratotic Reiter’s syndrome: in addition to keratotic papules Circinate balanitis. Glans penis. Psoriasiform lesions.
papules and plaques affecting the soles of the feet. there are pustular lesions, many of which have From Bunker C: Male Genital Skin Disease. Saunders
By courtesy of R.A. Marsden, MD, St George’s ruptured – keratoderma blenorrhagicum. By courtesy Ltd./Elsevier 2004.
Hospital, London, UK of the Institute of Dermatology, London, UK.
Fig. 12.29
Reiter’s syndrome: there is parakeratosis overlying a macropustule. The squamous
Fig. 12.27 epithelium shows psoriasiform hyperplasia. These features are indistinguishable
Reiter’s syndrome: there from pustular psoriasis.
are multiple erosions
on the glans penis. By
courtesy of The Institute of
Fig. 12.30
Reiter’s syndrome: high-power view showing parakeratosis and a pustule.
is infiltration of the epidermis by neutrophils, associated with vacuolation of

superficial keratinocytes, together with the formation of spongiform pustules
Fig. 12.28 and microabscesses (Fig. 12.30). The inflammation extends into the adja-
Reiter’s syndrome: in this
cent underlying dermis where it is predominantly mononuclear. The histol-
patient there are scaly
lesions on the glans penis. ogy is essentially identical to that seen in pustular psoriasis.2 Therefore, close
By courtesy of the clinicopathological correlation is critical to establish a diagnosis. Occasional
Institute of Dermatology, biopsies from typical lesions of patients with Reiter’s syndrome may disclose
London, UK. an underlying leukocytoclastic vasculitis.41
A small number of patients presenting with skin lesions that histologi-
cally showed sterile neutrophilic folliculitis with perifollicular vasculopathy
Reiter’s syndrome may resolve spontaneously, but more often it is have been documented.42 The authors suggested that this histological pattern
c haracterized by chronicity and recurrences.4 Rarely, it may prove fatal.4 may be a marker of systemic disease. Associations may include Reiter’s
Causes of death include aortic incompetence, atrioventricular block, terminal syndrome, inflammatory bowel disease, Behçet’s disease, hepatitis B infection,
cachexia, systemic amyloidosis and iatrogenic effects.39 scrofuloderma, connective tissue diseases and hematological dyscrasias.
Patients present with systemic symptoms and variable skin lesions including
Histological features folliculitis, vasculitis, acneiform eruptions, vesiculopustules and erythema
Essentially, just as the skin lesions of Reiter’s syndrome have psorias- nodosum-like features.
iform morphology (Fig. 12.29), they have the same histopathology and Early joint lesions are characterized by a neutrophil polymorph inflam-
ultrastructure as pustular psoriasis.40 matory cell infiltrate with little if any synovial changes. Older lesions show
The epidermis is acanthotic with elongation and hypertrophy of the epider- features suggestive of rheumatoid arthritis, including lymphoid aggregates, a
mal ridges and parakeratosis. The suprapapillary plates are thinned and there perivascular chronic inflammatory cell infiltrate and synovial hyperplasia.30
Differential diagnosis of Hewitt with chronic erosive gingival and genital lesions (genito-gingival
syndrome) has been described.15,16 Patients with genital lesions may have
Periodic acid-Schiff (PAS) and/or silver stains should always be performed
anal, oral, aural, conjunctival and esophageal involvement.17–24 Those
to exclude a fungal infection which can show similar histological
patients with predominantly mucosal disease clinically mimic mucous
features.
membrane pemphigoid but immunofluorescence studies are invariably
negative. A case of paraneoplastic lichen planus with orogenital involve-
Genital lichen planus ment and cicatrizing conjunctivitis in association with thymoma has been
described.25
Clinical features Lichen planopilaris has also been described on the vulva.26
Anogenital lesions may be found in up to 40% of patients with generalized Anogenital lichen planus carries a small increased risk of malignancy, usu-
disease. In some, however, the disease is restricted to the lower genital tract ally squamous cell carcinoma (SCC) (Fig. 12.43).27–30 Hypertrophic lichen
and/or the perianal region, and in these instances the diagnosis may be dif- planus of the glans penis should be regarded as having potential sinister bio-
ficult to establish.1,2 Lichen planus (LP) manifests the Koebner phenomenon logical behavior.28,31
which may partly explain the orogenital predilection.3 Genital lichen planus
in children is exceptional.4 Pathogenesis and histological features
The lesions are typical, violaceous or white patches or areas of erythema Studies of oral LP have supported an immunological basis with activated
and erosions. Wickham’s striae (frequently seen in oral involvement), although T cell to an unidentified antigenic stimulus.32 The histological features of
sometimes visible, are less often found on anogenital skin (Fig. 12.31). The anogenital lichen planus are often more difficult to recognize than those of
erosive form of LP is commoner at anogenital sites and can lead to scarring LP presenting on nonmucosal surfaces. The epidermis may be effaced or
and distortion of the architecture (Figs 12.32–12.34). The vulval vestibule thickened and there is a dense, band-like infiltrate hugging the dermoepider-
and vagina and cervix may also be involved and sometimes the vagina and or mal junction (Fig. 12.44). Many genital lesions are mucosal and the inflam-
the cervix are affected alone.5–7 Perianal disease can lead to deep, painful fis- matory cell infiltrate is often rich in plasma cells, in contrast with lesions of LP
suring and it is often the hypertrophic variant that involves this site. Women at other sites where lymphocytes and histiocytes predominate (Fig. 12.45).
with oral lichen planus often have genital disease and they frequently have The basal layer is often disrupted with some cytological atypia as regen-
asymptomatic lesions.8,9 eration takes place. Cytoid bodies may be seen but tend not to be promi-
The clinical variants of lichen planus affecting the anogenital skin are usu- nent. Sometimes there is focal accentuation of the granular zone of mucous
ally squamopapular with areas of erosion, hypertrophic and hyperpigmented membrane lesions. This is accompanied by parakeratosis. Focal secondary
flexural disease (Figs 12.35–12.39). In the male genital, LP can present as spongiotic changes are not uncommon, particularly in mucosal surfaces.
phimosis.10,11 Adhesions are seen in the uncircumcised male, both transcoro- In longstanding disease the dense, band-like infiltrate may be replaced by
nal and subcoronal. a patchy, scant infiltrate with small foci of lichenoid inflammation. Many
There is also an unusual variant of erosive LP in women that involves cases of male genital lichen planus are misdiagnosed as Zoon’s dermatitis or
the oral gingivae, vulval vestibule and vagina, known as the vulvovaginal- lichen sclerosus.
gingival syndrome (Figs 12.40–12.42).12,13 This can lead to severe vulval Immunofluorescence studies may show fibrinogen and IgM along the
and vaginal scarring with vaginal adhesions, constriction bands and, in some basement membrane zone and more rarely IgG or IgA.19 Cytoid bodies may
cases, complete stenosis.14 A male equivalent to the vulvo-vaginal syndrome also be labeled.33
Fig. 12.31 Fig. 12.32 Fig. 12.33

Lichen planus: perineal lesions showing conspicuous Erosive lichen planus: bilateral erosions are present. Erosive lichen planus: there is extensive erosion
striae. By courtesy of the Institute of Dermatology, By courtesy of the Institute of Dermatology, of the glans penis. By courtesy of the Institute of
London, UK. London, UK. Dermatology, London, UK.
Fig. 12.34 Fig. 12.35 Fig. 12.36

Vulval lichen planus: reticulated lesions of lichen Vulval lichen planus: in this example of resolving Perineal lichen planus: typical papules with
planus extending into the perineum. By courtesy of disease there are linear hyperpigmented lesions. Wickham’s striae are present. By courtesy of the
the Institute of Dermatology, London, UK. By courtesy of the Institute of Dermatology, Institute of Dermatology, London, UK.
London, UK.
Fig. 12.37 Fig. 12.38 Fig. 12.39

Hypertrophic perianal lichen planus: chronic scratching Penile lichen planus: there is involvement of the Penile lichen planus: the proximal shaft shows post
has resulted in superimposed lichenification. By shaft and glans. From Bunker C: Male Genital Skin inflammatory hyperpigmentation. From Bunker C: Male
courtesy of the Institute of Dermatology, London, UK. Disease. Saunders Ltd./Elsevier 2004. Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Fig. 12.40 Fig. 12.43
Vulvovaginal-gingival syndrome: there is extensive vestibular erythema and erosion with a Lichen planus: chronic penile lesion complicated by an ulcerated squamous cell
surrounding delicate white scale. By courtesy of the Institute of Dermatology, London, UK. carcinoma. By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.41
Vulvovaginal-gingival syndrome: there is ulceration of the vagina and cervix.
Fig. 12.44
Lichen planus: there is hyperkeratosis, acanthosis and a band-like inflammatory cell
infiltrate.
The clinical differential diagnosis includes psoriasis, Zoon’s balanitis in the
male, lichen sclerosus, viral warts, bowenoid papulosis and porokerato-
sis. Lichen planus is in the differential diagnosis of pruritus ani. A biopsy is
frequently necessary for diagnostic purposes but is more importantly done
in the follow-up of the rare cases of chronic anogenital disease where the
development of ulcero-erosive or verrucous features leads to concern about
the development of squamous cell carcinoma. Lichen planus often overlaps
with the features of lichen sclerosus, and in some patients the two disorders
may coexist. Hyalinization of the papillary dermis or the superficial lamina
propria is indicative of the latter condition. In patients suffering from such
a chronic overlap syndrome, particular care should be taken to recognize
dysplastic areas or SCC.
Fig. 12.42 Sometimes drugs can precipitate a generalized lichenoid eruption. A case
Vulvovaginal-gingival syndrome: note the intense erythema with erosion of the of a lichenoid drug eruption confined to the penis due to propranolol has
gum. By courtesy of the Institute of Dermatology, London, UK. been reported.34
There are two peaks of incidence; in females there is one in the premenar-
chal years and the other in the menopause, and in prepubertal and young to
middle-aged adult males. When the disease arises in childhood it tends to per-
sist, regression being uncommon.5 In girls, the condition can present at a very
early age with hemorrhagic perianal lesions (Figs 12.46, 12.47). Constipation
can occur as a complication of the painful fissuring of the anal canal. If there
is marked anogenital involvement, the condition may be mistaken for sexual
abuse.2 Perianal disease does not occur in males but in boys genital LS is
the most common cause of phimosis. Extragenital lesions occur in 11% of
women with genital lichen sclerosus.6 Such involvement occurs on the upper
Fig. 12.45
Lichen planus: (A) note
the hyperkeratosis,
hypergranulosis and
basal cell hydropic
degeneration; (B) in
contrast to cutaneous
disease, plasma cells as
shown in this field are
A often present in genital
lesions.
Fig. 12.46
Lichen sclerosus: severe
bilateral and symmetrical
disease with atrophy and
virtual loss of the labia
minora. Vulval lesions
are intensely pruritic. By
Lichen nitidus
Clinical features
This disease has an affinity for the penis.1 It can be difficult to diagnose
because the signs may be subtle even when the lesions are widespread, and
when itchy the signs due to excoriation and eczematization may eclipse those
due to the lichen nitidus.
Histologically, the appearances are the same as lichen nitidus occurring
elsewhere.
Lichen sclerosus Fig. 12.47

Lichen sclerosus: perianal
Clinical features disease is often present
in addition to vulval
Lichen sclerosus (LS) is a lymphocyte mediated dermatosis of unknown eti- involvement, giving rise
ology.1–3 It has a predilection for the anogenital skin in women and genital to the so-called hourglass
skin in men. Women are more frequently affected than men (10:1) and it is distribution. By courtesy
more common in white than nonwhite patients. It almost never affects men of the Institute of
circumcised at birth.4 Dermatology, London, UK.
trunk, groins, upper extremities, neck, lower trunk and lower extremities in Penile disease can affect the glans, and distal foreskin, the frenulum and ven-
decreasing order of frequency (Figs 12.48, 12.49). Involvement of the scalp tral subcoronal sulcus is a particular target. Lichen sclerosus is a scarring dis-
and face is rare and can be associated with alopecia.7–9 An exceptional case order and in women there may be marked anatomical changes with loss of
with plantar involvement has been documented.10 Extragenital lesions may the labia minora, burying of the clitoris, and urethral perimeatal stenosis. The
occur in the absence of genital lesions. The Koebner phenomenon is frequent vagina is unaffected. Urethral involvement is very rare.25 In men there may be
and LS has been described in association with scars, at the sites of radio- complete phimosis, constrictive posthitis due to a sclerotic band (‘waisting’),
therapy, and insulin injection and in association with a tattoo.11–14 Lesions transcoronal and subcoronal adhesions, erosion, ulceration and destruction
can also develop or recur in skin or myocutaneous grafts.15 Oral involvement or obliteration of the frenulum, effacement of the coronal sulcal architecture
including lip lesions as an isolated phenomenon or in association with genital and definition (e.g., loss of pearly penile papules), meatal ‘pin hole’ narrow-
lesions has been described.16–18 The exact incidence of the latter is unknown, ing. The involvement of the anterior urethra can be serious: 29% of patients
as suspected cases are not often confirmed by histological examination.19 undergoing urethroplasty for urethral stricture had pathological evidence of
Lichen planus can coexist with LS and this may account for some of the lichen sclerosus.
oral lesions.20 Coexistence of LS with morphea has also been documented.21 In a single case of vulval LS in a child, a melanoma developed later.26
A single case of multiple genital and extragenital lesions in a patient receiving An important complication of genital LS is the development of dysplasia
imatinib mesylate has been reported.22 A further case in association with allo- and SCC. The latter only very exceptionally has been reported in association
geneic stem cell transplantation and another of genital disease developing in with extragenital lesions.27 In the vulva (Figs 12.54, 12.55), dysplastic foci
scrotal skin used in a case of male-to-female gender reassignment have been may appear as hyperkeratotic adherent, gray–white areas, ice pick erosions or
documented.23,24 fixed areas of erythema.3 Such changes must be examined histologically. Less
The typical lesions of LS are porcelain-white papules and plaques with a than 4% of patients with vulval LS will develop a squamous cell carcinoma.3
crinkled surface. They can coalesce to form plaques. There are often associ- It has recently been shown that an important number of cases diagnosed
ated ecchymoses and areas of hyperkeratosis. The latter occurs in relation to as lichen sclerosus with progression to squamous cell carcinoma actually
the appendage ostia, which are dilated, giving rise to the physical sign of del- represent differentiated vulvar intraepithelial neoplasia and not lichen scle-
ling. Bullae only rarely occur. Common symptoms in women include pruritus, rosus.28 The main reason for the high number of misdiagnosed cases is prob-
burning and dyspareunia, and in men coital and urinary difficulties. Although ably the difficulty in diagnosing differentiated vulval neoplasia on histologic
anogenital LS is intensely pruritic, lichenification is often not conspicuous. grounds. These patients tend to have a more rapid progression to invasive
Female anogenital involvement is typically symmetrical and bilateral, and is squamous cell carcinoma. In the group of patients with true lichen sclerosus
described as having a figure-of-eight (hourglass) distribution when it affects and progression, a number of histologic features are seen which are absent
the perianal as well as vulval skin. In men the involvement is ‘tulip-like’ in cases without progression. It has been suggested that these criteria can
symmetrically affecting the distal penile shaft, glans and foreskin (not the peri- be used to identify patients at risk. They include parakeratosis, dyskerato-
anal skin) (Fig. 12.50). On the other hand, the presentation may be with sis, hyperplasia and basal cell atypia.28 In the male, the published risk of
complete phimosis (Fig. 12.51). Lesions on the vulva predominantly affect SCC complicating LS is between 4% and 8%.29–32 When excision specimens
the inner aspect of the labia majora, the labia minora, the prepuce of the of penile squamous cell carcinoma are examined, lichen sclerosus has been
clitoris, the fossa navicularis and the posterior commissure (Figs 12.52, 12.53). found in between 32% and 50% of cases.32–34 The type of penile squamous
Fig. 12.48 Fig. 12.49 Fig. 12.50

Lichen sclerosus: irregular white plaque. It should be Lichen sclerosus: healing lesion with a typical Lichen sclerosus: in males, lesions of the foreskin
noted that extragenital lesions sometimes occur in ‘wrinkled tissue paper’ appearance. By courtesy and glans may be complicated by urethral stricture
the absence of genital lesions. By courtesy of R.A. of R.A. Marsden, MD, St George’s Hospital, (so-called balanitis xerotica obliterans). By courtesy
Marsden, MD, St George’s Hospital, London, UK. London, UK. of the Institute of Dermatology, London, UK.
of patients, suggesting that a number of cases have a genetic component.40

About 21% of patients with LS have an associated autoimmune disease
including alopecia areata, vitiligo, hyperthyroidism, hypothyroidism, perni-
cious anemia and diabetes mellitus.41,42 Patients and first-degree relatives may
have circulating autoantibodies including those to thyroid, gastric parietal
cell and smooth muscle in addition to antinuclear factor.43 A significant asso-
ciation between LS and the presence of class II antigens including HLA-DQ7,
-DR7, -DQ8 and -DQ9 (alone or in combination) has been reported.44 It has
also been suggested that HLA-A2 possibly exerts a protective role, as it tends
to be absent in patients with extensive extragenital lesions. Also, linkage of
HLA-DR4 with -DQ8 is commoner in patients with marked structural dam-
age to the anogenital area. Circulating IgG antibodies to the glycoprotein
extracellular matrix protein1 have been found in the sera of 75% women
with genital LS.45 In a few otherwise healthy children with vulval lichen scle-
rosus, IgG autoantibodies against the BP180 antigen have been detected.46
In a recent study, women with genital lichen sclerosus were found to have
a higher incidence of psoriasis (predominantly extragenital) compared with
the general population.47,48
LS developing in premenopausal women has been linked to the use of oral
Fig. 12.51 contraceptives, particularly those with antianodrogenic properties.49
Lichen sclerosus: a more advanced case showing severe phimosis. By courtesy of
Additional proposed etiological factors include absence of collagenase,
an increase in collagen inhibitor enzyme and decreased elastase activity.1
Reduced dihydrotestosterone levels have been described in some patients and
cell carcinoma associated with lichen sclerosus is not usually associated with there is one report documenting the histological presence of variably acid-fast
HPV.35 Chronicity, asymmetry, erythema, zoonoid or erythroplasia, erosions, bacilli.50,51 As with morphea and atrophoderma, a causal relationship to
ulcers and verrucous change must be regarded with a very high index of Borrelia burgdorferi has been proposed but this putative connection derives
suspicion and a low threshold for biopsy. from cases in Europe and not the USA.52 There is no serological evidence in
British men with genital LS for an association with Borrelia.53 Borrelia has
Pathogenesis and histological features only exceptionally been demonstrated by nested PCR in LS.54 The variable
The etiology of LS is unknown. It has been suggested that genetic, hor- results may be due to techniques employed to detect Borrelia and it has been
monal and autoimmune factors may be of importance. Familial cases are suggested that focus floating microscopy should be the gold standard for detec-
well recognized and have been described in both sexes and in identical and tion.55 HPV (types 6, 16 and 18) has been reported in 70% of cases of child-
nonidentical twins.36–39 A recent study found a family history in up to 12% hood penile lichen sclerosus and in 17.4% of adult cases (types 16, 18, 45)
Fig. 12.52 Fig. 12.53 Fig. 12.54

Lichen sclerosus: symmetrical white lesions with Lichen sclerosus: there is extensive vulval disease with Lichen sclerosus: long-standing disease with
gross atrophy and hemorrhage. By courtesy of the involvement of the perineum and atrophy. By courtesy complete loss of the vulval architecture complicated
Institute of Dermatology, London, UK. of the Institute of Dermatology, London, UK. by the development of an ulcerated squamous
cell carcinoma. By courtesy of the Institute of
Fig. 12.55
Lichen sclerosus: an
ulcerated squamous cell Fig. 12.56
carcinoma has destroyed Lichen sclerosus: early lesion showing epidermal atrophy and marked basal cell
much of the left side hydropic degeneration. There is a narrow zone of papillary dermal hyalinization and a
of the vulva. Note the band-like infiltrate is present.
background of ulcerated
lichen sclerosus. By seems to be associated in a number of cases with elastophagocytosis, a feature
courtesy of the Institute of not reported in genital LS.68 Occasionally, pseudoxanthoma elasticum-like fibers
Dermatology, London, UK. may be seen in patients without pseudoxanthoma elasticum.69 Fully developed
lesions of LS show a thinned, effaced epidermis with interface change and a
compared with 8.7% of normal males in one study and in 33% of adult cases wide band of hyalinization in the upper dermis and a lymphohistiocytic infil-
(types 16, 18, 33, 51) in another.56–58 Topical steroid treatment of lichen scle- trate below the hyalinized area. Marked hyperkeratosis, often associated with
rosus may lead to HPV reactivation.59 HPV, however, has not been found in follicular plugging on hair-bearing skin, is frequently seen. Subepidermal edema
other studies of vulva LS.60 EBV was reported in 26.5% of samples in the is sometimes present and may be sufficient to cause subepithelial vesiculation
same study.60 However, the epidemiology and clinical tenor of lichen sclerosus (Fig. 12.60). Telangiectasia is common and purpura may be an additional fea-
is not that of an infectious or sexually transmitted disease. ture. Angiokeratoma-like lesions can also develop.70 A similar phenomenon is
In males, anatomical abnormality and trauma seem to be contributing fac- that of lymphangiectasia.71 Early lesions and the periphery of fully developed
tors.4,25,61 LS has been specifically related to hypospadias and its repair.25,62 lesions display lichenoid changes similar to lichen planus (see differential diag-
The presence of histopathological features of lichen sclerosus in a percentage nosis). Some cases may be associated with foci of marked and highly irregu-
of acrochordons (skin tags) has led to the suggestion that occlusion of flaccid lar acanthosis, often with a very jagged lower border (so-called squamous cell
skin is a pathogenic factor.63 In men, at least, all the evidence points to LS hyperplasia). Such cases should be carefully scrutinized for evidence of epithe-
being due to chronic intermittent occluded contact with urine. lial dysplasia (differentiated intraepithelial neoplasia) or adjacent carcinoma.
The histological changes are identical irrespective of the site involved
(Figs 12.56–12.59).64–66 However, genital lesions, as opposed to those occurring at
extragenital sites, often show absence of atrophy, lichen simplex chronicus-like
changes, spongiosis and dermal eosinophils.67 Extragenital LS, on the other hand,
Fig. 12.57 Fig. 12.58
Lichen sclerosus: this example shows the characteristic features of lichen Lichen sclerosus: close-up
sclerosus. Note the hyperkeratosis, epidermal atrophy and a broad band of dermal view of basal cell hydropic
hyalinization. Telangiectatic vessels are prominent. degeneration.
Fig. 12.59 Fig. 12.60 Fig. 12.61

Lichen sclerosus: in this view the lymphohistiocytic Lichen sclerosus: occasionally, intense edema may Zoon’s balanitis: there is involvement of the glans,
infiltrate is present deep to the zone of hyalinization. result in subepidermal vesiculation. prepuce and shaft of the penis. From Bunker C: Male
There is telangiectasia with hemorrhage. Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Differentiated intraepithelial neoplasia is by far the most common type of dys- The presentation is classically indolent and asymptomatic. Well-demarcated,
plasia found in squamous cell carcinoma associated with lichen sclerosus.72 glistening, moist, bright red or brown patches involve the glans and visceral
Currently, there is no evidence to suggest that oncogenic human papillomavirus prepuce with sparing of the keratinized penile shaft and foreskin (Fig. 12.61).
(HPV) is associated with LS-related SCC. The navicular fossa may be involved. Other signs include dark red stippling –
The occasional observation of endarteritis in LS led originally to the usage ‘cayenne pepper spots’ – and purpura with hemosiderin deposition, solitary or
of the term ‘obliterans’. In two cases in boys, a dermal lymphohistiocytic and multiple lesions of differing sizes (guttate or nummular), characteristically
granulomatous phlebitis was found, and one also had evidence of HPV.73 An symmetrical about the axis of the coronal sulcus and ‘kissing’. Although
exceptional case of LS with associated eosinophilic spongiosis representing vegetative and nodular presentations have been recorded, atypical or unusual
superimposed bullous pemphgioid has been reported.74 morphology should be viewed with great suspicion and biopsied.8,9 The clinical
Ultrastructural studies of LS show fragmentation, reduplication and forma- differential diagnosis includes erosive lichen planus, psoriasis, seborrheic
tion of gaps in the basal lamina.66,75 Langerhans cells appear to pass through dermatitis, contact dermatitis, fixed drug eruption, secondary syphilis,
these gaps. The mononuclear infiltrate in LS is composed of an admixture of histoplasmosis, erythroplasia of Queyrat and Kaposi’s sarcoma.10,11 As such,
T-helper and suppressor lymphocytes. Expression of p53 by epidermal cells a confident clinical diagnosis is not always possible or safe.12,13 Therefore a
has been reported in lichen sclerosus.67,76 The latter is more often seen in cases biopsy is advisable, and the pathologist should actively seek concomitant dis-
associated with squamous cell carcinoma.77 ease. Overt cases of lichen sclerosus, lichen planus, bowenoid papulosis and
penile cancer often appear to have ZB-like changes both on clinical examina-
Differential diagnosis tion and on histology:9,13–16 the signs of ZB may be secondary to underlying
Most cases of genital lichen sclerosus can be diagnosed clinically. Lichen preputial disease.8 Probably some of the clinical and histological variants that
planus and the much rarer mucous membrane pemphigoid are in the differ- have been reported, and the idea that ZB might be a premalignant condition,
ential diagnosis. A biopsy should be performed if there is clinical doubt or if reflect this phenomenon. ZB indicates a dysfunctional foreskin, potentially
the lesion is eroded or verrucous. Anogenital LS, particularly early lesions, concealing a more sinister dermatosis.10,17,18
may be difficult to distinguish from lichen planus (LP). Changes present in the
early stages of LS, and absent in LP, include a psoriasiform lichenoid pattern,
exocytosis of lymphocytes affecting the basal cell layer, basement membrane
thickening, foci of epidermal atrophy and loss of papillary dermal elastic Since Zoon’s original reports there have been many accounts in the literature,
fibers.65 The histological features may simulate mycosis fungoides.78,79 but the etiology remains uncertain. The evidence suggests that ZB is a chronic,
reactive, principally irritant dermatosis brought about by a dysfunctional
prepuce. Retention of urine and squames and excessive frictional trauma (ZB
Zoon’s balanitis is often located on the dorsal aspect of the glans and/or the adjacent prepuce,
sites of maximal friction on foreskin retraction) create the irritation. There is
Clinical features no evidence of an infectious cause, and immunohistochemical findings sug-
Zoon’s plasma cell balanitis (ZB) is a disorder of middle-aged and older gest that ZB represents a non-specific polyclonal tissue reaction, consistent
uncircumcised males, although an analogous condition has been reported to with an irritant dermatosis.6,7
afflict the vulva, mouth, lips and epiglottis.1–7 Exceptionally, the disease may Classically the epidermis shows attenuation with absent granular and
present in a circumcised male.5 horny layers, and diamond- or lozenge-shaped basal cell keratinocytes
with sparse dyskeratosis and spongiosis (Figs 12.62, 12.63). In the der- Clinical features
mis, there is a dense band of infiltration with plasma cells of variable
Lesions in females are exceedingly rare and affect the vestibule and the
density.13 Other signs include extravasated erythrocytes, hemosiderin and
labia minora.4–8 Few lesions have been described on the clitoris. The con-
vascular proliferation. Zoon stressed the presence of the plasma cell infil-
dition probably is not a single entity but a pattern of inflammation that is
trate in this condition, but in practice the plasma cell density can be very
seen on a mucosal surface in other chronic dermatoses, particularly lichen
variable 9,13,19 planus.9 The lesions are bright red with a varnished appearance and some-
times there is cayenne pepper-like speckling. There may also be areas of
Zoon’s vulvitis purpura.
This variant of Zoon’s is the female counterpart of the more common Alternative names proposed for these inflammatory changes include
Zoon’s balanitis and was also described by Zoon after it had been noted by chronic vulval purpura10 and persistent purpuric dermatitis.11 Similar lesions
Garnier.1–3 have been described in the oral cavity and other mucosal surfaces, including
the epiglottis, under such names such as plasma cell orificial mucositis and
atypical gingivostomatitis.12
The histology is the same as described above under Zoon’s balanitis. An
exceptional case of Zoon’s vulvitis with prominent mucinous metaplasia has
been described.13
Granuloma annulare
A few cases of granuloma annulare affecting the penis have been reported,
mainly in children and adolescents.1–4 Erythematous smooth, round and
linear nodules are described. The histology is identical to that seen elsewhere,
and often lesions tend to represent deep granuloma annulare.
Vesiculobullous conditions
Subepidermal autoimmune blistering diseases including bullous pemphi-
goid and mucous membrane pemphigoid are discussed elsewhere. Other
blistering disorders including pemphigus, Darier’s disease and Hailey–
Fig. 12.62 Hailey disease are discussed elsewhere. Pemphigus can involve the penis
Zoon’s balanitis: note the epidermal thinning, spongiosis and a dense superficial (the glans is the usual site) but very rarely in isolation. Pemphigus veg-
inflammatory cell infiltrate. etans presenting with a 4-year history of indolent tender balanitis, where
the glans penis was involved with a moist vegetative plaque with beefy red
erosions separating irregular hyperkeratotic mounds, has been reported.1
Involvement of the penis in mucous membrane pemphigoid is very uncom-
mon and may cause blisters, erosions, ulcers, transcoronal adhesions, scarring
and phimosis.2
The histology of bullous disorders in genital skin is the same as that seen
in lesions presenting elsewhere.
Genital papular acantholytic dyskeratosis

This term has been used to describe a condition where papules and nodules
develop on the genital skin and may be mistaken for warts.1,2 Histologically,
lesions demonstrate changes similar to Darier’s disease and Hailey–Hailey.
disease.3,4 It has been proposed that some cases may be a forme fruste of
the latter.5 Another term used for this entity is acantholytic dyskeratosis.6
Immunofluorescence studies are negative, although one case with positive
immunofluorescence consisting of intercellular IgG and C3 has been
reported.7
Penile acne
Clinical features
This is not an entity that is well recognized in the literature but it is
occasionally encountered in clinical practice. Young men complain of
Fig. 12.63 spots, boils or blackheads and on examination have comedones, papules,
Zoon’s balanitis: there pustules, inflammatory nodules and scars of the proximal penile shaft
is ‘lozenge-shaped’ (Figs 12.64, 12.65). An important differential diagnosis of acneform dis-
spongiosis and an intense ease presenting at any site is chloracne, due to occlusion of the skin with
plasma cell infiltrate. machine oil.
encountered in men (Fig 12.66). In classical hidradenitis, bridged comedones,

folliculitis and furunculosis, deep discharging sinuses, nodules, cysts, and scars
in the groins (Fig. 12.67), the natal cleft and buttocks2 may all be present
(and in the axillae and under the breasts) and the patient may have conglobate
acne. It is commoner in black individuals and affects the axillae preferentially
in women and the perineum in men. A urethral cutaneous fistula and phimosis
has been reported.3 It is a cause of dorsal perforation of the penis.4,5 Scarring
from the disease and its treatment can be extensive (Fig. 12.68). The morbid-
ity of hidradenitis may be appalling, interfering with sitting, sleeping, walking,
defecation and sexual activity. Depression is common.
Hidradenitis suppurativa can be considered to be a form of ‘apocrine acne’.
The role of endocrine factors is uncertain as is the primary part played by
bacteria. Chronicity and tissue destruction lead to the classical physical signs.
Disease that has persisted for more than 20 years carries a significant risk of
progression to squamous cell carcinoma and rarely verrucous carcinoma.6–9
Hidradenitis is usually a clinical diagnosis. Swabs should be taken for
bacteriological analysis. Rarely, a biopsy may be necessary to exclude carci-
noma or Crohn’s disease. Perineal Crohn’s disease mimics hidradenitis with
Fig. 12.64 its granulomatous inflammation, ulceration and fistula formation but it is less
Penile acne: comedones, painful. Also, the disease is absent from the axillae and it is rare for patients
cysts and healing inflamed to be free of overt gastrointestinal symptoms. Very florid perianal disease can
lesions are present on be seen in myeloma and leukemia in homosexual men and AIDS.10–12
the proximal shaft of
the penis. From Bunker
C: Male Genital Skin
Disease. Saunders Ltd./
Elsevier 2004.
Fig. 12.66
Pili incarnati: lesion from the groin showing and inflamed follicular lesion. From
Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Fig. 12.65
Penile acne: comedones,
papules and nodules are
evident. From Bunker
C: Male Genital Skin
Disease. Saunders Ltd./
Elsevier 2004.
The histology is identical to that of acne at classical sites.
Hidradenitis suppurativa
Clinical features
Hidradenitis suppurativa (termed chronic perianal pyoderma in Japan)
represents a clinical spectrum overlapping with chronic folliculitis, e.g., of
Fig. 12.67
the buttocks and penile acne.1 Pili incarnati (ingrowing hairs) and secondary
Hidradenitis suppurativa: there is extensive involvement of the groin. From Bunker
folliculitis is a common problem in the ‘bikini’ area in women but rarely C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
The microscopic appearance has not been described in detail but there
is non-specific superficial ulceration with a mixed inflammatory cell
infiltrate.
Sclerosing lymphangitis of the penis

Clinical features
Sclerosing lymphangitis of the penis (Mondor’s disease) is a rare condi-
tion which presents as a serpiginous cord-like thickening of the skin near
the coronal sulcus.1–4 Rarely, there is involvement of the dorsal aspect
of the shaft. There may be some inflammation and local tenderness.
The condition is usually self-limiting and resolves spontaneously after
a few weeks. Only occasional cases are persistent and may require sur-
gery.5 There does not appear to be a female equivalent to this disorder
but there has been a report of the disease involving the upper lip and the
labium minus.6
Fig. 12.68
Hidradenitis suppurativa: Pathogenesis and histological features
there is extensive
scarring as a result of the The etiology is unknown but vigorous or traumatic sexual activity is an
disease and also from important precipitant.7,8 In general, there does not seem to be any relation-
surgery. Courtesy of Prof. ship to venereal disease although cases have been reported following genital
Tim Allen-Mersh, London, herpes and Chlamydia infection.9,10 A case developing after coadministration
UK. From Bunker C: Male of tadalafil and fluconazole has been documented.11
Genital Skin Disease. The histological features are characterized by a thrombosed vascu-
Saunders Ltd./Elsevier 2004. lar channel, thought to be of either lymphatic or venous derivation. Some
authors separate sclerosing lymphangitis from Mondor’s disease based on
Histological features the involvement of lymphatics in the former and veins in the latter.12 Focal
Masson-like changes may be seen. Later in the course of the disease, the
The histology is identical to that of hidradenitis suppurativa occurring
thrombus is replaced by fibrous tissue and a few scattered mononuclear
elsewhere.
inflammatory cells are also seen. The wall of the affected vessel later becomes
thickened and sclerotic.
Aphthe
Clinical features Pyoderma gangrenosum
Aphthous ulceration of the penis and scrotum does occur but this is not an This is a rare genital affliction, including the variant superficial granulomatous
acceptable diagnosis in the perianal skin or genitalia without overt exclu- pyoderma1 that involves the penis and scrotum in adults and children. In chil-
sion of sexually transmitted diseases, and culture is reasonable practice.1 The dren the anogenital area is a site of predilection in addition to the head and
causes of aphthae are obscure. neck. Genital pyoderma gangrenosum may occur following local trauma such
The impression is that aphthe and idiopathic orogenital ulceration are as urological surgery1,2 or treatment for cancer.3 It may complicate ulcerative
commoner in HIV infection and worse, symptomatically and morphologi- colitis4 or chronic lymphocytic leukemia, or may be idiopathic.5–8 In idiopathic
cally. Giant lesions may occur. In HIV, all mucocutaneous ulcers must be cases, diagnosis is frequently delayed because it is not included in the differen-
biopsied and cultured; several pathologies may coexist.1 tial by the clinician in pursuit of a diagnosis of cancer or infection. Pathologists
may receive biopsies without this possibility being mentioned to them.9
The histology of idiopathic aphthous ulceration is entirely non-specific. Histological features
The histological features are identical to those seen in lesions elsewhere.
Lipschutz ulcer
Penile necrosis
Clinical features
This condition is seen in teenage girls who present with vulval ulceration of Clinical features
sudden onset. Lesions may be solitary or multiple.1–7 The initial lesion is a This serious situation has a number of causes and a wide clinical differen-
tender purpuric or hemorrhagic papule that rapidly enlarges and ulcerates. tial diagnoses. Many of the causes are discussed in this and other chapters,
The ulcers are deep, painful and have sharply delineated erythematous mar- for example decubitus ulcer, the strangulation and tourniquet syndromes and
gins. There may be an accompanying fever, malaise and cervical lymphade- other autoerotic misadventures and causes of artifact (priapism), pyoderma
nopathy. However, in most cases, other signs and symptoms are absent or not gangrenosum, infections such as herpes simplex, ecthyma gangrenosum and
prominent, and confirmation of the diagnosis requires serological tests. Other Fournier’s gangrene, and as a complication of serious illness (e.g., mucormy-
associated infections have included typhoid and paratyphoid, mycoplasma cosis in acute myeloblastic leukaemia).1 Necrosis can be the result of dia-
and cytomegalovirus.5–7 betic small vessel and end-stage renal disease2,3 and chronic renal failure
An analogous situation in males is not recognized. with secondary hyperparathyroidism and calciphylaxis,4 and can compli-
cate polycythemia, thrombocytopenia and leukemia, cryoglobulinemia and
Pathogenesis and histological features vasculitis. Inferior vena caval thrombosis as part of disseminated intravas-
The condition is a toxic reaction to a systemic infection. The most commonly cular coagulation can lead to necrosis and gangrene of the penis.5 Heparin
associated infection is Epstein-Barr virus (EBV) infection (infectious necrosis is a coagulopathy due to heparin-induced thrombocytopenia. Warfarin
mononucleosis).1–7 necrosis is a state of acquired protein C dysfunction .6,7
Histological features involvement is more common in patients with colonic disease (up to 80%).
In ‘metastatic disease’ the affected areas are not contiguous with the involved
The histological features consist of extensive necrosis of the skin and deeper
bowel and may occur in distant cutaneous sites including the face and
tissues and more specific changes may be found depending on the etiology of
limbs.8–12 Anogenital disease may present years before there is evidence of
the process.
gastrointestinal disease.13–16 Vulval edema can be the only manifestation and
occasionally it is unilateral.17,18 Crohn’s disease may involve the penis and
Spontaneous scrotal ulceration scrotum, presenting as penoscrotal lymphedema.19–21 More usually, how-
Five cases of spontaneous scrotal ulceration in young, previously fit men ever, the disease is associated with erosions, ulceration, abscesses, skin tags,
have been described by Piñol Aguade.1 Histology showed non-specific vas- sinus and fistula formation.22 Lesions can exceptionally mimic hidradenitis
culitis, and spontaneous resolution occurred. This entity may be related to suppurativa and pyoderma gangrenosum.23 Unilateral hypertrophy of the
idiopathic scrotal panniculitis and fat necrosis. Idiopathic scrotal necrosis in vulva has also been reported.24 Deep fissures (‘knife-cut’ sign) along the
a 2-month-old boy has been documented by Sarihan;2 trauma, extreme cold skin creases are a characteristic feature. Patients of any age with Crohn’s
and Fournier’s gangrene were excluded. disease including children may present with anogenital involvement.25 Oral
involvement includes edema, fissuring and mucosal ‘cobblestoning’. One
Scrotal fat necrosis patient presented with ‘metastatic’ Crohn’s disease and oral intraepithelial
IgA pustulosis.26
This condition is distinct from other causes of acute scrotum in prepubertal Crohn’s disease is not uncommonly associated with pyoderma gangrenosum
boys.1 It presents as acute tender, sometimes painful, swelling (classically, but and erythema nodosum. Other links include leukocytoclastic vasculitis, ery-
not always, after swimming in cold water). Masses may be palpable in the thema elevatum diutinum, granulomatous vasculitis, Sweet’s syndrome, epider-
scrotal wall. The patient is otherwise well, with no fever or leukocytosis.2,3 molysis bullosa acquisita, polyarteritis nodosa, pyostomatitis vegetans, vitiligo,
In adults, one case of idiopathic scrotal panniculitis has been reported4 and psoriasis, erythema multiforme, lichen nitidus, hidradenitis suppurativa and
another associated with pancreatitis.5 acne fulminans.27–43
The condition runs a chronic course. Development of Bowen’s disease in
a case of vulvovaginal Crohn’s disease has been reported.44 Rarely, squamous
Associations with systemic disease cell carcinoma may develop in long-standing disease.45–47
Crohn’s disease Histological features

The histology may show only edema, dilated lymphatics or lymphangiecta-
Clinical features sia. More commonly, there are dermal or rarely subcutaneous noncaseating
Anogenital lesions occur in about 30% of patients with intestinal Crohn’s granulomata (Fig. 12.73). The latter may have a perivascular distribution.45
disease, either by direct extension of active intestinal disease or as a The histological diagnosis can only be made after careful clinicopathological
manifestation of so-called ‘metastatic disease’ (Figs 12.69–12.72).1–7 Skin correlation.
Fig. 12.69 Fig. 12.70 Fig. 12.71

Vulval Crohn’s disease: there is intense erythema and Vulval Crohn’s disease: in this patient there is Vulval Crohn’s disease: note the erythema, edema
multiple vestibular erosions are present. By courtesy of marked edema with erythema and conspicuous and erosions. By courtesy of the Institute of
the Institute of Dermatology, London, UK. granulomatous lesions. By courtesy of the Institute Dermatology, London, UK.
necrosis has been reported.1 Rubio et al.2 describe a case of isolated penile
ulceration due to a necrotizing vasculitis, with no evidence of systemic
vasculitis that responded to systemic steroids. Fournier’s gangrene may
show histological evidence of necrotizing vasculitis,3 and priapism has been
documented as a manifestation of isolated genital vasculitis.4
Infectious diseases
Erythrasma
Clinical features
Erythrasma is a superficial infection of the skin at flexural sites, particularly
in the inguinal and genitocrural folds (Fig. 12.74).1–7 The skin between the
toes and natal cleft may also be involved. The affected areas are covered
in red–brown scaly plaques with well-demarcated edges. The rash is usually
asymptomatic or mildly itchy. The affected areas fluoresce coral pink under
Wood’s light. This feature is due to the presence of porphyrin and may be
absent in some cases.5 Very rare cases present with generalized involvement.6
Fig. 12.72 The disease may appear concomitantly with a dermatophytosis and this often
Perianal Crohn’s disease: makes the diagnosis difficult.7
multiple skin tags showing
massive edema are Pathogenesis and histological features
present. By courtesy The organism involved is an aerobic, Gram-positive corynebacterium,
of the Institute of C. minutissimum,3 which is a normal skin commensal. Overgrowth and
Dermatology, London, UK. dermatitis are encouraged by the damp and warm conditions of a flexural
zone. Obesity, friction, diabetes and immunosuppression are all contributory
factors.4
The characteristic clinical picture and the presence of fluorescence under
Wood’s light obviate the need for biopsies in most cases. A biopsy shows
the presence of rods and filamentous organisms in the stratum corneum
(Figs 12.75, 12.76). Inflammation is minimal.
Tinea
Tinea (or ‘ringworm’) refers to superficial dermatophytosis. Tinea is a com-
mon disease of the pelvic girdle, especially of the groins (Figs 12.77–12.79)
and is usually due to Trichophyton rubrum. It is not always spread from the
nails or feet although people with tinea manuum or unguium can spread it
to the groins or perianal skin because they are common sites of chronic itch.
Tinea cruris is itchy, and diagnosed by the presence of red–brown, scaly
patches with raised, deeper red edges extending from the groins onto the
abdomen (Fig. 12.80), buttocks (Fig. 12.81) and thighs. Annular lesions
are not always obvious. Diagnosis is not always easy because many patients
Fig. 12.73
Vulval Crohn’s disease: there is an ill-defined granulomatous infiltrate with
conspicuous giant cells in the deep reticular dermis.
Acute hemorrhagic edema of childhood

Clinical features
This is an unusual variant of leukocytoclastic vasculitis of infants and young
children that may present as tenderness, redness and swelling of the penis and
scrotum with the development of more widespread hemorrhagic lesions.1,2

Streptococci, staphylococci and adenoviruses have been implicated. The
histology shows a leukocytoclastic vasculitis.
Necrotizing vasculitis
Peniloscrotal ulceration due to necrotizing vasculitis in association with Fig. 12.74
Wegener’s granulomatosis, systemic lupus erythematosus, systemic vasculitis, Erythrasma: the flexural distribution and sharply demarcated border are characteristic
polyarteritis nodosa and hereditary spherocytosis with recurrent vascular features. By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.75 Fig. 12.76 Fig. 12.77

Erythrasma: bacilli are just visible in the upper Erythrasma: PAS stain showing elongated bacilli. Tinea cruris: there is a large erythematous lesion
stratum corneum. involving the inner thigh. From Bunker C: Male
Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Fig. 12.78 Fig. 12.79 Fig. 12.80

Tinea cruris: note the acute margin. From Bunker C: Tinea cruris: close up view. From Bunker C: Male Tinea cruris: in this patient, there is extensive
Male Genital Skin Disease. Saunders Ltd./Elsevier 2004. Genital Skin Disease. Saunders Ltd./Elsevier 2004. involvement. From Bunker C: Male Genital Skin
Disease. Saunders Ltd./Elsevier 2004.
have been previously misdiagnosed and/or partially treated with topical have been suppressed, although there is often subtle postinflammatory
corticosteroids or topical antifungal agents. This presentation is called tinea hyperpigmentation.
incognito (Fig. 12.82) in the previously topical corticosteroid-treated patient Tinea of the penis or scrotum1 is not common and when it occurs it is
where the symptom of itch and the signs of inflammation, including redness, usually associated with crural disease. Rarely encountered is tinea on the
the scale and the well-demarcated often scalloped, elevated active margins, glans penis with an itch or pain and producing an erythematous patch or a
Condyloma acuminatum (genital warts,

human papilloma virus( HPV) infection)
Clinical features
Genital warts (condyloma acuminatum) are usually caused by HPV types
6, 11, 16, 18, 30–32, 42–44 and 51–55.1–5 HPV-7, usually associated with
warts in butchers, can exceptionally be the cause of condylomas.6 HPV-6
and 11 account for approximately 90% of these lesions.2,7 However, more
than one HPV type can be isolated from a single lesion.8 They occur on the
glans penis and prepuce or shaft as soft, fleshy (sometimes filiform) plaques
and may extend into the meatus (Figs 12.83, 12.84). On the shaft, they are
less exophytic. Vulval lesions may be bulky and macerated, and can extend
into the introitus (Figs 12.85–12.87). Often, lesions are difficult to detect
on clinical examination.1,9,10 Vulval condylomata usually involve the labia
minora, interlabial sulcus or the area around the introitus. Similar fleshy
and filiform soft masses may occur perianally and in the anus, more often
in males (Fig. 12.88).11 Anal and cervical squamous carcinomas have also
been shown to contain HPV types 6, 16 and 18 in a significant proportion of
Fig. 12.81
Tinea cruris: note the bilateral involvement of the buttocks.
cases.4 Genital warts in children always raise the possibility of sexual abuse
but can occur with close nonsexual contact.12 However, nonvenereal viral
warts (verruca vulgaris) mainly caused by HPV type 2 can occur in both
young girls and less frequently in adult women, so HPV typing can be very
important.13 Young sexually active adults are the most frequently affected
(second and third decades), and often in association with other sexually
acquired infections.2,5,14
Rarely, condyloma acuminatum presents in the oral cavity.15 Recently,
condylomata have been reported in the abdominal pannus fold of a few obese
patients.16
It is important to recognize that a significant proportion of genital HPV
infections are asymptomatic.1,17 The female partners of male patients with
genital warts have been shown to have an increased risk of cervical HPV
infection and intraepithelial neoplasia.18 Cervical neoplasia associated with
pre-existent vulval warts has also been related to immunosuppression, at
least in some patients.19 Up to 80% of invasive cervical squamous carcinomas
have been shown to contain HPV DNA. Types 16, 18, 31–33, 35, 39, 42
and 51–54 are most commonly associated with cancer of the cervix, vulva
and penis.4,5,20 Malignant transformation of genital warts is rare but may be
found in association with penile bowenoid papulosis and vulval intraepithe-
lial n
eoplasia (VIN) usual type (undifferentiated).3,21–24
A large, exuberant and locally destructive variant of condyloma (Buschke-
Löwenstein tumor) may rarely be encountered.25,26 This is associated with
Fig. 12.82 HPV-6, 11 or 16. It is considered by many to be a variant of verrucous
Tinea incognito: there is extensive involvement of the abdomen, groins, thighs and
scrotum. This followed injudicious use of topical steroids. From Bunker C: Male
crop of scaly papules. Pandey et al.2 associated penile tinea (in India) with
occlusion due to the wearing of a langota – described as a T-shaped bandage
tied over the genitalia.
Trichosporosis
Clinical features
Trichosporosis due to Trichosporon beigelii is a common form of genitocrural
and perianal intertrigo in India.1 Predominant symptoms are itching or burning.
Scaly papules can accompany the intertrigo. Coexisting dermatophyte,
Candida, trichomycosis and erythrasma infection may be found. Infection
rarely occurs elsewhere, including the scalp.2,3
The infection involves the hairs but not the surrounding skin. Microscopic
examination of hair shafts shows white or brown soft nodules of varying size Fig. 12.83
that can easily be removed.2 The diagnosis is suspected by a KOH preparation Condyloma acuminatum: multiple erythematous, velvety plaques are present on
to identify variable-sized arthrospores and is confirmed by culture. the glans penis. By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.85
Condyloma acuminatum:
multiple gray lesions
are evident on the labia
minora and around the
vestibule. By courtesy
of the Institute of
Fig. 12.84
(A) in this patient the
lesions have a typical
filiform appearance;
(B) multiple condylomata
are present on penis and
scrotum. By courtesy
Genitourinary Medicine,
B St Thomas’ Hospital,
London, UK.
Fig. 12.86
c arcinoma, a subtype of well-differentiated squamous carcinoma (see below). Condyloma acuminatum:
However, the issue still remains controversial and other authors regard it in this patient the
as a distinctive entity. Juvenile laryngeal papillomata containing HPV-6 and condylomata are
11 can be seen in children born to mothers with condylomata acuminata.1 pedunculated and have
extended onto the thighs.
They may show malignant progression if irradiated. The condition has been
By courtesy of the
described in an HIV-positive patient.27 Institute of Dermatology,
London, UK.
Condylomata acuminata are characterized by marked acanthosis with a solid
or trabecular pattern and a broad, rounded, exophytic growth (Figs 12.89, rominent degenerative changes with cytoplasmic vacuolation, nuclear
p
12.90). There is a sharp, fairly regular, deep margin. The surface of the enlargement and metaphase arrest. The changes, however, tend to be more
lesion is hyperkeratotic and parakeratotic. Superficial vacuolated keratino- focal, and abnormal mitotic figures are not seen. Immunohistochemical stains
cytes (koilocytes) are characteristic (Fig. 12.91). The vacuolated epithelium for papillomavirus common antigen have been used to confirm the diagnosis
is often most marked in the declivities. Care must be taken not to confuse but this is only positive in about 60% of cases.30 More recently, in situ hybrid-
koilocytes with the vacuolated, glycogenated keratinocytes of mucosal ization in paraffin-embedded tissue has become available.
epithelia. Distinction can be made fairly readily as koilocytes have an enlarged, Giant condyloma acuminatum (Buschke-Löwenstein tumor) occurs most
wrinkled, hyperchromatic nucleus. frequently on the genitalia, and is larger and more cauliflower-like.24,25,31 It
Care should be taken in the histological interpretation of lesions that shows some tendency to endophytic growth, but without any suggestion
have previously been treated with podophyllin (although this treatment is of frank infiltration. It can recur locally. Anal condylomata may develop
seldom used nowadays since the advent of imiquimod).28,29 These can display bowenoid features, and occasionally invasive tumors supervene.3,4
Fig. 12.87
there is very extensive Fig. 12.89
disease. The patient Condyloma acuminatum: there is focal parakeratosis, slight papillomatosis and very
is at considerable risk marked acanthosis. The lower border is sharply demarcated.
of developing cervical
disease. By courtesy
St George’s Hospital,
London, UK.
Fig. 12.90
Condyloma acuminatum: this is a much more florid example. Note the gross
papillomatosis and very marked acanthosis.
Fig. 12.88 exposures, type of sexual practice and the location and number of the part-
Condyloma acuminatum: perianal involvement is likely to be associated with ner’s lesions.2 There is a close relationship between syphilis and HIV infec-
homosexual activity. By courtesy of R.A. Marsden, MD, St George’s Hospital, tion and both diseases can be acquired together.7–9 It is recognized that
London, UK. diseases such as syphilis that induce genital ulceration increase the risk of
acquiring HIV infection.9
The causative organism is Treponema pallidum, a spirochete with fastidi-
Syphilis ous growth requirements. Transmission is primarily sexual. An endemic form
known as bejel, caused by an identical organism, occurs in children living in
Clinical features conditions of poor hygiene and is transmitted by cutaneous inoculation.10
The incidence of syphilis fell dramatically after the introduction of penicillin Other endemic forms have been associated with shared drinking vessels when
in the 1940s. In recent years the incidence has been rising annually largely due some members of the community have oral or labial syphilitic lesions.
to the increased number of cases of human immunodeficiency virus (HIV) The typical initial lesion, a chancre, deveops 20–30 days after exposure
infection. Drug abuse and high-risk sexual behavior are also contributory to the organism at the site of inoculation. This can be anywhere on the
factors.1–3 ‘Prostitution for drugs’ is particularly important.2 The increase in anogenital skin, more often on the glans penis (especially the coronal sulcus),
the incidence of syphilis continues, especially in HIV-infected patients with the shaft or prepuce, or on the labia majora or minora (Figs 12.92–12.96).5
predilection for young homosexual black males.4 At least 5% of primary chancres arise at extragenital locations, most com-
In the sixteenth century, syphilis carried a high mortality associated monly oral but virtually every other part of the skin surface may be affected
with a chronic disfiguring and disabling disease. The disease currently including the tonsils, fingers, eyelids and nipples (Figs 12.97, 12.98).2,5,11,12
appears less aggressive, even in untreated cases. It is highly infectious, with Lesions in the vagina or cervix may go undetected. The chancre appears as an
the risk of transmission from an infected partner ranging from 30% to indurated, punched-out, painless ulcer. It is usually accompanied by painless
51%.5,6 The chance of acquiring the disease depends upon the number of lymphadenopathy. This resolves without scarring after 1–5 weeks.
Fig. 12.93
Primary syphilis: painless lymphadenopathy is often present. By courtesy of C. Furlonge,
Fig. 12.91 MD, Port of Spain, Trinidad.
there are conspicuous
koilocytes with irregular
nuclei and vacuolated
cytoplasm.
Fig. 12.94
Primary syphilis: in this patient the chancre has a punched-out appearance. By courtesy
Fig. 12.92
Primary chancre: the chancre is a painless ulcer with an indurated edge. The base is
yellow and harbors large numbers of spirochetes. By courtesy of F. Lim, MD, King’s
College Hospital, London, UK.
The secondary cutaneous lesions (syphilids) are highly infectious and may
mimic virtually any skin disorder. They present 6–8 weeks after the appear-
ance of the chancre.13 They develop insidiously (in up to 80% of patients),
with a roseolar, macular–erythematous rash, on the head, face and neck fol-
lowed by a polymorphic papular eruption.5 The macules measure 5–10 mm
in diameter, are not pruritic and particularly occur on the trunk, abdomen
and limbs, especially the palms and soles (Figs 12.99–12.104).13 The papular
lesions are characteristically coppery red in color and 3–10 mm in diameter.
Hypopigmentation of the neck is known as the ‘collar of venus’.13
Other manifestations described include condylomata (in intertriginous
areas), annular, lichenoid, papulosquamous lesions (psoriasiform), arcuate
lesions, corymbose brownish-red papules (Gr. korymbos, clusters of ivy flowers), Fig. 12.95
bullous, erythema multiforme like follicular and pustular variants on the skin, Primary syphilis: a typical chancre is present on the left labium majus. By courtesy
with erosive ulcers (mucous patches), often of ‘snail track’ type, and the (highly of R.N. Thin, MD, St Thomas’ Hospital, London, UK.
Fig. 12.96 Fig. 12.99
Primary syphilis: typical ‘kissing ulcers’ are present within the vestibule. By courtesy Secondary syphilis:
of D. Barlowe, MD, St Thomas’ Hospital, London, UK. the face is commonly
affected. Note the
numerous papules.
By courtesy of R.N. Thin,
MD, St Thomas’ Hospital,
London, UK.
Fig. 12.97
Primary syphilis: oral chancres are most often located on the lip. By courtesy of
R.N. Thin, MD, St Thomas’ Hospital, London, UK.
Fig. 12.100
Secondary syphilis: this patient shows a widespread hyperpigmented
maculopapular eruption. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
infectious) condylomata lata affecting the mucosae (Figs 12.105–12.108).14–21

Keratoderma can also be seen.22 Large hypertrophic condylomata are known
as framboiseform syphilids.12 Other variants described are acneform, varioli-
form and, rarely, necrotic (Fig. 12.109). Lesions tend to be widely disseminated
and often symmetrical in distribution.5 Papular involvement of the scalp may
result in nonscarring, patchy alopecia (Fig. 12.110).23 The alopecia induced
by secondary syphilis is known as alopecia syphilitica and has a characteris-
tic, moth-eaten appearance.24,25 The beard, eyebrows and eyelashes may also be
affected.5 Telogen effluvium has also been described.13
Rare ‘malignant’ forms of syphilis present with rapid progression, pap-
ulopustular lesions, much ulceration and rupial lesions (Gr. rhypos, filth;
necrotic lesions covered by dirty, lamellated encrustation resembling oyster
shells) mainly affecting the face and limbs.13,26,27 Patients can also present with
Fig. 12.98 fever, eye involvement, myalgia, lymphadenitis, and hepatosplenomegaly.28
Primary syphilis: a chancre is present at the edge of the anal ostium. By courtesy of This form of syphilis has been described in association with HIV infection
R.N. Thin, MD, St Thomas’ Hospital, London, UK. and is characterized by necrotic and ulcerative lesions.29–31
Fig. 12.101
Secondary syphilis: note the widespread papules and nodules many of which have
a hypertrophic appearance. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
Fig. 12.103
(A, B) Secondary syphilis:
erythematous and scaly
papules involving the
palms and soles are
present in this patient
with secondary syphilis.
(A) By courtesy of R.A.
Hospital, London, UK; (B)
by courtesy of R.N. Thin,
Fig. 12.102 MD, St Thomas’ Hospital,
B
Secondary syphilis: the palms are almost invariably affected. By courtesy of the London, UK.
Secondary syphilis manifestations have typically been described as

onpruritic, but this is not always the case.2,5,32 Indeed, in the series of 105
n
patients with secondary syphilis published by Chapel, 42% complained of
pruritus.33 Resolution may be accompanied by hypo- or hyperpigmenta-
tion.5 Lymphadenopathy, which may be widespread and is painless and rub-
bery, occurs in 50–85% of patients.5 The cutaneous manifestations are often
accompanied by pyrexia, headache, weight loss and non-specific muscle and
joint aches.13 Periostitis can rarely occur.34 Ocular involvement including
uveitis and retinitis can occur at any stage of the disease.35 Untreated lesions
of syphilis resolve in 2–10 weeks.13 When syphilis is treated with antibiotics,
there may be a self-limited febrile reaction known as the Jarisch–Herxheimer
reaction associated with systemic symptoms.
Atypical clinical forms of syphilis have been reported in HIV-positive
patients,36,37 and multiple genital ulcers may occur in primary syphilis as well
as concomitant ulcer with secondary syphilis.38
Secondary syphilis is followed by a latent phase, which may precede a
change to: Fig. 12.104
• seronegativity and cure, Secondary syphilis: in this patient, typical copper penny macules with surrounding
• persistent seropositivity without further lesions, annular scale (Biette’s collarette) contrast with confluent exfoliation on the palms.
• development of tertiary lesions. By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.105 Fig. 12.108
Secondary syphilis: this is a typical corymbose eruption. Note the circumscribed, Secondary syphilis: early perianal condylomata lata. By courtesy of R.N. Thin, MD,
confluent, erythematous scaly papules. By courtesy of the Institute of Dermatology, St Thomas’ Hospital, London, UK.
London, UK.
Fig. 12.106 Fig. 12.109
Secondary syphilis: pustular lesions, as seen on this patient’s face, are a rare Secondary syphilis: in
manifestation. By courtesy of R.N. Thin, MD, St Thomas’ Hospital, London, UK. this patient the lesions
greatly resemble pityriasis
lichenoides. By courtesy
London, UK.
These late lesions involve mainly the cardiovascular (aortic incompetence)

and central nervous system (tabes dorsalis and general paresis of the insane),
but cutaneous lesions are seen as noduloulcerative lesions and gummata that
tend to break down with central necrosis and suppuration. Gummata may
occur up to 15 years after the initial infection. They are painless, frequently
ulcerated, firm subcutaneous nodules that show a predilection for the scalp,
face, chest and legs (Fig. 12.111).35,39 Noduloulcerative late syphilitic lesions
present as superficial nodules that extend peripherally and heal centrally to
form ulcerated serpiginous plaques.40,41 Lesions of tertiary syphilis can be
seen in internal organs and may clinically mimic cancer.42
Infants born to infected mothers may have widespread lesions reflect-
ing a systemic infection (congenital syphilis). Development of the disease is
mainly associated with lack of antenatal screening.43 These include fibrosis
Fig. 12.107 in many organs, with inflammatory changes seen particularly in bones and
Secondary syphilis: note the symmetrically distributed ‘snail track’ ulcers. By courtesy lungs. Vesicular skin lesions and maldevelopment of teeth and bone are also
of R.N. Thin, MD, St Thomas’ Hospital, London, UK. sometimes evident. Later changes of congenital syphilis are classically frontal
produced by host inflammatory cells. A hyaluronidase is associated with the

surface of T. pallidum and may facilitate dissemination in tissues.45
After the first inoculation of the spirochete through mucosa or abraded skin, the
organism becomes systemically distributed before the primary c hancre develops at
the site of inoculation and numerous spirochetes can again be identified.
The chancre is characterized histologically by initial epidermal hyperpla-
sia with an intense lymphohistiocytic and neutrophil infiltrate in the dermis
(Figs 12.112–12.114). Plasma cells are present, but may be more numerous
in papular and papulosquamous secondary lesions (see below). The overlying
epithelium becomes ulcerated, and the adjacent epidermis often shows pseu-
doepitheliomatous hyperplasia and infiltration by neutrophils. The indura-
tion of the primary lesion is due to a large amount of mucoid substance.
Vascular endothelial cell swelling is often prominent. The organisms can be
demonstrated by dark-field examination of a smear taken from the primary
lesion. A silver stain such as Warthin-Starry or more recently immunohis-
tochemistry are also useful in demonstrating the organisms in tissue sections.
By electron microscopy, the spirochetes are often found in macrophages,
endothelial cells, plasma cells and in the intercellular space close to small
blood vessels.46 Resolution of the chancre, while appearing to coincide with
Fig. 12.110 immunity to further infection and demonstration of antibodies, neverthe-
Secondary syphilis: scalp involvement is not uncommon. Note the scaling and hair
less does not impede the widespread dissemination and proliferation of the
loss. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.
treponeme. This leads to its recrudescence in the secondary phase, a paradox
that is not understood.
Fig. 12.111
Syphilis: the presence of
gummatous cutaneous Fig. 12.112
lesions as seen in this Primary syphilis: biopsy from a chancre on the penis. Note the typical punched-out
elderly male is now a appearance.
very rare manifestation.
By courtesy of M.M.
bossing, a short maxilla, a high arched palate, chronic interstitial kerati-

tis, notched (Hutchinson’s) incisors, Mulberry’s molars, VIII cranial nerve
deafness and saddle nose.44 Other manifestations include painless hydroar-
throsis, perforation of the nasal septum and palate, and cardiovascular and
neurological changes, as seen in late-stage adult disease.

T. pallidum is a slender, coiled organism, 6–16 μm long, capable of an undulat-
ing, corkscrew-like motion. The organisms are readily visualized in material
from a primary chancre with dark-field illumination, but have only recently
been grown in culture. The usually nonpathogenic spirochetes, which live as
commensals around the gingiva, although still termed Treponema, are quite
different, not least in that they have a right-handed spiral in contrast to the
left-handed spiral of T. pallidum and other pathogenic spirochetes.
T. pallidum produces a nonantigenic mucin coat, which may be protective Fig. 12.113
in early infections. This mucoid element may be increased by a component Primary syphilis: note the marked endothelial swelling.
Fig. 12.114 Fig. 12.116
Primary syphilis: the infiltrate consists of lymphocytes, histiocytes and conspicuous Secondary syphilis: the infiltrate contains large numbers of plasma cells. This
plasma cells. specimen comes from a condyloma lata.
Secondary lesions show variable appearances depending to some extent

upon the clinical morphology (Figs 12.115–12.122).47–50 Purely macular
lesions are not distinctive and show a rather sparse perivascular lymphohistio-
cytic infiltrate with few, if any, plasma cells.13 The epidermis is normal. As the
lesions develop a papular morphology, superficial and deep perivascular infil-
trates develop, which may also adopt a band-like distribution. Involvement
of the subcutis is rare. Plasma cells become more numerous and parakerato-
sis, acanthosis, spongiosis and exocytosis may be evident. Thick-walled blood
vessels with swollen endothelial cells are characteristic. A prominent infiltrate
is often present around hair follicles and sweat glands. Early lesions showing
perivascular neutrophils and a heavy neutrophilic infiltrate mimicking Sweet’s
syndrome has been reported.51 Psoriasiform syphilids show parakeratosis and
acanthosis with extended (psoriasiform) epidermal ridges. The inflammatory
cell infiltrate is both perivascular and superficial, and band-like in distribu-
tion. Spongiform pustulation and neutrophil exocytosis may be evident, and
focal cell hydropic degeneration can sometimes be present.14,50 Keratinocyte
necrosis may occasionally be seen.50 Leukocytoclastic vasculitis is very rare.52
Fig. 12.117
Secondary syphilis: in this example, there is hyperkeratosis, irregular acanthosis
and a very dense dermal infiltrate.
Fig. 12.115
Secondary syphilis:
there is very marked
hyperkeratosis and
parakeratosis. The
epidermis shows
psoriasiform hyperplasia.
A dense inflammatory
cell infiltrate is present in
the lamina propria. This
specimen comes from a Fig. 12.118
condyloma lata. Secondary syphilis: spongiosis is evident.
Fig. 12.119 Fig. 12.122
Secondary syphilis: in this field, there is marked interface change. Secondary syphilis: numerous spirochetes are present (Warthin-Starry stain).
Erythrocyte extravasation may be a feature of both papular and papu-

losquamous variants. A granulomatous element has been described in both papular
and papulosquamous eruptions, but this is not a constant feature.50 In addition to
a dense dermal infiltrate, large numbers of plasma cells and occasional giant cells
are seen in corymbose syphilis. The number of organisms in secondary syphilis
varies. Traditionally, they have been identified by the use of silver stains, mainly
Warthin-Starry. However, the latter method is time consuming and difficult to
interpret. The organisms can also be identified by PCR and a polyclonal antibody
against Treponema pallidum is available for immunohistochemistry.53–56 Both
PCR and immunohistochemistry are much more specific than histochemistry in
the diagnosis of syphilis.55–57 In primary syphilis, the organisms are found both
within the epidermis and around blood vessels, while in secondary syphilis organ-
isms are mainly found within the epidermis, suggesting that these patterns can
be used as an aid in distinction between the two stages of syphilis.56 The bacteria
have also been identified in vivo in the epidermis by the use of reflectance confocal
microscopy.58 In a case of malignant syphilis, a surprisingly very low number of
organisms was found in the lesions.59 Spirochetes have been demonstrated within
hair follicles in a case of alopecia syphilitica.60
The nodular variants of secondary syphilis may be associated with granu-
lomatous or pseudolymphomatous histology.61–63 Some lesions can contain
Fig. 12.120 an impressive number of CD30-positive atypical T cells.64 The granulomata
Secondary syphilis: note the marked endothelial cell swelling.
can mimic those of sarcoid and may rarely have a palisaded distribution
resembling granuloma annulare.61,65 The rupial and condylomatous forms
are characterized by marked epidermal hyperplasia, spongiosis and a neutro-
phil infiltrate. The dermis contains a very heavy inflammatory cell infiltrate
including numerous plasma cells. Vascular changes are marked.
Late secondary lesions are typified by histiocytic granulomata.40 These are
not well circumscribed and do not usually include multinucleated giant cells.
They can be distinguished from tuberculosis by the presence of numerous
plasma cells peripherally and the swollen endothelia of small blood vessels.
Gummata are characterized by central necrosis similar to caseation, but
with a visible suggestion of residual cell outlines (Fig. 12.123). The necrosis
is surrounded by a lymphohistiocytic and plasma cell infiltrate with fibrosis.
Spirochetes are very scanty and very difficult to find with the use of silver
stains. Endarteritis is often evident.
Noduloulcerative lesions are granulomatous and typically there is no
significant necrosis. Plasma cells are said to be inconspicuous, which may
therefore cause considerable diagnostic difficulty.41,66
Granuloma inguinale
Clinical features
Granuloma inguinale (donovanosis) occurs in people with poor hygiene in
Fig. 12.121 tropical regions, mainly in India, Brazil, the West Indies, South China and West
Secondary syphilis: innumerable plasma cells are present. Africa; it was formerly seen in southern USA, but is now rare.1–7 The disease
Fig. 12.123 Fig. 12.125
Gumma: high-power view reveals ghost outlines of cells and connective tissue. Granuloma inguinale: in this patient there is extensive ulceration of the glans penis.
Note the typical ‘beefy’ appearance. By courtesy of C. Furlonge, MD, Port of Spain,
Trinidad.
is still seen in Australia in the Aboriginal population.8 The organism is of low
infectivity and is presumed to be spread by sexual contact, probably through
abraded skin. It occurs most often in the third to fifth decades.1 The incubation seen (mainly mouth or lips but also at unusual sites such as the foot).12,16–18
period is uncertain and may range from 2 to 3 weeks to several months.9 Exceptionally, presentation as a psoas abscess and as a pelvic mass mimicking
The initial presentation in females is usually of one or more indurated ovarian cancer has been described.19–21
papules or nodules on the inner aspect of the labia, the fourchette or around Very occasionally, there is a systemic infection with involvement of
the clitoris (Fig. 12.124).10 In males, the glans, prepuce, coronal sulcus or many organs including the liver, and osteolytic lesions in bone.22 The lat-
shaft is affected (Fig. 12.125). Dorsal perforation of the prepuce can occur ter may particularly relate to a primary cervical lesion.1 Spinal compression
as a late complication.11 The perianal and inguinal regions and the cervix has also been reported.23 Later complications include strictures of the ure-
may also be involved.12–15 In one case involving the cervix there was associ- thra, vagina or anus, destruction of the penile shaft with autoamputation
ated malacoplakia.15 The papules ulcerate irregularly and extend widely if and pseudoelephantiasis.1,24–27 As with other sexually transmitted diseases,
untreated. The base of the ulcer is ‘beefy’ and the margins are undermined patients with granuloma inguinale are often HIV positive and may also have
and indurated. Spread to contiguous ‘kissing’ areas may sometimes occur. syphilis.9,28 Genital squamous cell carcinoma is an uncommon but important
Variants include verrucous, necrotic and scarring lesions.1 Primary infection complication.1,29,30 Infection in children has rarely been reported and occurs
of the lymph nodes does not occur, but painful lymphadenopathy is common as a result of transmission from an infected mother at birth.31 Rare manifes-
due to secondary infection. Rarely, primary extragenital lesions may be tations of the disease in children include a mass in the neck, otitis media and
mastoiditis.32,33

Granuloma inguinale is caused by Calymmatobacterium granulomatis
(formerly Donovania granulomatis), an encapsulated short (1–2 μm)
Gram-negative rod with characteristic bipolar staining. It is transmitted by
sexual contact, but it is of low infectivity.1 The organism is found in feces and
this may act as a reservoir of infectivity or, in occasional cases, be the source
of genital infection. The higher incidence of infection in homosexuals may
support this concept.
The lesion is characterized by a very intense inflammatory infiltrate
in which plasma cells are predominant (Fig. 12.126). Focal forma-
tion of neutrophilic microabscesses is frequent. Pathognomonic mac-
rophages contain cytoplasmic cyst-like vacuoles in which bacteria can
be demonstrated by staining with Giemsa or the Warthin-Starry reaction
(Figs 12.127, 12.128).34 The bacteria can also be seen extracellularly. In
most cases there is associated acanthosis, which sometimes amounts to
pseudoepitheliomatous hyperplasia. Ulceration is common. A recent large
study has demonstrated frequent transepidermal elimination of organ-
isms.35 It is likely that this phenomenon may be an important mechanism
in the spread of the disease.
Fig. 12.124 Diagnosis is confirmed by the identification of typical organisms
Granuloma inguinale:
(Donovan bodies) on a scraping from an ulcer or in a biopsy stained with
early lesion showing an
ulcerated papule adjacent Giemsa or Warthin-Starry. More recently, polymerase chain reaction (PCR)
to the clitoris. By courtesy has been used successfully to confirm the diagnosis.36 Dark-field illumination
of J. Lawson, MD, microscopy should be performed to exclude syphilis. By electron microscopy,
University of Newcastle- the encapsulated microorganisms can be demonstrated within the phagosomes
upon-Tyne, UK. of macrophages.9,37
Chancroid
Clinical features
Chancroid (soft chancre, genital ulcer disease) is very common in some tropi-
cal areas of Africa, Southeast Asia, Central America and the Pacific.1–4 Poor
hygiene is a feature of communities where the disease is endemic.5 It is associ-
ated with an increased risk of transmission or acquisition of HIV.6,7 Genital
ulcers including chancroid appear to develop more commonly in HIV-positive
women during the first month of antiretroviral therapy.8 It has also been diag-
nosed more frequently in Western Europe and North America in association
with increased travel, immigration and prostitution. Chancroid was endemic
in New York City and southern Florida in the 1980s.6 It represented 3% of
genital ulcers in a sexually transmitted disease clinic in Paris.9 The disease is
acquired almost always by sexual contact and has a short incubation period
of 3 days to 2 weeks (median 7 days). Exceptionally, nonsexually transmitted
lower limb chancroid ulcers have been reported in patients from Papua New
Guinea and Samoa, in both adults and children.10,11 Concurrence with other
sexually transmitted d isease including gonorrhea can be seen.12
Fig. 12.126 The initial lesion is usually a transient vesicular tender papule, which
Granuloma inguinale: biopsy from the penis. Note the pseudoepitheliomatous rapidly ulcerates with copious suppuration. The ulcer is sharply circum-
hyperplasia. There are intense inflammatory changes. scribed with an undermined edge and is typically not indurated.2 These
lesions appear much more commonly in the male, usually on the penis
(Fig. 12.129). The prepuce, coronal sulcus, frenulum and glans are the most
favored sites.6 Circumcised males are at lower risk of developing the dis-
ease.13 Lesions in the female are seen on the fourchette, labia majora and
minora, and periclitorally. The perineum and perianal area may also be
affected. Multiple ulcers can be present, which have an irregular ragged edge
and slough-covered bases. Cervical and vaginal involvement is uncommon.
Variants of primary chancroid ulcers include giant and serpiginous forms,
follicular, transient and dwarf lesions; occasionally a condyloma lata-like pre-
sentation may occur.2
The ulcers are tender and especially painful when in contact with urine.
Lymphadenitis occurs in about 50% of cases approximately 1 week after the
genital lesion and, in 50% of these, suppuration (bubo formation) usually
follows. Sometimes rupture may occur, resulting in inguinal ulceration. In
other cases the course is variable, some resolving without treatment in a
few days while others go on for several weeks, developing phimosis or even
gangrene. Systemic infections do not occur.2

Fig. 12.127 Chancroid is caused by Haemophilus ducreyi, a Gram-negative coccobacil-
Granuloma inguinale: the infiltrate consists of lymphocytes, neutrophils, plasma lus, which grows in chains sometimes arranged in parallel. It is transmitted
cells and conspicuous pale-staining histiocytes. through minor abrasions during sexual intercourse. The subsequent lesion
comprises:
Fig. 12.128 Fig. 12.129
Granuloma inguinale: the histiocytes contain characteristic Donovan bodies Chancroid: irregular ulcer extending along the coronal sulcus of the penis. By courtesy
(Warthin-Starry stain). of R.A. Marsden, MD, St George’s Hospital, London, UK.
Fig. 12.130 Fig. 12.131
Chancroid: (A) biopsy Chancroid: note the coccobacilli growing in chains.
through an ulcer on the
glans penis; (B) note the
conspicuous plasma cells. homosexuals and in the context of HIV infection.1–5 It is less common in
By courtesy of S. Lucas, women.6–10
A MD, St Thomas’ Hospital, The disease evolves in three stages:
London, UK. • In stage 1 disease the primary lesion develops 3–30 days after contact
and is a small, transient, frequently asymptomatic papulovesicle
or ulcer on the penis, scrotum, rectum, vulva, vagina and/or cervix
(Figs 12.132,12.133).11 The most commonly affected site on the vulva
is the fourchette.6 Primary lesions have been described on the fingers
and tongue.12 Rarely, lymphogranuloma venereum has been reported
presenting with a psoas abscess.13 Cat scratch disease may clinically
simulate this disease.14
• Stage 2 develops within a few weeks of the primary lesion and consists
of enlargement of the regional lymph nodes; the inguinal nodes in the
male, and, in the female, the inguinal and/or pelvic lymph nodes. The
lymphadenopathy is severe and initially painless and hard; later the
nodes (buboes) soften and discharge viscous pus. The tissue around
the nodes becomes involved in the inflammatory process so that they
• a superficial zone of neutrophils, red cells, bacteria and cell debris,

• a middle zone of edematous granulation tissue,
• an underlying infiltrate of histiocytes, lymphocytes and plasma cells
(Figs 12.130, 12.131).
The enlarged lymph nodes show central necrosis with a surrounding mixed
inflammatory response of neutrophils and macrophages.
Diagnosis is confirmed by isolation of the organism by culture in a blood-
enriched medium containing vancomycin at 33°C. The bacterium may be
identified by its chain-like growth in scrapings from the margin of the ulcer,
but secondary organisms are often present and it is more helpful to identify
the organism in an aspirate from a necrotic lymph node. DNA in situ hybrid-
ization and polymerase chain reaction for H. ducreyi has been developed.14,15
DNA from the organism has been detected by polymerase chain reaction in
esophageal lesions of HIV-positive patients.16
Lymphogranuloma venereum Fig. 12.132

Lymphogranuloma
venereum: note the ulcer
Clinical features on the right labium majus.
Lymphogranuloma venereum is endemic in Asia, Africa and South America By courtesy of S. Lucas,
and was considered to be rare in developed countries until several outbreaks MD, St. Thomas’ Hospital,
were reported in a number of European countries and the USA, mainly in London, UK.
Schistosomiasis
Clinical features
Schistosoma hematobium and Schistosoma mansoni are both found exten-
sively in Africa. S. mansoni also occurs in the West Indies and in parts of
South America. S. japonicum is present in China, Japan and Southeast Asia.
These trematodes (blood flukes) do not often cause major disease of the skin,
but skin lesions do occur at various stages of infestation.1–13
Invasion of the human host by the aquate cercarial stage may be associated
with dermatitis (swimmer’s itch).3,9,11 This rash is erythematous, pruritic and
urticarial, but eventually resolves to leave a pigmented spot. It is more often
encountered with invasion of avian species.3
In schistosomiasis (bilharziasis) the mature worms may be associated
non-specifically with erythematous itching macules at the time of release of large
numbers of eggs. This probably represents a systemic reaction to antigen libera-
tion. A more severe reaction seen particularly with S. japonicum is Katayama
disease or Yellow River fever. In addition to erythema, macules and pruriginous
lesions, patients may also have fever, malaise, chills, sweats, arthralgias, headache,
Fig. 12.133 lymphadenopathy, hepatosplenomegaly and peripheral blood eosinophilia.3
Lymphogranuloma venereum: there is an ulcer on the penile shaft covered with Specific skin lesions are seen, usually around the genitalia and most often
necrotic debris. By courtesy of the Institute of Dermatology, London, UK. in women mainly before puberty, when ova are deposited there (Fig. 12.134).
They appear as grouped solid papules, which subsequently become warty
become matted together. Along with lymphadenopathy, the patient may and vegetative, resembling condyloma acuminatum (Fig. 12.135). The labia
also experience malaise, joint pains and hepatosplenomegaly. Erythema majora are often involved first. Occasionally, progression to squamous cell
nodosum, light-sensitive eruptions and erythema multiforme may carcinoma occurs. Periurethral granulomata due to schistosomes may be asso-
complicate this phase and are more common in women. ciated with thrombosis and necrosis, sometimes resulting in fistula formation
• Stage 3 disease consists of complications of the early inflammatory in the perineum (‘watering can perineum’).3 In late lesions prominent scarring
changes. Involvement of the deep iliac and perirectal lymph nodes may occur. More rarely, entrapped ova are seen in other areas of skin, but
resulting from drainage from a high vaginal, posterior urethral, cervical the means of their migration to those sites is not understood. Extragenital
or rectal primary lesion may be complicated by a stricture of the rectum lesions of schistosomiasis have been described in the trunk (mainly periumbil-
5–10 cm from the anus.15 This is associated with periproctitis and ical but also in the axilla, back and inframammary area), face and proximal
proctocolitis, which sometimes fistulates.16,17 Rectal carcinoma is an lower limbs.4,6,8,14 Facial lesions may be associated with ocular involvement.8
occasional late complication.18 In both sexes, genital lymphedema and Extra-anogenital schistosomiasis, also known as extra-anogenital bilharzia-
even elephantiasis can develop after the lymphadenopathy. This may be sis cutanea tarda, is very rare and its recognition is extremely important as
a continuing problem and can be associated with secondary cutaneous it is usually a sentinel as well as a potential external marker of recurrent
erosions and ulceration. visceral disease.14 Interestingly, it has been noted that this type of disease often
Systemic lesions are rare, and include cardiac and pulmonary involvement, occurs in pre-existing cutaneous pathology including a squamous papilloma,
keratoconjunctivitis, episcleritis, uveitis, papilledema and retinal hemorrhages, squamous cell carcinoma, scarring and hidradenitis suppurativa.14
meningitis, hepatitis and cutaneous manifestations such as erythema nodosum
and erythema multiforme.7,19

Lymphogranuloma venereum is caused by strains L1, L2 and L3 of the
bacterium Chlamydia trachomatis.20,21 The C. trachomatis species is divided
into 15 prototypic serovars according to analysis of their outer membrane pro-
tein.22 Only serovars L1 to L3 are associated with lymphogranuloma venereum.
Most cases of lymphogranuloma venereum are caused by C trachomatis
L2. Chlamydiae are nonmobile, coccoid, obligate intracellular parasites.23,24
They depend upon their host cells for ATP metabolites and multiply within
membrane-bound vacuoles in the host macrophage cytoplasm.20 They
stain faintly blue with hematoxylin and eosin, Gram-negative with the
Brown-Hopps tissue Gram stain and black with the Warthin-Starry silver
impregnation technique.25 On the rare occasions that the primary lesion is
viewed histologically, the base of the ulcer is lined by intensely inflamed
fibrous granulation tissue. Plasma cells and microabscesses are present.
The lymphadenitis has a characteristic picture of stellate central necrosis
with neutrophils and a surrounding palisaded granulomatous reaction with
occasional giant cells.
The central necrosis is slowly absorbed and replaced by fibrosis. As a Fig. 12.134
consequence, lymphedema develops distally. The lymphatics are typically Schistosomiasis: early
lesion showing labial
inflamed and granulomata may be seen.
erythema and swelling.
Diagnosis is supported by complement fixation tests (rising titers) or These features are
monoclonal antibodies.24 PCR may also be used to confirm the diagnosis.24–26 a response to ova
The Frei skin test is no longer performed. Confirmation of the diagnosis is deposition. By courtesy of
best established by isolation of the organism in tissue culture and by lymph P. Dowd, MD, Middlesex
node biopsy.27 Hospital, London, UK.
Fig. 12.135 Fig. 12.137
Schistosomiasis: this warty pale nodule has almost completely replaced the left Schistosomiasis: these ova are surrounded by a heavy infiltrate with conspicuous
labium majus; other vulval manifestations include schistosomal condylomata, ulcers eosinophils.
and rarely, vitiligo. By courtesy of the late M.S.R. Hutt, MD, St Thomas’ Hospital,
London, UK.
Pathogenesis and histological features and variable numbers of eosinophils. Poorly formed granulomata with
Langhans giant cells are also sometimes a feature. S. hematobium is
Part of the life cycle of schistosomes takes place in water snails. After their recognized by its terminal spine (Fig. 12.138). S. Mansoni has a lateral
release from the snails, the cercaria penetrates the skin of humans and migrate spine and S. japonicum has no spine. The dead ova typically calcify and
as schistosomes to the portal veins where they mature into adult male and provoke a chronic, frequently granulomatous, inflammatory response.
female worms. Adult females then migrate to the mesenteric plexus (S. mansoni The overlying epidermis is usually acanthotic, sometimes to the point of
and S. japonicum) or vesical plexus (S. haematobium). Ova are deposited pseudoepitheliomatous hyperplasia and may occasionally contain intra-
in the venules, and the clinical and pathological sequelae are a direct conse- epidermal ova undergoing transepidermal elimination (Fig. 12.139).15,16
quence of the immunological response to their presence. Smearing crushed biopsies between two glass slides with 0.5% tryptan blue
Eggs are released into the urine or feces where they hatch, releasing in saline helps to highlight the ova.17 Adult parasites can sometimes be iden-
miracidia, which enter the snail host. Involvement of the female genital tract tified in anogenital and extragenital lesions.14
is usually due to S. hematobium and occurs as a consequence of worms being Identification of the type of schistosoma can be made by molecular
transported via anastomoses between the vesical and uterovaginal venous methods.18
plexuses.
Histologically, adult worms are occasionally seen within the lumina of
dilated deep dermal veins and lymphatics (Fig. 12.136). Viable ova may
be present with a recognizable miracidial structure (Fig. 12.137). These
are usually located within abscesses containing numerous neutrophils
Fig. 12.138
Schistosoma hematobium:
Fig. 12.136 the terminal spine is
Vulval schistosomiasis: adult worms within a dilated lymphatic; the male characteristic of this
characteristically embraces the female in the gynecophoric canal. species.
Fig. 12.139 Fig. 12.140
Schistosomiasis: there is marked acanthosis. Ova are present within a breach in the Amebiasis: biopsy from a vulval ulcer, which developed as a result of direct spread
epidermis. from the anus.
Amebiasis cutis
Clinical features
Cutaneous lesions of Entamoeba histolytica are rare and more likely to occur
in adults,1–3 although cases in children have been described.4–6 These are most
commonly seen after surgical treatment of intestinal or hepatic amebiasis, but
may also occur by direct extension, perianally from the bowel or from hepatic
involvement, and by direct inoculation of the skin from other infected lesions.
Penile amebiasis may follow anal intercourse or vaginal intercourse if the
female has amebic vaginitis. HIV infection should be suspected.7 Cutaneous
lesions have been recorded on the trunk, buttocks, face (including the eyelid
and the orbit), genitalia, perineum and on the legs.3,8–12 The cervix is often
affected in genital lesions.13 Subcutaneous swellings called amebomas have
been described.9 Patients with deep tissue involvement tend to have associ-
ated contiguous disease and the prognosis tends to be worse. In HIV/AIDS
the outcome is associated with coexisting systemic diseases and death may
ensue in patients with extensive internal involvement.14
Lesions present as cutaneous ulcers with a central necrotic zone covered by a
purulent exudate, an undermined margin and an erythematous halo. The ulcers
Fig. 12.141
are irregular, but sharply defined. They spread and do not heal spontaneously.
Amebiasis: the floor of the ulcer is covered by a dense fibrinous exudate.
They are extremely painful and may be destructive. Presentation can also be
with fistulae, fissures, abscesses and polypoid or warty lesions.14 Occasionally
the latter are large and resemble ulcerating tumors. Sometimes they mimic
squamous cell carcinoma.15,16 Cases of amebiasis presenting as balanitis have
been described.17 Although painful swelling and ulceration are the principal
clinical features, frequency, dysuria and retention may be complications
Lesions are characterized by prominent ulceration, necrosis and a mixed
inflammatory cell infiltrate composed of lymphocytes, histiocytes, plasma
cells and neutrophils. The trophozoites of E. histolytica are found within
the purulent ulcer exudate and are best identified with PAS staining
(Figs 12.140–12.142).13,18 They are distinguished by their tendency to phago-
cytose red blood cells. Trophozoites and cysts are usually found in the patient’s
feces. The organisms are surrounded by neutrophils, with some lymphocytes
and plasma cells. The adjacent epidermis appears acanthotic and this may be
marked or pseudoepitheliomatous in verrucous forms. In some cases there is
thrombosis or vasculitis with intravascular amebic trophozoites.13
Demodecidosis
The pathological role of the mite Demodex folliculorum in human cuta- Fig. 12.142
neous diseases such as rosacea is controversial. However, Hwang et al.1 Amebiasis: there are numerous trophozoites present. Note the ingested red
have described a man with a long-standing pruritic eruption of multiple, blood cells.
Miscellaneous conditions 479
onomorphic, match-head sized, flesh-colored papules on the penis and

m
scrotum. Histology demonstrated intrafollicular mites and the patient was
cured with topical crotamiton.
Malacoplakia
Clinical features
Malacoplakia (soft plaque) is a result of impaired macrophage function in the
inflammatory response to bacterial pathogens, most notably Escherichia coli
but other organisms, including Staphylococcus aureus, Proteus, Pseudomonas,
Klebsiella and mycobacteria can be involved. Primary or acquired immuno-
deficiency has been found in 40% patients.1 The latter include HIV and solid
organ transplantation, mainly renal and, very rarely, heart transplant.2–4
It is most frequently described affecting the urinary tract, but it can involve
many other organs including the gastrointestinal system, lymph nodes, lower
genital tract, brain, bone, lungs, adrenals and skin.5–13 Cutaneous lesions may
be dermal and/or subcutaneous and are most common around the genitalia
(particularly the vulva) or perineum in about 41% of cases, but can be seen
at other sites including the trunk in 20% of patients, head and neck in 20%, Fig. 12.144
limbs in 10% and axilla in 10%.7 Multiple cutaneous sites can be involved Malacoplakia: the Michaelis-Gutmann bodies can be highlighted with the von Kossa
and in an exceptional case there was involvement of the skin with extension reaction.
into the calvarium and the brain parenchyma.7 Involvement of Bartholin’s
gland has also rarely been reported.14 Cutaneous manifestations are variable Fournier’s gangrene
and include papules, plaques, polyps, ulcers and sinuses. Vaginal bleeding
may occur. There may be associated malacoplakia at other sites. Fournier’s gangrene is analogous to necrotizing fasciitis and Meleney’s gan-
Underlying or related conditions, which are usually associated with immu- grene. The disease begins with urethral or appendageal polybacterial infection.
nosuppression, include carcinoma, rheumatoid arthritis, systemic lupus Most of the organisms isolated are resident urethral or lower gastrointestinal
erythematosus, hepatitis C, sarcoidosis, leukemia, lymphoma and transplan- flora, and most patients have mixed infections. In children, staphylococci and
tation.5,8,15 The skin lesions are nonprogressive, but are typically persistent. streptococci are most commonly isolated.1 A necrotizing vasculitis is initiated
that involves skin, subcutis, fascia and muscle. Classically painful erythema-
Pathogenesis and histological features tous swelling of the genitals occurs (particularly the scrotum 2, where a dark
Malacoplakia is characterized by confluent sheets of histiocytes with eosinophilic red or a black spot may appear) that spreads to perianal or lower abdominal
granular cytoplasm and small, usually eccentric, nuclei. There are characteris- skin and there may be urnary retention.3 There is crepitus but no suppura-
tic cytoplasmic, calcified, von Kossa-positive inclusions known as Michaelis- tion.4 In adults there is systemic toxicity but this may be absent in children.3
Gutmann bodies (Figs 12.143, 12.144). These are sometimes laminated and Necrosis of skin and deeper tissues can occur rapidly, and there is a very
this can be accentuated with PAS staining. They may also be positive on staining high mortality unless the diagnosis is made promptly and radical manage-
with Perl’s reaction for iron. The Michaelis-Gutmann body is sufficiently distinc- ment undertaken. Preceding surgery and instrumentation in patients with the
tive to allow cytological distinction of malacoplakia in a preparation from a skin listed risk factors is particularly important.
scraping.16,17 The histiocytic infiltrate may be mixed with neutrophils, lympho- In adults, the mortality is approximately 25% but it is lower in
cytes and plasma cells, with associated granulation tissue. Electron microscopy children.3,5
of malacoplakia shows the histiocytes to contain numerous phagolysosomes, The clinical differential diagnosis of Fournier’s gangrene includes trauma,
sometimes with intact and/or partly digested bacteria. It appears that the herpes simplex, cellulitis (streptococcal, staphylococcal), streptococcal necro-
phagolysosomes accumulate in response to chronic bacterial infections. tizing fasciitis, gonococcal balanitis and edema, ecthyma gangrenosum, aller-
gic vasculitis, polyarteritis nodosa, necrolytic migratory erythema, vascular
occlusion syndromes and warfarin necrosis.
Miscellaneous conditions
Vulvodynia
Vulvodynia is the term used to describe a burning or soreness of the vulva in
the absence of any visible cause. It is a sensory disorder and has now been
divided into two categories: touch provoked (vestibulodynia) and spontane-
ous vulvodynia. It is a clinical and not a histological diagnosis but it is worthy
of a mention as it is in the older textbooks under the heading of vestibulitis.
The term vestibulitis is a misnomer as it is not an inflammatory dermatosis
as was once thought.1 The inflammatory changes reported on biopsies from
women with this sensory disorder were non-specific and could also be found
in healthy normal vestibular epithelium.2–4 Vestibulitis, now termed touch
provoked vulvodynia (vestibulodynia), is characterized by a constellation of
symptoms and signs which include secondary dyspareunia and point tender-
ness in the vulval vestibule (particularly at 5 and 7 o'clock over the openings
to the greater vestibular glands of Bartholin) and variable erythema at these
Fig. 12.143 sites (Fig. 12.145).5 In a study to validate these criteria, erythema was found
Malacoplakia: the infiltrate consists of histiocytes with eosinophilic cytoplasm. Note to be an unreliable clinical sign.6 There is no relationship to HPV infection or
the pale blue, laminated Michaelis-Gutmann bodies. chronic candidal infection.7,8
Fig. 12.146
Fig. 12.145 Scrotal calcinosis: (A)
Vestibulitis: there is marked vulval erythema. By courtesy of C. Furlonge, MD, Port characteristic yellow
of Spain, Trinidad. papules and nodules are
present; (B) close-up view
of the lesions.
Idiopathic calcinosis By courtesy of the
A Institute of Dermatology,
London, UK.
Clinical features
Genital calcinosis is uncommon. It occurs much more frequently in the scro-
tum than in the vulva, where it has only seldom been reported.1–8 Very rarely,
idiopathic calcinosis may develop in the penis or areola of the nipple.9,10
Lesions present as single or multiple hard nodules in children and young
adults (Fig. 12.146). Occasionally nodules break down and discharge chalky
material. Some lesions are polypoid and in this setting the clinical diagnosis is
difficult if only a single lesion is present.11–13 Very young children can excep-
tionally present with single or multiple calcified scrotal lesions secondary to
meconium periorchitis.14,15

Although originally thought to represent an idiopathic condition, it more
likely that this disorder develops from dystrophic calcification of epidermoid
cysts or the contents of cystically dilated eccrine ducts.16–22 It has also been
suggested that the condition can result from dartos muscle degeneration.23
Scrotal calcinosis is characterized by single or multiple dermal nodules of
dystrophic calcification (Fig. 12.147). In some cases, there is histological evi- B
dence of a pre-existing and partially destroyed cyst.
in Japan and have predilection for the genitourinary system but can occur
Dermatitis artefacta elsewhere including the rectum.6–8 Granulomatous penile nodules (Tanko’s
Dermatitis artefacta localized to the anogenital area is sometimes encoun- nodules) have been described due to the insertion of glass spheres under
tered (Figs 12.148–12.150). At this site the injuries may be sustained in the penile skin.9
the course of sadomasochistic sexual gratification1 due to algolagnia (love
of pain). A biopsy is usually obtained to exclude penile cancer but it is Histological features
important also to consider pyoderma gangrenosum; although rare, it is There is a foreign body-type granulomatous reaction in the dermis. ‘Lipid’
frequently omitted from the differential diagnosis of anogenital ulceration vacuoles are surrounded by dense fibrous tissue. Rare extensive necrosis in a
by nondermatologists. case of primary sclerosing lipogranuloma has been documented.8
Sclerosing lipogranuloma Pilonidal sinus

Sclerosing lipogranuloma (paraffinoma) may involve the scrotum, penis This condition mainly occurs in the sacrococcygeal region and has only rarely
and exceptionally the epididymus.1–3 It usually represents a tissue response been reported as occurring in the penis.1–8 Only about 20 cases have been
to exogenous material (usually paraffin, silicone and even mineral oil and reported in the literature. Lesions present in uncircumcised adults with a pre-
Vaseline) and is seen most commonly in the paratesticular area second- dilection for the dorsal aspect of the coronal sulcus. It has been postulated that
ary to the injection of size-enhancing materials.4,5 A very small number of penile pilonidal sinus develops because the coronal sulcus acts as a cleft where
cases of sclerosing lipogranuloma appear to be primary, are more common hairs can accumulate and eventually penetrate the shaft and the foreskin as a
Pigmented lesions 481
Fig. 12.147 Fig. 12.148 Fig. 12.149

Scrotal calcinosis: the calcium deposits stain purple Dermatitis artifacta: there is gross destruction of Dermatitis artifacta: note the circumferential
with hematoxylin and eosin. Sometimes a pre- the penile shaft. From Bunker C: Male Genital Skin ulceration. Reproduced with permission from
existent epidermoid cyst can be identified. Disease. Saunders Ltd./Elsevier 2004. Bunker CB and Mallon E, Management of penile
erosions and ulcers, Postgraduate Doctor Middle
East, 1998;21:163–168. Copyright © Professional
Managerial and Healthcare Publications Limited.
From Bunker C: Male Genital Skin Disease. Saunders
Ltd./Elsevier 2004.
result of friction between these two surfaces. The symptoms are those of chronic
inflammation and abscess formation. Pilonidal sinus has been associated with
actinomycosis, squamous cell carcinoma and verrucous carcinoma.1,8–10
The histopathology is identical to that of pilonidal sinus occurring at the usual site.
Pigmented lesions
Melanocytic lesions are not the only cause of genital pigmentation.
Postinflammatory hyperpigmentation following an inflammatory dermatosis
such as lichen planus is much more commonly encountered. However, only
melanocytic genital lesions are discussed in this section.
Genital melanosis
Clinical features
This condition of the genital skin is characterized by pigmentation with no
overt evidence of a preceding inflammatory dermatosis.1–5 However, in men
the clinical suspicion is usually raised of past or chronic low-grade lichen
Fig. 12.150 sclerosus, lichen planus, Zoon’s balanitis or non-specific balanoposthitis. The
Dermatitis artifacta: this pigmentation may vary in its intensity and is typically irregular. The problem
is a view of the natal
usually affects several sites including cutaneous and mucosal surfaces. The
cleft. Note the central
ulceration and surrounding
pigmentation develops slowly and can be very extensive.
lichenification. From Unifocal lesions can also sometimes occur. Small discrete single or multiple
Bunker C: Male Genital lesions are usually described as genital melanotic macules.4 The commonest sites
Skin Disease. Saunders are the glans and shaft of the penis and the inner aspects of the vulva including the
Ltd./Elsevier 2004. vestibule (Figs 12.151, 12.152). Lesions may also affect the vagina and cervix.6,7
resence of other markers of this disease.12,13 Dowling Degos may also

p
present with genital melanosis.
Genital melanosis is characterized by increased pigmentation of basal
keratinocytes and melanocytes (Fig. 12.153). By definition, there is no
increase in melanocyte number. If, however, melanocytes are present in
increased numbers, the term ‘genital lentiginosis’ may be more appropriate.14
In real terms, the difference is academic. There is no evidence of junctional
activity or cytological atypia. Pigment-laden macrophages may be conspicu-
ous in the underlying dermis. An important pitfall is the presence of coexis-
tent lichen sclerosus, as the dermal changes may mimic a completely regressed
melanoma.15
Genital melanocytic nevi

Clinical features
Acquired melanocytic nevi in the genitalia have been estimated to affect the
Fig. 12.151 various races in the following proportions: whites 9.5%, Latins 21.5% and
Penile melanotic macule: there is a small irregular pigmented macule on the glans
blacks 3.5%.1 The prevalence of vulval melanocytic nevi has been reported as
penis. By courtesy of the Institute of Dermatology, London, UK.
2.3% in one series.2 Junctional, compound and dermal nevi can all occur and
may demonstrate worrisome histological features, often raising the possibil-
ity of malignancy.2–6 Melanocytic lesions presenting in flexural areas (atypical
genital nevi, atypical flexural nevi, milk-line nevi, atypical melanocytic nevi
of genital type), including the axillae, umbilicus, inguinal creases, pubis, scro-
tum and perianal area, similarly may show identical disturbing histological
features.6
In women, the presentation is in young girls or adults and lesions vary in
size from a few millimeters to up to 1 cm (Fig. 12.154). Lesions are typically
located on the labia minora, mucosal surface of the clitoris or labia majora.
Atypical genital nevi should not be confused with dysplastic nevi, which
may also present on the external genitalia, particularly the labia majora.4
Melanocytic lesions on male genital organs are possibly less common than
in females.

Both ordinary and atypical genital nevi can show BRAF V600E mutations
as do nevi and melanomas occurring elsewhere.7 In cases with BRAF muta-
tions, expression of IGFBP7 is maintained, offering a possible explanation as
to why these lesions do not have aggressive behavior even harboring BRAF
mutations.
Banal (ordinary type) and dysplastic nevi are identical to their nongenital
counterparts and are discussed elsewhere.
Fig. 12.152
Vulval melanosis: there
are multiple irregular
pigmented macules on
the vulva and adjacent
skin. By courtesy of the
London, UK.
The condition is considered benign but there are rare anecdotal reports
of melanoma ensuing in areas of melanosis.8,9 This, however, has only been
described in penile melanosis. Melanoma rarely occurs in the context of
vulval melanosis and this is likely to be due to the fact that in the latter con-
dition there is no increase in the number of melanocytes but only basal cell
layer hyperpigmentation. Penile lesions, on the other hand, often display an
increase in the number of basal melanocytes. Single lesions are very difficult
to distinguish on clinical grounds from either a lentigo or an early junctional
nevus.
Cases of multiple genital lesions associated with oral pigmentation
have been described as Laugier-Hunziker disease (idiopathic lenticular
mucocutaneous pigmentation).10,11 It is worth remembering that rare cases
of Carney's complex may present with lentigines in genital skin and the Fig. 12.153
correct diagnosis will only be possible if close attention is paid to the Vulval melanosis: there is marked basal cell pigmentation.
Fig. 12.154 Fig. 12.156
Atypical vulval nevus: there is an irregular darkly pigmented lesion on the perineum. Atypical genital-type nevus: this is a shave biopsy from the labium majus showing
By courtesy of the Institute of Dermatology, London, UK. a compound melanocytic nevus. The papillomatosis and obvious retraction artifact
around the junctional nests are typical features.
Atypical genital nevi can be a source of considerable diagnostic difficulty

and sometimes alarm which is unfounded as lesions there do not usually
progress to melanoma.8–12 Flexural nevi at other sites are often similar
although the changes are usually less marked. They may be junctional or
compound, symmetrical or asymmetrical, and are typically fairly small, mea-
suring only a few millimeters to 1.0 cm in diameter. The associated epidermis
is typically hyperplastic, and papillomatosis can be marked (Figs. 12.155,
12.156). The junctional component is usually lentiginous and nested and
commonly involves the adnexae in addition to the epidermis. The nests are
often large, surrounded by a retraction artifact and, unlike banal nevi, are
situated along the sides in addition to the tips of the rete; they may also be
located overlying the dermal papillae (Fig. 12.157). Transepidermal elimi-
nation of nests is commonly present and some degree of pagetoid spread
may be a feature.13 The nevus cells are epithelioid in type and often atypical
(Figs 12.158–12.160). The dermal component is composed of morphologi-
cally similar nevus cells, which mature with depth. The cytological atypia can
affect both junctional and dermal components and in some cases is severe.
These features, in addition to dermal mitoses, which are commonly present,
may be extreme and raise the possibility of melanoma. Genital melanoma
is, however, generally a condition of elderly women. The biologic potential
Fig. 12.157
Atypical genital-type
nevus: high-power view
highlighting the retraction
artifact.
of these lesions is benign. Nevertheless, incompletely excised nevi or lesions

which extend very close to the radial margin would be best re-excised.
Although there may be some overlap with genital dysplastic nevus, the
latter can be distinguished by the presence of elongation of the rete ridges, a
more lentiginous distribution of the melanocytes, and the induction of lamel-
lar and eosinophilic fibrosis in the papillary dermis in association with a vari-
able mononuclear inflammatory cell infiltrate and pigmentary incontinence.
Any other type of nevus may occur on genital skin including Spitz nevus,
Reed nevus, deep penetrating nevus and blue nevus. Recently, a small series of
epithelioid blue nevi of genital skin in patients with no evidence of Carney’s
complex was reported.14 These lesions were described on the foreskin and
labium minus. Cases of divided or ‘kissing’ nevus (Fig. 12.161) have been
Fig. 12.155 reported affecting the penis, analogous to the situation in the eyelid.15–17
Atypical vulval nevus: scanning view of a polypoid lesion from a 17 year old female. Congenital ‘bathing trunk’ nevi may involve the anogenital area and pose
Note the heavily pigmented nests at the top of the field. By courtesy of the Institute significant management problems as they carry a very high risk of multifocal
of Dermatology, London, UK. malignant transformation.
A A
Fig. 12.160
(A, B) Atypical genital-type
B nevus: this example from
the vulva of a 20-year-
Fig. 12.158 old female shows severe
(A, B) Atypical genital-type nevus: in this example the junctional nests are large cytological atypia. The
and due to fine melanin pigmentation; the cytoplasm has a grayish hue. Note the biological behavior of this
nuclear hyperchromatism. nevus variant is uncertain
although the likelihood of
malignancy is very low.
B It should, however, be
completely excised.
Melanoma
Clinical features
Female genital melanoma is rare and accounts for around 3% of all female
melanomas and 2–10% of female genital tract malignancies.1–16 Mucosal
female tract melanomas account for 18% of all mucosal melanomas.17 The
vulva is the most frequently involved site followed by the vagina and much
less often the cervix (Fig. 12.162).5,6,8,10,11,18 The labia majora and the cli-
toris are the most commonly affected sites.18 Most patients present in the
sixth and seventh decades of life.19 Less than one-third of cases occur in
patients younger than 50 years of age. Melanoma of the vulva in children
has been very exceptionally reported and in some cases reported in associa-
tion with lichen sclerosus.20,21 An association with melanosis is very rare and
a tumor in a young woman, a frequent user of tanning parlors, has been
documented.22,23
Fig. 12.159 Clinical presentation varies from flat to raised polypoid brown to black
Atypical genital-type nevus: in this field, there is nuclear hyperchromatism and mild lesions. Ulceration may be present. Less commonly, patients complain of
pleomorphism. pruritus and/or bleeding. Amelanotic melanomas are reported to be rare,
Fig. 12.163
Penile melanoma: note the large size, irregular border and variable pigmentation.
Fig. 12.161
Divided or ‘kissing’ nevus: note the pigmented lesions on the shaft and the glans
penis. From Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
found that young age, localized disease and negative lymph nodes were
independent prognostic factors.28 The 5-year disease-specific survival was
75.5%, 38.7% and 22.1% for patients with localized, regional, and distant
disease, respectively.28
Melanoma of the male genital skin is very rare, as are those arising around
or on the anus (Fig. 12.163).29–32 Penile metastasis of cutaneous melanoma
elsewhere is exceptional.33 The commonest site in men is the glans but rare
cases may present elsewhere, including the shaft and the scrotum.34–36 The
diagnosis can be delayed because of the patient’s reluctance to seek medi-
cal help.37 Exceptional cases complicating penile melanosis, penile nevi, have
been reported, also a penile melanoma which developed simultaneously with
squamous cell carcinoma.38–40 Because of the rarity of the disease, estimation
of prognosis is difficult. In the few cases reported, the prognosis appears poor
but this seems to be related to late presentation, delay in diagnosis and prob-
lems in achieving complete clearance because of the site. A study of a series
of 19 primary mucosal penile melanomas and a review of 47 cases reported
in the literature found 2- and 5-year survival rates of 63% and 31%, respec-
tively.40 All patients presenting with nodal and/or distant metastasis died of
Fig. 12.162 disease within 2 years.41 The prognosis is similar in patients who present
Vulval melanoma: tumors with metastatic disease on the penis from a primary tumor elsewhere.42 Poor
at this site are very rare. prognosis was associated with ulceration, Breslow thickness of more than
They are commonly 3.5 mm and a tumor diameter of more than 15 mm. The behavior of mucosal
thick at presentation penile melanoma appears to be the same as cutaneous melanoma elsewhere
and therefore generally
of s imilar thickness.
associated with a poor
prognosis. By courtesy of
M. Ridley, MD, Institute of Pathogenesis and histological features
Dermatology, London, UK. An important number of mucosal melanomas have shown mutations in c-kit
as opposed to melanomas arising in skin exposed intermittently to the sun, in
but they represented 27% of all cases in a large Swedish series.18,24,25 They which BRAF mutations are frequently found.43,44 The presence of c-kit muta-
may clinically mimic squamous cell carcinoma or extramammary Paget’s tions offers the possibility of targeted therapy to those melanomas harbor-
disease. ing the mutation. A study of vulvar and vaginal melanomas detected HPV-3
Some tumors arise within a pre-existing nevus.18 A recent study found the and epidermodysplasia verruciformis-associated types of HPV in a number of
latter to occur in around 5% of cases.18 Most of these are of the superficial lesions.45 Since these HPV types are not usually found in the vulva or vagina,
spreading type. it has been suggested that they may play a role in the pathogenesis of mela-
The 5-year survival varies enormously, ranging from 15% to 54%.4–13,26 nomas at these sites.
A study of 219 vulval melanomas reported a 5-year survival rate of 47%.27 Histological features of genital melanoma are identical to melanomas else-
As with melanomas presenting elsewhere, tumor thickness is the best where. Until recently, there was no consensus as to the most common type of
predictor of survival.1,27 Staging has also been found to be an independent genital melanoma. Recently, however, a large study found that 57% of vulval
predictor of survival.27 In addition, in stage I disease only, ulceration and the melanomas were mucosal lentiginous, 22% nodular, 12% unclassified and
presence of clinical amelanosis were found to be independent predictors of 4% superficial spreading.16 Desmoplastic and neurotropic variants may also
survival.27 Radical surgery for vulval melanoma does not seem to influence occasionally be encountered. Multiple in situ penile melanomas have been
outcome. A multivariate analysis of 644 patients with vulval melanoma documented.46
Epithelial lesions
Benign mucinous metaplasia and mucinous
syringometaplasia
Benign mucinous metaplasia of the penis and vulva is exceptionally rare.1,2
It has been reported on the labia and foreskin. The clinical features are non-
distinctive, and histologically benign mucus-containing cells are found within
the epidermis with a predilection for the upper layers. Distinction from extra-
mammary Paget’s disease is difficult but the cells in benign mucinous meta-
plasia lack cytological atypia and contain nuclei with basal orientation.1
Mucinous syringometaplasia is very rare in genital skin and can be distin-
guished from benign mucinous metaplasia because the cells in the former are
not confined to the epidermis but extend into adnexal structures.3
Endometriosis and endosalpingiosis

Cutaneous endometriosis is uncommon, is predominantly seen in young Vulval endometriosis: in this example, there is stromal decidualization.
females and usually develops in a scar following an abdominal operation
such as a cesarean section.1–5 On occasion, it appears to develop spontane- latter is seen, decidual cells are positive for CD30, the latter being a poten-
ously in the integument (e.g., in the umbilicus, the inguinal region and the tial pitfall in diagnosis.15 Other stromal changes include smooth muscle meta-
perineum). Endometriosis of the vulva is rare and may occur in an episiotomy plasia, lipoblast-like cells some with intranuclear inclusions, myocytes with
scar or after curettage.6,7 Clinically, it presents as a bluish nodule, which is degenerative changes and exceptionally elastosis and perineural invasion.14
often painful, and sometimes shows cyclical variation in size and symptoms.8 Menstrual bleeding into the deposits often leads to hemosiderin deposition,
Rarely, it may bleed during menstruation. Malignant transformation in cuta- scarring and chronic inflammation.
neous endometriosis is extremely rare.9 Histologically, in endosalpingiosis, the cyst (which is unilocular) is lined by
Cutaneous endosalpingiosis is a similar condition in which cysts lined by an admixture of ciliated columnar, nonciliated mucus-secreting columnar and
tubal epithelium develop as a consequence of salpingectomy.10 It is exceed- intercalated dark cells.10 In contrast to endometriosis, there is no associated
ingly rare in the skin and most cases have presented in an abdominal scar stroma and foci of hemorrhage and/or hemosiderin are not seen.
and occasionally in the umbilicus.11,12 One case was associated with severe
abdominal pain.13 Median raphe cyst
Histological features Clinical features
The diagnosis of cutaneous endometriosis depends upon the detection of both
Median raphe cyst (urethroid cyst) is a rare lesion that usually presents on
endometrial glands and stroma (Figs 12.164, 12.165).2 Endometrial glands
the ventral aspect of the penis of young adults, with a predilection for the
are lined by tall columnar epithelium with basophilic cytoplasm and basally
glans (Fig. 12.166).1–4 Perineal and scrotal lesions may occasionally be seen
located oval vesicular nuclei. All types of metaplastic changes of the müllerian
epithelium can be seen including tubal, oxyphilic, hobnail, mucinous and pap-
illary syncitial.14 Mitotic activity may sometimes be marked and rarely atypical
mitotic figures are identified.14 The stroma is composed of small spindle cells
and is usually edematous. Occasionally, decidualization is evident. When the
Fig. 12.166
Median raphe cyst: there
is a translucent cystic
swelling on the glans
penis. From Bunker
Fig. 12.164 C: Male Genital Skin
Vulval endometriosis: endometrial glands with edematous stroma are present in Disease. Saunders Ltd./
the reticular dermis. Elsevier 2004.
Epithelial lesions 487
and are rarely polypoid.5–7 Some lesions present as a cordlike induration.8

The cyst is usually congenital but tends to become visible only in adult life,
often after trauma or infection. Exceptional development after orchiopexy
has been documented.9 Lesions are most commonly solitary, asymptomatic
and measure only a few millimeters in diameter. Large lesions are very rare.10
Exceptional cases present with multiple cysts and spontaneous regression has
also been reported.11 Pigmented cysts are due to the presence of melanocytes
in the lining.10,12,13 Simple excision is curative.

It is likely that the cyst originates not as a result of defective closure of the
median raphe but secondary to anomalous budding and separation of the
urethral columnar epithelium from the urethra.3
The cyst is lined by pseudostratified columnar epithelium (Figs 12.167,
12.168). Rarely, mucin-containing cells or ciliated cells are seen.14,15
Immunohistochemical stains show that the cells lining the cyst are positive
for cytokeratin 7, cytokeratin 13 and CAM 5.2, and negative for cytokeratin
20. It has been suggested that this pattern of keratin expression supports the
theory that the cells lining the cyst represent a columnar mucinous epithelium
Fig. 12.168
that has undergone immature urothelial metaplasia.16 Scattered melanocytes Median raphe cyst: the cyst is lined by pseudostratified epithelium. By courtesy of
and neuroendocrine cells (positive for chromogranin and synaptophysin) may C. Gulmann, MD, Beaumont Hospital, Dublin, Republic of Ireland.
also be identified.16 Although this lesion may mimic an apocrine cystadenoma,
this line of differentiation is unlikely, as the cells in the cyst are negative for
human milk fat globulin 1.17
Bartholin duct cyst

Clinical features
These lesions present in women of reproductive age as a result of obstruction
of the main duct of Bartholin’s gland.1 They are relatively uncommon and
occur in the posterior aspect of the labium majus. Size varies from 1 cm to
several centimeters in diameter. Cysts are usually asymptomatic but the devel-
opment of a Bartholin’s gland abscess is a relatively common complication as
the retained glandular secretions become infected.
The cyst is lined by transitional epithelium, which frequently undergoes
squamous metaplasia (Figs 12.169, 12.170).2 Very rarely, a papilloma has
Fig. 12.169
Bartholin duct cyst: low-power view of the cyst. By courtesy of C. Crum, MD, Brigham
and Women’s Hospital and Harvard Medical School, Boston, USA.
been reported developing within a cyst.3 The exceptional development of a

high-grade squamous cell carcinoma associated with HPV 16 within a cyst
has also been described.4
Mucinous cyst
Clinical features
These are rare lesions in men that present as small flesh-colored, midline,
translucent, mobile, papules (2 mm) to nodules (25 mm), usually easily deter-
mined to be cystic on clinical grounds.1,2 They do not have a punctum. Either
they are asymptomatic or they become infected or interfere with sex. They
have usually been present from birth or childhood and are common near the
glans penis or on the foreskin but may occur anywhere from the urethral
Fig. 12.167
meatus to the anus and present at any age in life. The assessment of such cysts
Median raphe cyst: low-
power view of cyst. should involve the exclusion of secondary infection, for example gonorrhea.
By courtesy of C. Vulval lesions are mainly seen adult women and presents as a solitary
Gulmann, MD, Beaumont or, less often, multiple lesions in the vestibule.3–5 Rare cases are found in
Hospital, Dublin, Republic adolescents. This cyst arises as a result of obstruction of the duct of a minor
of Ireland. vestibular gland. Simple excision is curative.
Fig. 12.170 Fig. 12.172
Bartholin duct cyst: the Mucinous cyst: the cyst is lined by mucin-secreting epithelium. By courtesy of C. Crum,
cyst is lined by transitional MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
epithelium. By courtesy
of C. Crum, MD, Brigham
and Women’s Hospital and
Harvard Medical School,
Boston, USA.

Lesions in women were thought to be derived from müllerian epithelium.
It is more likely, however, that lesions in both men and women derive
from ectopic urogenital sinus epithelium.2,6,7 The cyst is lined by a layer
of mucinous epithelium with occasional focal squamous metaplasia
(Figs 12.171–12.173).3–5 Myoepithelial cells are not identified.
Mesonephric cyst
Clinical features
This lesion presents in the lateral part of the vulva as a small, asymptomatic,
blue–red cystic lesion containing clear fluid. It is thought to be derived from
remnants of the mesonephric duct. Simple excision is curative.
Fig. 12.173
Mucinous cyst: the mucin stains bright red with mucicarmine. By courtesy of C. Crum,
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
The cyst is lined by a single layer of cuboidal or columnar nonciliated cells
surrounded by a layer of smooth muscle.1
Mesothelial cyst
Clinical features
Mesothelial cyst (cyst of the canal of Nuck) presents as a lesion varying in size
from less than 1 cm to 5 cm or more. It arises on the upper and lateral aspect
of the labium majus at the level of the insertion of the round ligament. Some
cases are associated with an inguinal hernia. Simple excision is curative.
Fig. 12.171
Microscopic examination reveals a unilocular cavity lined by a single layer of
Mucinous cyst: low-power
view of mucin-containing flattened mesothelial cells.1
cyst. Note the
nonkeratinizing surface Periurethral cyst
epithelium. By courtesy
of C. Crum, MD, Brigham
and Women’s Hospital
Clinical features
and Harvard Medical This cyst presents as a small or, exceptionally, large swelling lateral to the
School, Boston, USA. urethral meatus.1,2
Histological examination shows a cavity lined by transitional epithelium
(Figs 12.174, 12.175).
Penile horn
Cutaneous horn (Fig. 12.176) is a type of verrucous lesion marked by exces-
sive and increasing keratosis, and a penile horn is a rare lesion with only
a handful of reported cases.1–6 The hyperkeratosis of the cutaneous horn
may derive from numerous dermatological lesions including burns, nevi,
angiomas, Bowen’s disease, condylomata, seborrheic keratoses/basal cell
papillomas, basal cell carcinoma, pseudoepitheliomatous hyperkeratotic and
micaceous balanitis, verrucous carcinoma and squamous carcinoma.1,7–10
Chronic inflammation and recent circumcision for long-standing phimosis
are important predisposing factors. The lesion is premalignant or, in one-
third of cases, malignant at presentation with squamous cell carcinoma as
the underlying pathology. Precise diagnosis is achieved by adequate excision
and histology of the whole lesion, with follow-up because recurrence may
occur.11 Fig. 12.176
Penile horn: this lesion arose from an underlying squamous cell carcinoma. Courtesy
of Dr. J. Ponce de Leon, Barcelona, Spain. Reproduced by kind permission of
Blackwell Science from Ponce de Leon J et al. Cutaneous horn of glans penis.
Br J Urol 1994;74:257–8. From Bunker C: Male Genital Skin Disease. Saunders Ltd./
Elsevier 2004.
Pseudoepitheliomatous, keratotic and

micaceous balanitis
Clinical features
Pseudoepitheliomatous micaceous and keratotic balanitis (PEMKB) is a rare
penile condition that was first described by Lortat-Jacob and Civatte.1,2 It
presents as thick, scaly, micaceous patches3–6 on the glans penis of older
uncircumcised men. Clinically, white, hyperkeratotic and crusted ‘micaceous’
plaques develop on the glans penis. These lesions are resistant to treatment
and a verrucous (penile horn) or erosive tumor may emerge from them
(Figs. 12.177, 12.178). It has been misdiagnosed as Reiter’s disease. Some
consider that PEMKB is a form of locally invasive verrucous carcinoma,7 others
that it is a variant of lichen sclerosus.8 Metastatic spread has not occurred
Fig. 12.174 except where there was a penile horn9 and in one patient who developed an
Periurethral cyst: low-power view of unilocular cyst. By courtesy of C. Crum, MD, aggressive soft tissue sarcoma of the penis.10 There is no association with
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. human p apillomavirus infection.11
Fig. 12.177
Fig. 12.175 Pseudoepitheliomatous micaceous and keratotic balanitis: verrucous plaques are
Periurethral cyst: the cyst is lined by transitional epithelium. By courtesy of C. Crum, present on the glans penis. Courtesy of B. Kumar, MD, Chandigarh, India. From
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
abnormal basal cytology is a result of epithelial reparation (e.g., lichen planus

or basal hyperplasia arising from HPV infection). A newer classification has
therefore been proposed to remove this grading system and replace it with two
types of VIN: VIN undifferentiated (usual type) and VIN differentiated.5
Undifferentiated usual type VIN: This is atypia involving two-thirds to full
thickness of the epidermis of the vulva, previously known as VIN 2 or VIN
3, respectively. This type of VIN is usually associated with the oncogenic type
HPV infection. Changes previously described as VIN 1 are now regarded as
flat condyloma (HPV-associated).5
Differentiated VIN (or carcinoma in situ): This is atypia confined to the
basal area of the epidermis, previously termed VIN3 differentiated. This often
occurs on a background of LS either surrounding an SCC or just prior to the
development of malignant change. This type of VIN does not appear to be
associated with HPV infection. Differentiated VIN has a higher risk of pro-
gression to invasive squamous cell carcinoma.6
This terminology is still far from perfect, particularly as differentiated VIN
may mistakenly be thought of as having a better prognosis than undifferenti-
ated VIN. Contrariwise, differentiated VIN developing against a background
of lichen sclerosus is much more likely to be associated with progression to
Fig. 12.178 invasive tumor and aggressive behavior than HPV-associated undifferentiated
Pseudoepitheliomatous micaceous and keratotic balanitis: note the verrucous
lesions. Most often, it is seen in vulvectomy specimens from women with SCC
plaque. There is underlying lichen sclerosus. Courtesy of B. Kumar, MD, Chandigarh,
India. From Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004. arising in a background of lichen simplex or lichen planus.
Clinical features
Histological features Clinical lesions of undifferentiated VIN (usual type) may be unifocal and dis-
Biopsies from early lesions show mild to moderate epidermal hyperpla- crete or multifocal and diffusely distributed about the external genitalia and
sia with no cytological atypia and a variable focal lichenoid mononuclear perineum, where the anus may also be affected. Multiple small papules at this
inflammatory cell infiltrate. Larger lesions display pseudoepitheliomatous site were for many years described as bowenoid papulosis due to the mistaken
hyperplasia and often there is transition to verrucous carcinoma. belief that these lesions could be histologically distinguished from Bowen’s
disease. It is now appreciated that histologically the two conditions are indis-
tinguishable. The majority of young healthy patients have only a small risk of
Genital intraepithelial neoplasia and progression to invasive disease but the immunocompromised are at a much
greater risk, particularly in the setting of perianal disease.7 Similarly, pigmented
squamous cell carcinoma multifocal Bowen’s disease is now classified within the spectrum of VIN.
In this text, the term intraepithelial neoplasia is restricted to squamous intra- The morphology of the lesions ranges from papules to plaques, which may
epithelial neoplasia and does not include extramammary Paget’s disease or be skin-colored, white, erythematous or pigmented (Figs 12.179–12.181).
melanoma in situ. The terminology used for premalignant vulval epithelial The surface often has a warty texture; less commonly, lesions are papil-
lesions has been confusing and unsatisfactory for many years. In 1986, older lomatous, particularly around the anus where they may become polypoid
terms such as Bowen’s disease, erythroplasia of Queyrat, bowenoid papulo- (Fig. 12.182). The main presenting symptom is pruritus.
sis, multifocal pigmented Bowen’s disease, severe dysplasia and carcinoma in
situ, which represented full-thickness atypia, were abandoned in favor of a
grading system into three categories similar to that used for cervical intraepi-
thelial neoplasia.1–3 VIN grades 1, 2 and 3 represent the degree, in thirds, that
the epithelium is atypical (Table 12.1). This terminology has been extended
to include other perineal sites, for example perianal intraepithelial neoplasia
(PaIN 3) and the penis ( discussed elsewhere).
Furthermore, unique to the vulval skin, ‘VIN 3 differentiated’ was intro-
duced to describe a variant where the neoplastic cells do not extend throughout
the full thickness of the epidermis, which remains well differentiated. However,
this terminology does not compare like with like, since the cervix is covered
by mucosa and most of the epithelium covering the vulva is skin, the only
area that is a mucosa being the vestibule. This newer terminology did not take
into account the clinical and biological differences between the cervix and the
vulva and there was also a misconception that there was a natural progression
through grades 1–3 to invasive squamous cell carcinoma (SCC). In addition,
there were problems with interobserver variation, particularly with VIN 2 and
3, and also poor correlation clinically with some lesions that were histologi-
cally VIN 1 and 2.4 Changes similar to VIN 1 are often found in states where
Table 12.1
Classification of vulval intraepithelial neoplasia
Fig. 12.179
Intraepithelial neoplasia:
• VIN 1 – mild dysplasia intensely erythematous
• VIN 2 – moderate dysplasia ulcerated lesion.
• VIN 3 – severe dysplasia or carcinoma in situ (differentiated and By courtesy of the
undifferentiated VIN) Institute of Dermatology,
London, UK.
Fig. 12.180
there are numerous scaly
papules accompanied
by condylomata. In the
older literature, the former
was known as bowenoid
papulosis. Pigmented Fig. 12.182
lesions are also present. Intraepithelial neoplasia: perianal lesions presenting as multiple small papules
These were once known (bowenoid papulosis). By courtesy of the Institute of Dermatology, London, UK.
as multicentric pigmented
Bowen’s disease. The terms warty and basaloid undifferentiated VIN refer to histological
By courtesy of the variants and are not biologically distinct entities. In some lesions there may
Institute of Dermatology, be a mixture of the two.
London, UK.
Clinical lesions of differentiated VIN (simplex) are not often recognized
and are poorly described. Since invasion can develop rapidly, any suspicious
areas should be biopsied. It is usually a small hyperkeratotic white papule
or plaque or a punched-out ulcer or erosion with a firm border. The lesion
invariably arises in a background of a chronic atrophic dermatitis such as
lichen sclerosus (with associated epidermal acanthosis) or other conditions
associated with squamous hyperplasia.
Undifferentiated VIN (usual or classic type)
In this major subtype, there is complete loss of cellular stratification throughout
the epidermis with large hyperchromatic cells, dyskeratosis, multinucleated
cells and numerous typical and atypical mitoses.13
Two distinct types of undifferentiated VIN have been described but are
clinically and biologically the same:
• warty, characterized by individual cell keratinization and premature
cellular differentiation; pleomorphism may be marked and abnormal
mitoses are often conspicuous (Fig. 12.183),
Fig. 12.181
there is an erythematous
plaque with focal scaling.
By courtesy of the
London, UK.
Multifocal vulval and perianal lesions are strongly associated with the
oncogenic papilloma viruses, particularly HPV-16 and -18, and almost exclu-
sively occurs in smokers.8,9 HPV-16 is found more frequently than HPV-18.10
It is believed that there is a failure of the host to mount an immune response
to HPV and that patients who are immunocompromised are at particular
risk. However, many of the patients do not have an identifiable immune defi-
ciency. Anogenital intraepithelial neoplasia, in addition to being multifocal,
can be multicentric and there is a history in two-thirds of female patients of
current or past cervical intraepithelial neoplasia.11
Vaginal involvement is very uncommon. The morphology of the lesions Fig. 12.183
is quite variable, some resembling typical warts, others islands of erythema, Undifferentiated VIN: there is full-thickness dysplasia with very marked nuclear
erosion or white patches.12 pleomorphism. Note the abnormal mitosis.
• basaloid, with atypical parabasal cells extending throughout the full term ‘VIN 3 differentiated’ was coined by the ISSVD. However, this change
thickness of the epithelium (Fig. 12.184). is poorly recognized by many pathologists and there is a significant risk of a
The two variants often overlap histologically and are, as mentioned before, report of VIN 1 being issued, with potentially d isastrous consequences.
part of the same spectrum. It is important to note that occasional cases of differentiated VIN negative
Two cases of VIN associated with HPV16 and with prominent mucinous for HPV display complete replacement of the epidermis by basaloid, homo-
differentiation have been reported.14 geneous undifferentiated keratinocytes.16
Undifferentiated VIN tends to be diffusely positive for p16 and negative Differentiated VIN can be associated with p53 mutations and p53 is often
for p53. positive not only in the basal cell layer but also in upper layers of the epi-
dermis.15 A similar staining pattern can be seen in inflammatory conditions
Differentiated VIN (simplex) including lichen sclerosus.17 It has recently been shown that high levels of p53
In some cases of vulval lichen sclerosus there is an associated basal keratino- expression in differentiated VIN correlates with DNA aneuploidy.18 p16 is
cyte cytological atypia with dyskeratosis and normal differentiation through- usually negative in cases of differentiated VIN.
out the overlying epithelium (Fig. 12.185).15 The rete ridges may be long and
forked with keratin pearls. This change may reflect invasive disease or herald Squamous cell carcinoma of the genital
its imminent onset. To reflect the seriousness of this epithelial change, the
epithelia
Vulval squamous cell carcinoma
There are two main etiologies for vulval squamous cell carcinoma (SCC):1–3
• The majority (> 60% of cases) arise in elderly women against a
background of a chronic scarring dermatosis, usually lichen sclerosus
but less often lichen planus. In these patients, the tumors develop directly
within the background dermatosis and may be preceded by differentiated
VIN. They are not usually associated with HPV.4–11 Squamous cell
carcinoma arising in the background of differentiated VIN appears to
have a higher tendency for local recurrence.12
• The second group consists of younger women with a background
of undifferentiated VIN (usual type) which is associated with HPV-
16 and -18, smoking and a previous or current history of squamous
intraepithelial lesion (SIL/CIN). HPV-16 is the most common type of
HPV found in association with vulval squamous cell carcinoma.13
Interestingly, a recent study of human papillomavirus genotypes in inva-
sive vulval squamous cell carcinoma found HPV in 70% of cases (mainly
HPV-16) and the average age of the patients was 65. Patients with no evi-
dence of HPV were older than those with proven HPV but these differences
were not statistically significant.14
Fig. 12.184 In addition, much more rarely, vulval carcinoma has been described in
Basaloid VIN: there is full-thickness replacement of the epidermis by a fairly
association with chronic granulomatous disease, hidradenitis suppurativa,
uniform population of small cells with densely basophilic nuclei and imperceptible
Fanconi’s anemia, and the genodermatosis Netherton’s syndrome.15–19
cytoplasm.
A tumor in a young woman with Cohn’s disease and one developing within
a localized vulvar lesion of Hailey-Hailey disease after tacrolimus therapy
have been documented.20,21
Patients with the warty and basaloid histological subtypes of vulval SCC
tend to be younger than those with conventional keratinizing SCC and in
one series there seems to be a predominance of black patients with this his-
tological subtype.22 The majority of vulval SCCs develop on the inner aspect
of the labia majora and periclitorally.23 Patients present with a mass that is
sometimes associated with pruritus, ulceration, bleeding, discharge or pain
(Fig. 12.186). Multifocal tumors are very rare.24 Vulval SCC usually spreads
via lymphatics to inguinal, femoral and pelvic lymph nodes. Midline tumors
are often associated with bilateral lymph node spread.25
The overall 5-year survival for patients with vulval SCC depends on the
depth of stromal invasion and the presence or absence of lymph node metas-
tasis.26–32 A study has found that patients with stromal invasion of more than
9 mm had higher risk of local recurrence.33 In the absence of lymph node
spread, the 5-year survival is up to 90% but this rate falls to less than 70% in
patients with inguinal lymph node metastasis and to less than 25% in those
with pelvic lymph node spread.27 The presence or absence of lymph node
Fig. 12.185 metastasis is the single most important factor determining prognosis.34 Other
Differentiated VIN: there is factors that have been found to be independently associated with prognosis
basal dysplasia associated
include older age, advanced stage, size of the tumor, positive margins and
with dyskeratosis and
degree of differentiation. It has been suggested that HPV-positive tumors have
normal differentiation.
By courtesy of C. Crum, a worse prognosis than those that are HPV negative.35,36 Warty and basaloid
MD, Brigham and SCCs of the vulva are often associated with HPV infection and there is some
Women’s Hospital and suggestion that the prognosis of the basaloid subtype may be worse than that
Harvard Medical School, of conventional SCC (see below).6,22 Warty squamous cell carcinoma of the
Boston, USA. vulva is more often associated with high risk HPV other than HPV-16.14
Genital intraepithelial neoplasia and squamous carcinoma 493
Fig. 12.188
Verrucous carcinoma: this
tumor arose in the gluteal
cleft of an elderly female.
Note the characteristic
sharply demarcated lower
border.
verrucous carcinoma may be associated with human papillomavirus albeit in

Fig. 12.186
a minority of cases.14 The benign histological appearances of this tumor often
Vulval squamous cell carcinoma: this tumor arose against a background of
long-standing carcinoma in situ (Bowen’s disease). By courtesy of the Institute
lead to an incorrect histological report of condyloma or squamous papilloma,
of Dermatology, London, UK. with resulting undertreatment. Vulval verrucous carcinoma can coexist with
ordinary squamous cell carcinoma.15 A case of vulval verrucous carcinoma in
an HIV-positive patient has been documented.16
Tumors with less than 1-mm stromal invasion do not require lymph node
dissection and the appropriate surgery is curative. Histological features
Verrucous carcinoma is characterized by an exophytic and endophytic
Verrucous carcinoma growth pattern.17,18 The latter, which may extend deeply into subcutaneous
tissues or beyond, has a bulbous and sharply delineated lower border, lacking
Clinical features the infiltrative characteristics of conventional SCC (Figs 12.189–12.191).
Verrucous carcinoma is a low-grade, slow-growing squamous cell carcinoma The epithelium is well differentiated, showing no appreciable cytological
(SCC) first described in 1948.1 The precise incidence of verrucous carcinoma atypia; mitoses, which are generally sparse, are confined to the lower layer.
is difficult to assess accurately because of the confusing number of different Intraepithelial neutrophil abscesses are commonly present. In some tumors,
terms that have been applied to this tumor in the past. There has been some koilocytes may be seen, supporting an HPV-associated etiology. One study
debate as to whether verrucous carcinoma, well-differentiated epidermoid describes a distinctive triad of marked epithelial acanthosis, loss of the granu-
SCC, epithelium cuniculatum and giant condyloma of Buschke-Löwenstein lar cell layer with superficial epithelial cell pallor, and multilayered parak-
are all one and the same or separate entities. It is now generally accepted that eratosis.19 It has been suggested that this could be a precursor to verrucous
they are identical lesions.2,3 carcinoma and is designated vulvar acanthosis with altered differentiation.
The tumor presents as a warty exophytic plaque and usually occurs at
three anatomical sites: the oropharynx, sole of the foot and the anogenital
skin (Figs 12.187, 12.188).2,4–6 Verrucous carcinoma of the vulva may arise
on a background of lichen sclerosus or lichen planus.7–9 Oral and lower limb
neoplasms may be associated with various types of HPV.10–13 Similarly, genital
Fig. 12.189
Verrucous carcinoma:
low-power view showing
the characteristic growth
Fig. 12.187 pattern comprising deeply
Verrucous carcinoma: note the keratotic warty tumor mass. By courtesy of the penetrating, blunt, finger-
Institute of Dermatology, London, UK. like processes.
• squamous intraepithelial lesion of low and high grade,

• dysplasia,
• penile intrepithelial neoplasia grade 3.
Taking into account similarities in morphology and pathogenesis between
vulval and penile carcinoma, we have recently proposed a new nomenclature
for penile preinvasive lesions.7,8 In this section, we present a simplified version
taking into account the etiopathogenetic correlation of precursor HPV and
non-HPV-related lesions with their invasive counterparts.9 The term penile
intraepithelial neoplasia (PeIN) is preferred over older terminology.10–13
PeIN is classified into differentiated (non-HPV-related), undifferentiated
(HPV-related) and mixed differentiated–undifferentiated categories.
Undifferentiated PeIN may be further subclassified into warty, basaloid,
mixed warty/basaloid and other variants. PeIN may be solitary or multifocal,
and may or may not be associated with infiltrative SCC. PeIN unassociated
with invasive cancer occurs in younger patients and tends to be of the undif-
ferentiated type, positive for HPV. Patients with HPV may also develop
warty or basaloid PeIN. Conversely, when PeIN is associated with invasive
SCC, the predominant histological subtype is the differentiated variant, pre-
senting in 65% of the cases and usually negative for HPV. The explanation
for this apparent paradox may be the clinical and pathological underrecogni-
tion or underdiagnosis of differentitated PeIN. Differentiated PeIN tends to
Fig. 12.190 affect the foreskin of older patients whereas undifferentiated PeIN generally
Verrucous carcinoma: the
affects the glans of younger patients.
epithelium is uniformly
well differentiated and The gross appearance of PeIN is heterogeneous and does not allow a
often displays a ground- clear distinction between the two main types. Differentiated PeIN tends to
glass cytoplasmic pallor. be white, whereas undifferentiated PeIN is typically reddish or darkly pig-
mented. Lesions vary from flat to slightly elevated, and can be pearly white or
moist erythematous, dark brown or black and present as macules, papules, or
plaques. They may be warty, granular or villous (Figs. 12.192–12.195). The
contours are sharply delineated or subtle and irregular.
Microscopically, differentiated PeIN is characterized by hyperkeratosis,
parakeratosis, variable hypergranulosis and acanthosis with elongated and
anastomosing rete ridges. There is subtle abnormal maturation (enlarged
keratinocytes with abundant eosinophilic cytoplasm) (Fig. 12.196), whor-
ling and keratin pearl formation (usually in deep rete ridges), prominent
intercellular bridges (spongiosis) and sometimes acantholysis. Atypical
basal or prickle layer cells are present and a prominent nucleolus may
be seen (Fig. 12.197). At low power, the atypia may seem to be pres-
ent only in lower levels of the epidermis; however, at higher magnifica-
tion, there is subtle but abnormal maturation in all levels of the epithelium
(Figs 12.198–12.200).
Fig. 12.191
Verrucous carcinoma:
intraepithelial neutrophil
abscesses are often
present.
Penile squamous cell carcinoma

Penile intraepithelial neoplasia (PeIN)
In this text, penile intraepithelial neoplasia refers to purely squamous lesions
and excludes Paget’s disease and melanoma in situ. There is a wide spec-
trum of morphological lesions reflecting the diverse pathogenesis of penile
squamous cell carcinoma (SCC). Historically, there has been variable nomen-
clature and multiple classifications of penile precursor lesions have been
proposed:1–6
• Bowen’s disease, Fig. 12.192
• erythroplasia of Queyrat, Intraepithelial neoplasia: multiple eroded lesions are present. By courtesy of the
• carcinoma in situ, Institute of Dermatology, London, UK.
Fig. 12.193 Fig. 12.196
Intraepithelial neoplasia: in this example, viral warts are present in addition to multiple Differentiated PeIN: with acanthosis, hyperkeratosis, retained squamous maturation,
small papules on the glans (bowenoid papulosis). By courtesy of the Institute of and minimal atypia.
Fig. 12.194
Fig. 12.197
Intraepithelial neoplasia: this patient presented with multiple ulcerated lesions and
Differentiated PeIN: with marked atypia, more prominent at the bottom layers.
a thick, scaly plaque. By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.195
Intraepithelial neoplasia: there is intense erythema of the glans penis and the distal Fig. 12.198
shaft. This lesion is also referred to as Bowen’s disease and in the older literature as Differentiated PeIN: atypia are seen throughout the epithelium; note the presence
erythroplasia of Queyrat. By courtesy of the Institute of Dermatology, London, UK. of dyskeratosis.
Fig. 12.199 Fig. 12.201
Differentiated PeIN: squamous hyperplasia (left field ) merging into differentiated PeIN Differentiated PeIN: with underlying lichen sclerosus characterized by dense
(center field ), the latter in continuity with invasive squamous cell carcinoma (right field). hyalinized subepithelial tissue.
In basaloid PeIN, the epithelium is replaced by a monotonous population

of small or intermediate-sized immature cells with high nuclear:cytoplasmic
ratio (Figs 12.202–12.205). Short spikes or spindle-shaped cells may be
noted. Apoptosis and mitotic figures are numerous. Basaloid PeIN should
be distinguished from transitional cell urethral carcinoma in situ, which may
secondarily involve the penile meatal region.15
In the warty variant, the epithelium has an undulating/spiky surface with
atypical parakeratosis. There is cellular pleomorphism and koilocytosis
(multinucleation, nuclei with irregular contours, perinuclear halos and dysk-
eratosis) (Figs 12.206–12.208). Mitosis may be numerous.
Basaloid lesions are monotonous and flat, whereas warty lesions are spiky
and pleomorphic with prominent koilocytosis. Frequently, lesions show over-
lapping features of both, namely mixed warty–basaloid PeIN. These mixed
lesions have an irregular surface with koilocytic changes while the lower
half of the epithelium is predominantly composed of small basaloid cells.
This is not a surprising finding, taking into consideration that warty and
basaloid carcinomas are both HPV-related tumors. Warty PeIN should be
distinguished from the common condyloma which does not display atypia
Fig. 12.200 except at the level of the upper koilocytotic layer.
Differentiated PeIN: the presence of nuclear atypia (right field) allows the distinction
of differentiated PeIN from squamous hyperplasia (left field)
The differential diagnosis is squamous hyperplasia which, by definition,

shows no atypia. In the absence of specific penile dermatological conditions
which may be associated with hyperplasia, it is likely that most acanthotic
squamous lesions represent differentiated PeIN.
It is not surprising that the precursor lesions of well-differentiated invasive
tumors show such a high degree of differentiation. It is important to recog-
nize this lesion because it appears to be the most frequent precursor lesion of
penile carcinoma, especially of the keratinizing and well-differentiated vari-
ants. Unfortunately, most studies on differentiated PeIN are retrospective and
have been based on penectomies performed for invasive carcinoma.
There is a preferential association for differentiated PeIN and lichen scle-
rosus (Fig. 12.201).14 It is therefore important to maintain a high index of
suspicion when dealing with hyperkeratotic/hyperplastic epidermal lesions
with subtle keratinocytic atypia arising in the setting of long-standing lichen
sclerosus.
Undifferentiated PeIN (the HPV-related type) shows distinctive morpho-
logical features. Lesions can be subclassified into basaloid, warty and mixed
warty–basaloid PeIN. In accordance with their common pathogenesis, it is
frequent to find mixtures of warty and basaloid patterns in the same speci-
men. We classify a lesion as either warty or basaloid when there is more than Fig. 12.202
90% predominance of one type over the other. Basaloid PeIN: with acanthosis, parakeratosis, and slightly irregular surface.
Fig. 12.203 Fig. 12.206
Basaloid PeIN: with epithelial thickening, parakeratosis, and an overall ‘blue’ appearance Warty PeIN: with prominent parakeratosis and abundant koilocytes, more prominent
due to altered squamous maturation. at upper layers.
Fig. 12.207
Fig. 12.204
Warty PeIN: showing its characteristic spiky, parakeratotic surface.
Basaloid PeIN: the epithelium is replaced by a monotonous proliferation of small to
medium-sized cells with basal-like features
Fig. 12.208
Fig. 12.205 Warty PeIN: nuclear atypia is discernable throughout the epithelium, with conspicuous,
Basaloid PeIN: with abundant mitoses and apoptotic figures throughout the epithelium. sometimes pleomorphic koilocytosis (right field ) and marked parakeratosis.
Rarely, a mixed lesion composed of differentiated and undifferentiated • chronic inflammation,

PeIN is encountered. If an associated invasive cancer is present it also shows • history of tear or injury to the penis,
mixed morphology of more than one subtype of invasive squamous cell • physical inactivity,
carcinoma. • history of warts,
Other exceptional and less well-studied morphologic patterns of pre- • ultraviolet irradiation,
cursor lesions include pleomorphic, spindled cell, clear cell, pagetoid and • partner with cervical cancer,
small cell. All of these are likely to represent variants of the undifferenti- • immunosuppression,
ated group. • smoking,
With few exceptions there is good correlation between the microscopic • HPV,
appearance of the preinvasive lesion and the associated invasive carcinoma. • lichen sclerosus.
Usual and differentiated subtypes of SCC are associated with differenti- Early circumcision appears to be associated with a lower incidence of penile
ated PeIN while warty and basaloid invasive carcinomas are associated with cancer when compared to later circumcision. Penile carcinoma in circumcised
warty or basaloid PeIN. These observations further support the concept of a men is very rare; it has been reported in association with irregular scarring
bimodal pathway of penile tumorigenesis.9 in patients undergoing ritual circumcision. Postcircumcision penile cancer
appears to be biologically aggressive.29
Bowenoid papulosis High incidences of both penile and cervical cancers are seen in some areas
Patients with bowenoid papulosis are younger (mean age 30 years) than those of the world. However, pathologically, penile cancers are similar to vulval
with penile cancer and present with multiple papules affecting the skin of cancers. The overall prevalence of HPV DNA in penile carcinoma (42%)
the shaft, glans, sulcus or foreskin. Some lesions regress spontaneously.16–21 is lower than that seen in cervical carcinoma (near 100%) and is similar to
Histologically, at low-power magnification there is acanthosis and either a vulval carcinoma.7 Subtypes of penile cancer such as basaloid and condyloma-
spiky or flat appearance. High power shows a proliferation of small basophilic tous are consistently associated with HPV, whereas the virus is infrequent in
cells with a spotty distribution of atypical forms. Hyperkeratosis, parakeratosis the usual, verrucous, papillary and sarcomatoid squamous cell carcinoma.9,24
and melanin pigmentation may be present. Human papillomavirus types These two groups of tumors appear to develop along different pathogenetic
16 and 18 have been associated with bowenoid papulosis; hence, sexual pathways. HPV-16 is the most common type of HPV associated with penile
transmission is suspected. The histological appearance of bowenoid papulosis cancer. HPV-related anogenital cancers, including penile carcinoma, are
is similar to that of basaloid or mixed warty–basaloid PeIN and the diagno- significantly more frequent in HIV-infected patients when compared with the
sis should be suggested only when there is a clinical presentation of multiple general population.30,31
papular lesions in younger patients.
Clinical features
Flat ‘acetowhite’ penile lesions The mean age of patients with penile SCC is around 60 years. HPV-related
Peniscopic studies of male sex partners of women with HPV-associated tumors such as condylomatous and basaloid cancers affect younger patients
squamous intraepithelial lesion (SIL/CIN) have revealed a clinical lesion (45–55 years) while verrucous and pseudohyperplastic carcinomas occur at
described by Bleeker et al. as ‘flat penile lesion’.22 It was identified in 60% an older age (70–80 years).32 An exophytic or non-ulcerated lesion is the
of 230 cases and affected the inner foreskin surface, frenulum and coro- usual presenting sign. In non-Western countries, up to 40% of patients pres-
nal sulcus. HPV was identified in the majority of the lesions by in situ ent with inguinal lymph node metastasis and 10% with disseminated disease.
hybridization. Grossly (only evident after acetic acid reaction), 2–4 or more This high figure contrasts with a significantly lower incidence of regional and
well-demarcated 1–2-cm white flat lesions with a mosaic vascular pattern systemic metastasis in North American patients (13 and 2.3% respectively).33
were seen. Microscopically, there was squamous hyperplasia or low grade The frequency of in situ and invasive carcinoma varies according to geo-
PeIN. In a minority of cases high-grade PeIN was present. Follow-up of 118 graphical region. In areas of high frequency, the majority of tumors are ini-
men with flat lesions showed a benign clinical course and regression in 90% tially dignosed as invasive tumors whereas in regions of low incidence, most
of the cases in 5 years, usually within 12 months. cases are diagnosed as in situ lesions. In a series of 500 invasive carcinomas
diagnosed in Paraguay, we found only 20 cases of carcinoma in situ (4%),
Invasive squamous cell carcinoma whereas in 1605 cases from the SEER database in USA the figure was 37%.33
Geographical differences may reflect the incidence of invasive cancers.
Squamous cell carcinoma arises on the mucosal surface of the penis extending
from the preputial orifice to the urethral meatus, comprising the inner Usual squamous cell carcinoma
surface of the foreskin, coronal sulcus and glans.23 Squamous cell carcinoma
presenting on the outer skin of the penis is very unusual. Distal urethral Grossly, SCC of the usual type displays wide morphologic appearances vary-
tumors, morphologically similar to some penile tumors, are not discussed in ing from white–gray exophytic to flat or reddish, ulcerated endophytic masses.
this text. The cut surface shows white–gray neoplastic tissues invading variable penile
Penile cancer incidence rates in the West are in the range of 0.3–1.0/100 000 anatomical levels (lamina propria, corpus spongiosum or corpus cavernosum
of the population although there is considerable variation amongst the in the glans and dartos or skin in the foreskin). In the fresh state or after fixa-
different countries. The incidence of penile SCC varies from a high incidence tion there may be a contrast between the white color of the tumor and the
in Uganda, Kenya and some regions of South America, to a lower incidence reddish, darker penile tissue. The boundaries between tumor and stroma are
in Northern Europe and the United States, Japan and Israel.2 Comparing usually jagged and irregular. Adjacent associated squamous hyperplasia or
cases from the United States and Paraguay, we have found no geographi- PeIN can be visualized as a deeply white line measuring 1–2 mm in thickness
cal differences in the morphology, relative incidence of histologic subtypes in the adjacent epithelium.
or in the presence or absence of HPV according to histologic subtype.9,24
Differences in geographical distribution of penile cancer are attributed to Histological features
environmental factors. Several epidemiological studies have indicated the Microscopically, tumors vary from well-differentiated keratinizing to solid
following risk factors: 25–28 anaplastic carcinomas with scant keratinization (Figs 12.209–12.211).
• socioeconomic deprivation, Most tumors are highly keratinized and of moderate differentiation. Poorly
• poor hygiene, differentiated carcinomas may have variable and usually focal amounts
• lack of access to running water, of spindled cell, giant cell, solid, acantholytic, clear cell, small cell, warty,
• phimosis, basaloid or glandular components. When these features predominate, there
• smegma retention, is a morphological justification for separation of the neoplasm as a special
• lack of circumcision, subtype of squamous cell carcinoma.
Subtypes of squamous cell carcinoma

Table 12.2 TS2
Subtypes of squamous cell carcinoma
Papillae Koilocytosis Interphase HPV

Warty Condylomatous Present Jagged + High
pleom risk
Verrucous Noncondy Absent Broad Absent
lomatous
Papillary Complex Absent Jagged Absent
Giant Condylomatous Superficial Broad + Low risk
condyloma
Fig. 12.209
Usual squamous cell carcinoma: well-differentiated (grade 1) usual SCC with
keratinizing tumor nests composed of neoplastic cells showing minimal atypia
limited to the basal/parabasal layers.
A B
C D
(A) Verrucous carcinoma: tight papillae separated by keratin (in red ). Broadly
based boundaries between tumor and stroma. (B) Papillary carcinoma: irregular
papillae without koilocytosis. Jagged tumor–stroma limits. (C) Giant condyloma:
condylomatous papillae, surface koilocytosis (white dots) and broad non invasive
base. (D) Warty (condylomatous) carcinoma: irregular condylomatous papillae,
diffuse koilocytosis and jagged boundary between tumor and stroma.
Fig. 12.210
Usual squamous cell carcinoma: moderately differentiated (grade 2) usual SCC with Clinical features
more evident atypia (upper right field ) but retained squamous maturation.
Verrucous carcinoma
Verrucous carcinoma (VC) is a slowly growing, well-differentiated tumor,
with a papillomatous appearance and a broad bulbous invasive border
contrasting with the irregular infiltrating margin of usual squamous cell
carcinoma. Described by Dr. Lauren Ackerman in 1948 in the buccal mucosa,
verrucous carcinoma continues to pose diagnostic problems with other verru-
ciform tumors sharing some of its characteristics.34 Condyloma, papillary and
condylomatous carcinoma have all been published under the designation of
verrucous carcinoma or Buscke-Löwenstein tumor. We have proposed a clas-
sification of verruciform neoplasms that helps to differentiate verrucous car-
cinoma from other similar lesions.35 It is important to follow strict diagnostic
criteria since classic penile verrucous carcinoma is associated with virtually no
metastatic potential.36,37 There is a spectrum of combined tumors with focal
or significant verrucous features, which need to be distinguished from typical
verrucous carcinoma. The most frequent combination is that of a verrucous
carcinoma with usual invasive SCC. These mixed or hybrid verrucous carci-
nomas have a metastatic rate of about 25%.38–40 Verrucous carcinoma may
also be associated with sarcomatoid carcinoma sporadically or after radiation
therapy.41 HPV has been consistently rare or absent in various studies.9,24,42
Verrucous carcinoma is rare, accounting for 7% of all penile SCC.2 It
Fig. 12.211 presents during the sixth to seventh decades and the average duration of the
Usual squamous cell carcinoma: poorly differentiated (grade 3) usual SCC with disease is 56 months, the longest amongst all penile malignant tumors. Any
prominent atypia but evidence of squamous differentiation. penile epithelial compartment may be affected and it is equally frequent in
the foreskin or glans penis. Most tumors are unicentric but multicentric cases
or association with other subtypes such as the pseudohyperplastic variant has
been observed.
Grossly, it is an exophytic papillomatous tumor with some variation in
the configuration of the papillae, from multinodular with cobblestone mor-
phology to filiform with a spiky appearance. The cut surface reveals a white
serrated tumor and a broad demarcation between the lesion and stroma.
Verrucous carcinoma is superficial, rarely penetrating beyond lamina propria
or superficial dartos or corpus spongiosum.
Microscopically, the tumor is diffusely well differentiated, resembling nomal
squamous epithelium except for the presence of occasional atypical nuclei
in the basal or parabasal layers. Features include papillomatosis, hyper- to
orthokeratosis, acanthosis and a broad-based interface between the tumor
and stroma, the latter considered pathognomonic for this tumor. Koilocytosis
is not present. Although some papillae may harbor fibrovascular cores, this
is not a characteristic feature. The space between papillae is occupied by a
keratin-filled crater that on a tangential cut appears as keratin-filled pseudo-
Fig. 12.213
cysts. The stroma may show a dense lymphocytic infiltrate, sometimes blur- Verrucous carcinoma: showing acanthosis, parakeratosis, papillomatosis, and a
ring the interface between the tumor and the underlying connective tissue broad-based tumor–stroma interface.
(Figs 12.212–12.216). Microscopic small nests of well-differentiated inva-
sive keratinized SCC in the lamina propria (1–3 mm in depth) may rarely be
observed. We have not observed metastasis in these cases. A designation for
such a lesion could be microinvasive verrucous carcinoma. This entity dif-
fers from hybrid verrucous carcinoma where large areas of the tumor show
features of a moderately to poorly differentiated invasive typical squamous
cell carcinoma (Figs 12.217–12.219). Associated lesions which may be seen
in the adjacent epithelium include squamous hyperplasia and differentiated
PeIN. The hyperplasia often adopts the features of verrucous hyperplasia.
Lichen sclerosus is a further frequently found associated condition and may
be pathogenetically related to verrucous carcinoma.43 Verrucous carcinoma,
if insufficiently resected, is prone to local recurrence. Regional metastases are
not seen in typical (pure) lesions.
Condylomatous (warty) carcinoma

Clinical features
Condylomatous carcinoma is a slowly growing, verruciform low- to interme-
diate-grade HPV-related tumor, grossly similar to giant condyloma but with
malignant histology and potential for nodal metastasis.35 It accounts for 7%
of all penile SCC affecting patients younger than those with the usual SCC. Fig. 12.214
A history of previous viral warts is frequently obtained. The foreskin, coronal Verrucous carcinoma: neoplastic cells are extremely well-differentiated with minimal
sulcus and glans are usually involved. Macroscopically, the cut surface shows atypia limited to the basal/parabasal layers.
Fig. 12.212 Fig. 12.215
Verrucous carcinoma: exophytic, verruciform proliferation with papillae showing Verrucous carcinoma: with epithelial thickening, minimal atypia, parakeratosis, and a
inconspicuous fibrovascular cores. well-defined, rounded tumor front.
Fig. 12.216 Fig. 12.219
Verrucous carcinoma: with slightly irregular tumor front and foci suspicious for Hybrid verrucous carcinoma: usual SCC component composed of poorly differentiated
microinvasive verrucous carcinoma (upper right field). neoplastic cells.
a papillomatous growth generally penetrating into the corpora spongiosa and

cavernosa. The interface of tumor and stroma varies from broadly based to
jagged and irregular.
Microscopically, the tumor papillae are condylomatous and of various shapes
(round, ovoid or spiky, long or short) but always with a prominent central
fibrovascular core and koilocytotic changes (Figs 12.220–12.224). Unlike
benign condyloma, koilocytosis is not restricted to the surface epithelial cells
but is also present in deep invasive portions of the tumor (Fig. 12.225).
Hyper- and parakeratosis, cellular pleomorphism and clear cell change may
be prominent. The biological behavior of condylomatous carcinoma is inter-
mediate between that of other types of low-grade verruciform tumors (verrucous
and papillary) and squamous cell carcinoma of the usual type. Deeply inva-
sive, high-grade condylomatous carcinoma may be associated with inguinal
nodal metastasis.
The differential diagnosis is with other verruciform tumors, verrucous and
papillary carcinoma and giant condyloma. The histologic evaluation of type
Fig. 12.217 of papillae, presence of koilocytosis, interface of tumor and stroma and pres-
Hybrid verrucous carcinoma: composed of a typical verrucous carcinoma (left field) ence of HPV helps in the differentiation of these neoplasms (see Tables 12.1
and a usual SCC (right field). and 12.2).
Fig. 12.218 Fig. 12.220
Hybrid verrucous carcinoma: verrucous component with pushing tumor borders and Condylomatous carcinoma: exhibiting an exophytic, papillomatous pattern of growth
well-differentiated neoplastic cells; note the underlying stromal reaction. with conspicuous fibrovascular cores.
Fig. 12.221 Fig. 12.224
Condylomatous carcinoma: showing an irregular, jagged infiltrative tumor front Condylomatous carcinoma: showing abundant koilocytes, more prominent at the
(right field). upper layers, and marked parakeratosis.
Fig. 12.222 Fig. 12.225
Condylomatous carcinoma: with papillomatosis, evident fibrovascular cores, and Condylomatous carcinoma: deep infiltrative nests with koilocytes and surrounding
irregular tumor–stroma interface. stromal reaction.
Koilocytosis, condylomatous papillae and jagged irregular boundaries

between tumor and stroma are present in warty but not in verrucous carcino-
mas. In papillary carcinomas, papillae are complex and show no koilocytosis.
Giant condylomas are broadly based noninvasive tumors with surface koilo-
cytosis (see Table 12.2).35,44 Associated precursor lesions of condylomatous
carcinoma include PeIN of the warty or basaloid types.
Papillary carcinoma, NOS

Clinical features
Papillary carcinoma, NOS is the third type of penile low-grade verruciform
carcinoma.2,3,45 Patients are on average around 60 years old. The tumor is
grossly exophytic, large and irregular and involves the glans, coronal sulcus
and foreskin. The cut surface shows a papillary neoplasm involving corpus
spongiosum or dartos. Papillary carcinoma is a slowly growing tumor with a
low but definite incidence of inguinal nodal metastasis.
Fig. 12.223 Microscopically, the appearance is that of a well-differentiated papillary
Condylomatous carcinoma: papillae with conspicuous koilocytosis, slight squamous neoplasm. There is hyperkeratosis and papillomatosis. Papillae are
parakeratosis, and underlying chronic stromal reaction. variable and complex, short or long, with or without a fibrovascular core
(Figs 12.226–12.228). The tips may be straight, undulated, spiky or blunt.

Hyperkeratosis and acanthosis are prominent. Keratin cysts or intraepithelial
abscesses are sometimes present. The base of the lesion is irregular and infil-
trative. The interface between tumor and stroma is characteristically jagged
(Fig. 12.229). Koilocytotic-like changes are usually absent. Differentiating
features from verrucous and condylomatous carcinoma are based on the het-
erogeneity of the papillae, the lack of koilocytosis and the jagged irregular
interface between tumor and stroma. The latter feature is crucial to distin-
guish papillary from verrucous carcinoma. HPV studies may be necessary to
differentiate papillary neoplasms, usually negative for HPV, from low-grade
condylomatous carcinoma. Another tumor to be distinguished from papil-
lary carcinoma NOS is the infrequent papillary basaloid SCC.2 In this tumor,
papillae harbor a thin fibrovascular core and the cells are small and ana-
plastic, resembling basaloid or transitional carcinoma. This unusual penile
neoplasm is often deeply invasive. Low-grade squamous intraepithelial lesion
and lichen sclerosus are frequently associated with papillary carcinoma.
Fig. 12.228
Papillary carcinoma, NOS:
showing an irregular,
jagged tumor front of
invasion and prominent
stromal reaction.
Fig. 12.226
Papillary carcinoma, NOS: showing papillomatosis with complex papillae and
irregular fibrovascular cores.
Fig. 12.229
Papillary carcinoma, NOS: irregular tumor nests at the tumor base surrounded by
intense chronic inflammation.
Basaloid carcinoma
Clinical features
Basaloid carcinoma is an aggressive, HPV-related variant of SCC occurring in
the fifth decade and preferentially affecting the glans.46 It has been proposed
that it originates within the squamous–transitional junction of the meatal
region. Rarely, basaloid carcinoma may develop in the foreskin. It accounts
for 4% to 10% of penile SCCs. The median age is 53 years. More than half
of patients show inguinal metastasis at clinical diagnosis. Grossly, there is an
ulcerated irregular mass. The cut surface reveals a tan, solid tumor, deeply
invasive into the corpus spongiosum or cavernosum.
Fig. 12.227
Papillary carcinoma, NOS: Histological features
with rounded and tipped
papillae, hyperkeratosis, Microscopically, there are separate or confluent solid nests composed of
and irregular fibrovascular small basaloid cells, usually with central necrosis (comedonecrosis) or
cores. central abrupt keratinization (Figs 12.230–12.233). Nuclei are anaplastic
Fig. 12.230 Fig. 12.233
Basaloid carcinoma: at low-power view showing deeply infiltrative tumor nests. Basaloid carcinoma: composed of neoplastic cells with indistinctive cellular borders,
high mitotic/apoptotic rate, and central (comedo-like) necrosis.
and nucleoli inconspicuous. There are numerous mitotic figures. Occasional

palisading at the nest periphery may be noted but it is usually not as promi-
nent as is seen in basal cell carcinoma of the skin. Basophilic intermediate or
large cell nuclei may be noted in some cases. Pseudoglandular features are
sometimes present (Figs 12.234, 12.235) (adenoid–basaloid carcinomas).
PeIN of the warty–basaloid type is often found in the epithelium adjacent to
the invasive cancer.
Unusual morphological features of basaloid carcinomas

In accordance with their common HPV etiology, some tumors show mixed
basaloid–condylomatous features. The condylomatous component is super-
ficial and papillary and the deep counterpart a typical basaloid carcinoma.
There are deeply invasive nests with central keratinization or comedonecro-
sis surrounded by clear cells with koilocytotic-like changes and peripheral
small basaloid cells. These mixed tumors behave as basaloid carcinomas,
with frequent nodal metastasis. Another unusual morphological presenta-
tion is that of a papillary lesion composed entirely of small basaloid cells
(transitional-like papillary basaloid carcinoma). Deep portions of the tumor
Fig. 12.231 show the classic features of a basaloid carcinoma. Unlike other penile
Basaloid carcinoma: with tumor nests showing central, abrupt parakeratosis, and papillary tumors, the papillae are entirely composed of small cells simulating
retraction artifact. a transitional urothelial carcinoma.
Fig. 12.232 Fig. 12.234
Basaloid carcinoma: tumor nest composed of a monomorphic population of cells Basaloid carcinoma: with tumor nests exhibiting open central areas due to central
with evident atypia and central parakeratotic debris. necrosis, simulating a glandular space.
Fig. 12.235 Fig. 12.237
Basaloid carcinoma: with central, necrotic debris and a pseudoglandular appearance. Sarcomatoid carcinoma: high-grade pleomorphic cells intermingled with spindled cells.
Sarcomatoid carcinoma (carcinoma with heterologous

differentiation, metaplastic carcinoma)
Clinical Features
Sarcomatoid carcinoma is an aggressive penile neoplasm composed predomi-
nantly of spindled cells. It may arise de novo, follow a recurrence of usual
squamous cell carcinoma or develop after irradiation therapy of a verrucous
carcinoma. It accounts for about 1–4% of all penile carcinomas and prefer-
entially involves the glans penis although the foreskin may also be affected.47
As with usual SCC, the mean age is around 60. Grossly, it presents as a bulky
5–10-cm ulcerated or rounded polypoid mass, which on sectioning shows
almost invariably deep invasion into the corpus cavernosum. Regional metas-
tases occur in 85% of sarcomatoid carcinomas and mortality is high.
Microscopically, there are variable proportions of squamous and spindled
cell carcinoma but the latter usually predominates. The sarcomatoid com-
ponent includes leiomyosarcoma, fibrosarcoma, myxosarcoma, epithelioid
angiosarcoma, classic angiosarcoma and so-called pleomorphic malig-
nant fibrous histiocytoma (Figs 12.236–12.240). Heterologous bone and Fig. 12.238
cartilage formation is sometimes focally present. Rarely, the tumor shows Sarcomatoid carcinoma: pleomorphic and spindled malignant cells in a myxoid
pseudoglandular and/or pseudovascular differentiation (Figs 12.241, 12.242). background.
Fig. 12.236
Sarcomatoid carcinoma: composed of neoplastic spindle cells simulating a high-grade Fig. 12.239
sarcoma. Sarcomatoid carcinoma: differentiated PeIN with underlying sarcomatoid carcinoma.
The squamous component typically shows the morphology of usual SCC but
areas of verrucous, papillary or basaloid carcinoma may also be observed,
indicating that sarcomatoid transformation may occur in practically any
tumor type. HPV is usually absent. Differential diagnosis includes sar-
coma and melanoma. Immunohistochemistry is essential for tumors with
little or no epithelial component and for small biopsy specimens. The spin-
dled cells are usually positive for vimentin, various cytokeratins and p63.
In our experience, cytokeratin 34betaE12 and p63 appear to be the more
specific and sensitive markers to categorize these tumors as epithelial. AE1/
AE3 and Cam 5.2 tend to be more variable and often only focally posi-
tive, sometimes highlighting scattered single cells. Smooth muscle actin
can be focally positive; however, desmin, muscle-specific actin, myogenin
and S-100 are negative. Tumors which display specific sarcomatous com-
ponents such as leiomyosarcoma or angiosarcoma display the expected
immunohistochemistry.
Pseudohyperplastic carcinoma
Clinical features
Fig. 12.240 Pseudohyperplastic carcinoma is a clinicopathologic entity characterized by a
Sarcomatoid carcinoma: neoplastic cells in sarcomatoid carcinomas showing low-grade ordinary squamous carcinoma preferentially affecting the foreskin
nuclear positivity for p63 immunohistochemistry. of older patients (eighth decade) in association with lichen sclerosus.48 The
tumor is well differentiated (resembling normal squamous epithelium) and in
small biopsy specimens it may mimic pseudoepitheliomatous hyperplasia. It
is often multicentric and the second or third independent lesion is sometimes
verrucous. We have observed similar cutaneous tumors in association with
severe solar elastosis or in scars after burns. Grossly, it is a flat or slightly
elevated lesion measuring about 2 cm.
In a series of 10 cases, recurrence was noted in the glans of one patient
who was circumcised for a multicentric carcinoma of the foreskin 2 years
after diagnosis. No metastases developed in any of these cases.
Characteristic microscopic features are keratinizing nests of squamous cells
with minimal atypia surrounded by a reactive stroma (Fig. 12.243). The
consistent association with lichen sclerosus suggests that this inflammatory
condition may play a pathogenetic role.
Carcinoma cuniculatum
Clinical features
This tumor was originally documented on the sole of the foot. It is a deeply
Fig. 12.241 penetrating, albeit low-grade squamous cell carcinoma which, because of its
Sarcomatoid carcinoma: low-power view of a sarcomatoid carcinoma with irregular burrowing growth pattern, was designated epithelioma cuniculatum by Ayrd
spaces simulating vascular lumina. in 1954.49 Seven cases of this unusual variant of SCC have been reported in
Fig. 12.242 Fig. 12.243
Sarcomatoid carcinoma: high-grade pleomorphic cells mimicking the pattern of Pseudohyperplastic carcinoma: showing a downward proliferation of irregular tumor
growth of angiosarcomas (‘pseudoangiosarcomatoid carcinoma’). nests composed of extremely well-differentiated neoplastic cells.
the penis.50 The mean age of presentation was 77 years. Grossly, the tumor is
white–gray, exo–endophytic and papillomatous with a cobblestone or spiky
appearance. It affects the glans and often extends to the coronal sulcus and
foreskin (average size 6 cm). The hallmark of the lesion is visible on the cut
surface where deep invaginations of the tumor form irregular, narrow and
elongated neoplastic sinus tracts that connect the surface of the tumor to deep
anatomical structures.
Despite the deep penetration, none of the reported cases of carcinoma
cuniculatum has shown nodal or systemic disease at time of diagnosis.
Microscopically, the tumor partially resembles verrucous carcinoma with a
bulbous front of invasion. There may, however, be irregular foci of invasive
squamous cell carcinoma of the usual type (Figs 12.244–12.246). Carcinoma
cuniculatum should be distinguished from classical verrucous carcinoma,
which is also well differentiated, but rarely invades beyond the lamina pro-
pria and has a sharply delineated front.
Clear cell carcinoma

Clear cell features may be noted in squamous cell carcinoma. We have Fig. 12.246
Carcinoma cuniculatum: with its characteristic verruciform pattern of growth (left
observed some examples of solid, poorly differentiated SCC composed largely
field ) associated with an invasive usual SCC (right field).
of PAS-positive clear cells and have attributed the appearance to cytoplasmic
hyperglycogenation, similar to cervical lesions.2,3 Clear cells may also be con-

spicuous in some condylomatous carcinomas.
A purported different penile tumor composed exclusively of clear cells, and
designated clear cell carcinoma, has recently been reported from Austria.51
The tumors were large, exophytic, partially ulcerated and widely invasive, all
located in the foreskin inner surface.
Microscopically, clear cell carcinoma is composed of large neoplastic cells
with clear, PAS-positive cytoplasm (Fig. 12.247). HPV-16 is consistently
present. Follow-up information in the Austrian series showed that all five
patients had groin cystic clear cell metastases. Two patients were reported as
alive and the others either dead or with evidence of disease at last follow-up.
Adenosquamous carcinoma
Clinical features
Adenosquamous carcinoma is an exceedingly rare variant thought to arise
within misplaced glandular cells within the perimeatal region of the penis. It
Fig. 12.244 consists of squamous cell carcinoma with foci of mucinous glandular differ-
Carcinoma cuniculatum: at low-power view showing its verruciform pattern of
entiation. It is believed to arise from the epithelial surface of the glans, where
growth extending deep into penile erectile tissues.
Fig. 12.245 Fig. 12.247
Carcinoma cuniculatum: with a broad-based tumor front, intense stromal reaction, Clear cell carcinoma: composed of polygonal cells with evident atypia and a clear,
neoplastic cells with minimal atypia, and prominent parakeratosis. faintly eosinophilic cytoplasm.
foci of squamous cell carcinoma in situ may be noted. Clinicopathologic aids in their distinction. Another important differential diagnosis is adeno-
features and outcome are similar to usual SCC. Grossly, a large firm granular carcinoma arising in Littre glands. This tumor is ventrally located around the
neoplasm deeply invading penile corpora is present. The few reported cases of penile urethra.
adenosquamous carcinomas have behaved aggressively with frequent nodal
metastasis. Acantholytic (adenoid, pseudoglandular) carcinoma
Clinical Features
This unusual variant of SCC is characterized by prominent acantholysis and
Microscopically, there is an admixture of squamous cell carcinoma and
the formation of pseudoglandular spaces.54 The median age of the patient is
mucin secreting adenocarcinoma (Figs 12.248, 12.249). The squamous
54 years. Tumors are generally large, involve multiple penile anatomical com-
component generally predominates.52 The glandular epithelium expresses
partments and deeply invade into erectile corpora.
carcinoembryonic antigen (CEA). Differentiated PeIN is usually present in
the adjacent glans mucosa. Adenosquamous carcinomas should be distin-
guished from mucoepidermoid, adeno-basaloid and pseudoglandular SCCs. Histological features
In mucoepidermoid carcinomas, there are isolated cells or group of squamous The pseudoglandular spaces contain keratin, acantholytic cells and necrotic
cells containing mucin without forming glandular structures.53 In adeno- debris (Figs 12.250, 12.251). CEA and mucin stains are negative. Compared
basaloid tumors, there are well-formed mucin secreting glands but the solid with usual SCC, pseudoglandular SCC shows higher-grade foci, invades deeper
component is a basaloid carcinoma. Pseudoglandular (adenoid or acantho- anatomical structures and is associated with a higher incidence of regional
lytic) SCC most frequently represents SCC of the usual type in which there metastasis and mortality. The differential diagnosis includes gland-forming
is considerable dyskeratosis and acantholysis with secondary pseudolumen penile tumors (surface adenosquamous, mucoepidermoid and urethral adeno-
formation simulating glandular structures. The lack of mucin production carcinomas) and the angiosarcomatous variant of sarcomatoid carcinoma.
Fig. 12.248
Fig. 12.250
Adenosquamous carcinoma: showing neoplastic nests composed of cells with
Acantholytic carcinoma: deeply infiltrative tumor nests with extensive areas of
glandular and squamous differentiation.
central acantholysis, giving the lesion a glandular appearance.
Fig. 12.249 Fig. 12.251
Adenosquamous carcinoma: tumor nest with a high-grade squamous component Acantholytic carcinoma: tumor nest with central acantholysis showing an admixture
associated with areas of glandular differentiation. of neutrophils, necrotic debris, and desquamated cells.
Cloacogenic carcinoma 509
Giant condyloma
Described by Buschke and Löwenstein, this is an exophytic tumor which
reaches a very large size after many years of evolution.55 There has been much
confusion in the correct classification of this lesion which has been confused
with verrucous carcinoma. In our opinion, verrucous carcinoma is a different
tumor (see above). In giant condylomas, patients are older than those with
condyloma acuminatum and younger than those with condylomatous (warty)
carcinoma. Grossly, it presents as a cauliflower-like tumor showing a papil-
lomatous growth with a sharp demarcation between the lesion and stroma on
the cut surface. The deep border may affect lamina propria, dartos or corpus
spongiosum. Histologically, it may have an exo- add/or endophytic growth
pattern with morphology identical to condyloma acuminatum. However, in
our recent experience, there is a morphological spectrum:
• entirely benign, composed of differentiated squamous cells and
indistinguishable from condyloma acuminatum,
• focally atypical,
• entirely atypical but without invasion,
• associated with superficial microinvasive squamous cell carcinoma,
• associated with overtly invasive squamous cell carcinoma (see diagram). Fig. 12.254
The condylomatous papillae show a central fibrovascular core and super- Giant condyloma: with a pushing, downward proliferation extending into penile
ficial koilocytotic changes (Figs 12.252–12.255). The differential diagnosis erectile tissues.
Fig. 12.255
Fig. 12.252
Giant condyloma: with koilocytosis, easily recognized in the upper layers, and mild
Giant condyloma: showing a papillomatous, exophytic pattern of growth, conspicuous
atypia at the base of the papillae (‘atypical condyloma’).
fibrovascular cores, and a broad tumor base.
includes condyloma acuminatum and noninvasive condylomatous carcinoma

(see Table 12.1). Condyloma acuminatum affects younger patients, is smaller
and lesions are usually multiple, affecting not only the squamous epithelium
of penile mucosal epithelial compartments but also the outer skin of the fore-
skin and shaft. Giant condyloma affects older patients, is usually bulky and
unicentric. The distinction of giant condyloma from well-differentiated con-
dylomatous carcinoma may be difficult. Identification of low-risk HPV in
giant condyloma and HPV-16 in condylomatous carcinomas may aid in the
differential diagnosis.
Cloacogenic carcinoma
This rare tumor presents in middle-aged women as a superficial ulcerated
adenocarcinoma composed of colonic-type glands arising in direct continuity
with vulval surface epithelium (Figs 12.256–12.258).1–5 It is independent of
the perivulval glands and, by definition, direct extension or metastasis from
an underlying large intestinal or visceral adenocarcinoma has been excluded.
The clinical features are not distinctive but tumors may present as lesions
simulating Bartholin’s gland infection.6 In a single case, the neoplastic glands
Fig. 12.253 also contained Paneth cells.5 The origin of this tumor is not known but it is
Giant condyloma: with overt koilocytosis, slight parakeratosis, and no cellular atypia. thought most probably to arise from an area of gastrointestinal metaplasia
Fig. 12.256 Fig. 12.258
Cloacogenic vulval adenocarcinoma: scanning view showing vulval squamous Cloacogenic vulval adenocarcinoma: close-up view showing the tumor cells
epithelium on the far right. Colonic epithelium is present on the left. Mucus-secreting distended by intracytoplasmic mucin.
carcinoma extends throughout the underlying connective tissue.
Fig. 12.257 Fig. 12.259
Cloacogenic vulval
Cloacogenic vulval
adenocarcinoma: high-
adenocarcinoma: the
power view of the junction
tumor is associated with
between squamous and
abundant mucin secretion
colonic epithelium.
forming large lakes.
or from heterotopic intestinal tissue (Fig. 12.259).7 Vulval cloacogenic car- Papillary hidradenoma typically presents in middle-aged women as a
cinoma should not be confused with the similarly named tumor of the anal small (1–2 cm diameter) solitary asymptomatic nodule in a vulval, perineal or
canal. Tumor cells are positive for CK7 and CK20 and negative for estrogen perianal location.4,6 Rare lesions attain a large size.8,9 Ulceration is exceptional.
and progesterone receptors.8 Most often it affects the labium majus, but on occasion it arises on the lateral
aspect of the labium minus, fourchette or clitoris (Fig. 12.260).6,10 Perianal
lesions are very uncommon.11 It is often associated with the anogenital glands
Adnexal tumors (see below).6,12 Lesions may present with bleeding or pruritus and some are
ulcerated.6 Exceptionally, tumors are multiple and such cases tend to be
Papillary hidradenoma (mammary-like gland located on the same side of the vulva.1,2,13 Very rarely lesions may have been
described on the nipple, eyelid and external auditory canal.3,4
adenoma of the vulva)
Clinical features This tumor is now believed to be derived from anogenital mammary-like glands
Papillary hidradenoma (hidradenoma papilliferum, mammary-like gland ade- and the name mammary-like gland adenoma of the vulva has been proposed.6
noma of the vulva) occurs almost exclusively in females.1–6 A single example The epidermis may be normal, acanthotic or ulcerated. The tumor forms a
of a perianal variant has been described in a male.7 fairly well-demarcated nodule in the dermis or lamina propria and sometimes
Cloacogenic carcinoma 511
Fig. 12.260
Papillary hidradenoma: the
lesion presents as a warty Fig. 12.262
nodule. By courtesy of the Papillary hidradenoma:
Institute of Dermatology, the papillae have a
London, UK. fibrovascular core.
shows foci of continuity with the overlying epithelium.5 The growth pat-
tern consists of a mixture of tubular, papillary and solid areas.6 It is com-
posed of epithelium-covered papillary processes projecting into cystic spaces
(Fig. 12.261). The epithelial lining is typically double layered, comprising
outer small myoepithelial cells with oval hyperchromatic nuclei and inner tall
columnar cells with eosinophilic cytoplasm, sometimes manifesting decapi-
tation secretion (Figs 12.262, 12.263). Squamous cells can be identified.
Oxyphilic metaplasia of tumor cells is common.14 Tumor cells are epithelial
and myoepithelial, and the latter can display clear cell change.6 Occasionally,
the lining is only one cell thick (columnar). Diastase-resistant, PAS-positive
intracytoplasmic granules are usually present. The occasional finding of
a normal mitotic figure has no sinister implication. The larger villi have a
fibrous core in which occasional ductal structures may be identified. Often,
the fibrous tissue surrounding the tumor is compressed to form a pseudo-
capsule. Some tumors have a pattern identical to those of breast tumors
including syringocystadenoma papilliferum, erosive adenomatosis, sclerosing
adenoma and ductal adenoma.6 An inflammatory cell component is not a
significant feature but foamy histiocytes can be seen.6 Exceptionally rarely,
Fig. 12.263
Papillary hidradenoma: the papillae are covered by a double layer of epithelial cells,
the inner showing typical decapitation secretion.
a malignant variant may be encountered.15,16 The malignant component is

usually an apocrine carcinoma but an adenosquamous carcinoma has also
been documented.15
HPV has only occasionally been detected in this tumor.14
Benign tumors of Bartholin’s gland

Clinical features
Benign tumors of the Bartholin gland are very rare and the vast majority are
nodular hyperplasias.1 They occur mainly in young women. Occurrence in
postmenopausal women is exceptional.2 Adenomas are exceptionally rare,
as are adenomyomas.1,3,4 They all present as a small asymptomatic mass on
Fig. 12.261 the posterolateral aspect of the vulva and are usually diagnosed clinically as a
Papillary hidradenoma: whole mount preparation showing sharply circumscribed cyst. Bilateral lesions are very rare.5 Both hyperplasia and adenomas may be
papillary tumor. associated with pain.5,6 Nodular hyperplasia often presents in younger patients.
Nodular hyperplasia is well circumscribed and lobular with preserva-
Basal cell carcinoma
tion of the normal duct–acinar relationship.1 Focal inflammation and
squamous metaplasia of the ducts is commonly seen. Dilated ducts Clinical features
and sometimes ruptured ducts with extravasated mucin can be noted.7 Basal cell carcinoma can arise on the anogenital skin (Figs 12.264, 12.265).
Adenomas are well circumscribed and composed of small- to medium- Prior genital irradiation for cancer or ringworm is a theoretical risk fac-
sized glands with focal papillary projections and lined by columnar, tor that appertains to basal cell carcinoma at other sites. Vulval and penile
mucin-producing cells with no cytological atypia and very rare mitotic tumors are seen mainly in elderly patients.1 They usually present as an eroded
figures. Tubules and acini proliferate in a haphazard way in contrast to plaque, which may be pigmented. Less commonly, the tumor forms a nodule
the hyperplasias, where the normal architecture is preserved.1 A single or an ulcer. Symptoms vary from discomfort to pruritus.2,3 Neoplasms occur
case of a papilloma arising from the duct of a Bartholin’s cyst has been most frequently on the labia majora, and sometimes can be multiple.4 Tumors
reported.8
In one case of hyperplasia, clonality was demonstrated, suggesting that the
process may be neoplastic rather than reactive.7
Adenoma of minor vestibular glands

Clinical features
Adenoma of minor vestibular glands (paravestibular tumor) is exceedingly
rare and occurs in the vulvar vestibule.1–3 It is likely that it represents a
hyperplasia rather than a true neoplasm. The lesion is very small and usually
represents an incidental finding in a biopsy taken for another reason.4
Histologically, it consists of a small nodular aggregate of mucin-secreting
glands lined by columnar cells.
Bartholin’s gland carcinoma

Clinical features
This rare tumor accounts for only between 2% and 7% of vulval neoplasms.1–8
It presents as a painless hard deep subcutaneous nodule, which, as it expands, Fig. 12.264
becomes fixed and painful. The lesion measures from 1 cm to several centime- Vulval basal cell
ters and is located in the posterior aspect of the labium majus. It often invades carcinoma: erythematous,
keratotic plaque on
deeply into fat, muscle or bone and may be associated with a Bartholin’s
left labium majus. By
gland abscess. The diagnosis is often delayed because of the latter association.
Adult and elderly women are usually affected. Exceptional cases have been Dermatology, London, UK.
described during pregnancy.4
It is often difficult to decide when a tumor has originated from Bartholin’s
gland and particular attention should be paid to exclude a metastasis from
elsewhere. Distinction from a sweat gland carcinoma can also be a diagnostic
problem. Rarely, the tumor is associated with extramammary Paget’s
disease.9,10 In recent years, a consistent association has been found between
these tumors and HPV-16.11,12 Recurrence rates vary and have been reported
to be as high as 54%.13 Up to 40% of patients present with inguinofemoral
metastases. In these the 5-year survival is less than 50% but this decreases
to around 18% when two or more lymph nodes are involved.5,7,8 Adenoid
cystic carcinoma of Bartholin’s gland has a high local recurrence rate and
occasionally presents with metastatic disease.14–17
About 40% of Bartholin’s gland carcinomas are adenocarcinomas.4,7 A further
40% are squamous cell carcinomas and 15% are adenoid cystic carcinomas.18–21
The remainder are transitional, adenosquamous or anaplastic carcinomas.5,8
A case of lymphoepithelioma-like carcinoma and two low-grade epithelial–
myoepithelial carcinoma of the Bartholin gland have been documented.22,23
A case of high-grade squamous intraepithelial neoplasia in a Bartholin’s cyst
has also been reported.24
Exceptional cases of neuroendocrine carcinoma have also been Fig. 12.265
Perianal basal cell
described.2,25 Malignant mixed tumor very rarely originates from Bartholin’s
carcinoma: ulcerated
gland.26 A neoplasm can only be accepted as originating from the gland if perianal nodule with a
there is continuity with it. Adenocarcinomas may be mucinous or papil- pearly white rolled border.
lary.5 Cytogenetic analysis of a single case of adenoid cystic carcinoma of By courtesy of the
Bartholin’s gland revealed complex chromosomal abnormalities involving Institute of Dermatology,
chromosomes 1, 4, 6, 11, 14 and 22.27 London, UK.
Soft tissue tumors 513
can rarely occur in the context of Gorlin’s syndrome.5 Inadequate excision

accounts for a high recurrence rate and exceptional metastases to regional
lymph nodes.6,7 Mohs surgery is often recommended to ensure adequate local
excision and acceptable cosmetic results.
Histologically, the appearances are identical to basal cell carcinomas occur-
ring elsewhere. There has been one case report of the variant fibroepithelioma
of Pinkus affecting the base of the penis.8
Metastatic tumors
The anogenital skin is a rare site for metastatic tumors.1–4 Those that are Fig. 12.266
Juvenile xanthogranuloma:
described are usually from a nearby primary site; for example, vulval metas-
lesions are present
tases may be derived from vaginal, cervical, endometrial, ovarian, renal cell on the lateral shaft of
carcinoma and choriocarcinoma. A large study of metastatic vulvar tumors the penis. Courtesy
found that about 46.9% arise from gynecological primaries and 43.9% from of R. Haufmann, Ulm,
nongynecological primary tumors. The rest of the tumors were metastases Germany. Reproduced
from an unknown primary.4 Vulval metastases usually present as a mass or, with permission from
less commonly, with pain or ulceration.4 Penile metastases most often arise Haufmann RE, Bachor, R.
from the prostate, colon, bladder and kidney. Rarely, they derive from else- Juvenile xanthogranuloma
where including pulmonary carcinoma, squamous cell carcinoma of the of the penis. J Urol.
tongue and cutaneous melanoma.5 The metastases are most commonly sited 1993: 150: 456–457. From
Bunker C: Male Genital
on the labia majora or periclitorally and in the corpus cavernosum of the
Skin Disease. Saunders
penis. Tumor thrombi are often found in the erectile tissue of the penis, pre- Ltd./Elsevier 2004.
dominantly in the corpora cavernosa.5 Penile metastasis may result in pria-
pism.6 They usually represent an ominous sign.5 Metastases may also arise in
an episiotomy scar. An exceptional metastasis to a Bartholin gland has been
reported.7,8 Langerhans cell histiocytosis
This condition is regarded as an abnormality of immune function. It usually
Lymphoma and leukemia affects the genital area as part of disseminated disease but can rarely appear
at this site alone.1–5 Females are affected much more often than males and
Although lymphoma is the most frequent secondary tumor of the testis, it
presentation can occur at any age from infancy to old age. Anogenital lesions
is rare in other parts of the urogenital tract and few case reports exist.1,2
may present as ulcers, erosions, papules, nodules or plaques. Involvement of
Primary anal lymphomas are also extremely rare and the cases described
the penis is very rare.6 Presentation as a fleshy papule on the dorsal penis7 and
have been anorectal, mainly of the plasmablastic variant, associated with
primary penile ulceration8 have been reported.
EBV and AIDS.3
In infants, the diaper area may be affected, typically with a seborrheic-like
Dehner and Smith included two cases of primary lymphoma in their series
dermatitis or purpuric papules.
of soft tissue tumors of the penis, both presenting as painless subcutaneous
nodules without evidence of systemic lymphoma.4 One case presented with
painless priapism and erythematous nodular ulceration of the shaft of the Soft tissue tumors
penis, another case with progressive swelling of the glans penis and another
with chronic penile ulceration.5,6
Doll and Diaz-Arias described a fungating nodular tumor of the scrotum
Keloid
in an HIV-negative homosexual that was shown to be immunoblastic T-cell It has been asserted that the skin of the penis never forms keloid,1,2 but
lymphoma.7 it has been reported after circumcision3 and other forms of trauma4,5 and
Ulceration of the penis due to leukemic infiltration secondary to chronic may be commoner than suspected.6 Keloid has been simulated on the
lymphocytic leukemia has been reported.8,9 Scrotal ulceration due to leukemia dorsum of the penis (Fig. 12.267) by chronic edema caused by a condom
cutis in acute myelogenous leukemia has also occurred.10,11 Lymphoma may catheter.7
present with perianal ulceration abscess and suppuration.12 Perianal infiltra-
tion, ulceration or abscess occurs in 5% of hematological malignancies.13 Fibroepithelial stromal polyp
The histopathology of genital lymphomas is identical to that occurring
elsewhere in the skin. The most commonly reported anogenital B-cell lym- Clinical features
phoma is of the diffuse large cell type.
Fibroepithelial stromal polyp (mesodermal stromal polyp, pseudosarcoma
botryoides), which presents in women of reproductive age, predominantly
Juvenile xanthogranuloma affects the vagina and, less commonly, the vulva.1–9 Involvement of the
cervix is rare.2 In the vagina, the lower third is the most frequent location.
This lesion usually affects the head and trunk but can involve the genitalia Presentation in the very young (including a congenital lesion) or the elderly is
(Fig. 12.266).1 Multifocal penile presentation has been documented,2 also a uncommon.10,11 Interestingly, about one-third of patients are pregnant, sug-
solitary perineal papule,3 and a scrotal swelling.4 Clinicopathologically identical gesting that hormonal influences play a significant role in the pathogenesis
solitary lesions may be seen in adults. The histology is of lipid-laden histiocytes of these tumors.5 Lesions can be single or, more rarely, multiple and bilat-
and giant cells, negative for CD1 and S-100 which are found in Langerhans eral,12 the latter occurrence being most frequently seen in pregnancy. Tumors
cell histiocytosis. Juvenile xanthogranuloma is not associated with abnormal are usually less than 2 cm in diameter and are often pedunculated. Giant
lipids but there may be a relationship with urticaria pigmentosa, diabetes mel- lesions are exceptional.13,14 Local recurrence may occur following incomplete
litus, neurofibromatosis, cytomegalovirus infection and leukemia. excision but the behavior is benign.
Fig. 12.267 Fig. 12.269
Chronic edema simulating edema: note the dorsal proximal swelling and ventral
Fibroepithelial stromal polyp: in this field, there is striking nuclear atypia. By courtesy
urethral fistula. Courtesy of Dr. Rameshwar Bang, Safat, Kuwait. Reproduced
of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School,
from Bang RL. Penile oedema induced by continuous condom catheter use and
Boston, USA.
mimicking keloid scar. Scand J Urol Nephrol 1994;28:333–5. From Bunker C: Male
Low-power examination reveals a polypoid and often pedunculated lesion
with fibrovascular stroma and showing variable cellularity. Small to
medium-sized blood vessels with thick walls are conspicuous (Fig. 12.268).
Hypocellular tumors contain abundant collagen and only scattered spindle-
shaped or stellate cells displaying mild focal or no cytological atypia and
occasional to frequent multinucleated cells. With increasingly cellular tumors,
there is more prominent cytological atypia and mitotic figures may be con-
spicuous (Figs 12.269, 12.270).8,9,15
Occasional atypical forms may be seen. Such variants are more frequent in
pregnant patients. Multinucleated tumor cells become more prominent with
a tendency to concentrate in the stroma adjacent to the epithelium. The cel-
lularity is more prominent towards the center of the lesion.8 Small collections
of mononuclear inflammatory cells are also commonly present.
Tumor cells are positive for desmin, vimentin and estrogen and progester-
one receptors.9,16,17 Positivity for actin is rare and macrophage markers are
negative.12
Fig. 12.270
Fibroepithelial stromal polyp: the presence of multiple mitoses as shown in this
field can be a source of concern to the unwary. By courtesy of M. Nucci, MD,
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Ultrastructural studies show cells with features of fibroblasts and

myofibroblasts.17,18
The main differential diagnosis, particularly for lesions presenting in the
vagina, is sarcoma botryoides. The latter lesion, in contrast, tends to occur at a
much younger age, lacks a cambium layer, displays invasion of the epithelium
by tumor cells, and is composed of small, undifferentiated tumor cells.19
Lymphedematous fibroepithelial polyp of

the glans penis and prepuce
Clinical features
Only a handful of cases of this distinctive entity have been reported.1 Patients
Fig. 12.268 developed polypoid or cauliflower-like, usually long-standing, lesions on the
Fibroepithelial stromal polyp: there are thick-walled vessels associated with a glans penis or prepuce associated with chronic catheter use and phimosis.
variably cellular loose connective tissue stroma. By courtesy of M. Nucci, MD, All reported cases are in adults with a median age of 40 years. There may be
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. local recurrences.
Lesions are polypoid with a hyperplastic epidermis and an edematous stroma
with telangiectasia and sometimes focal proliferation of vascular channels. In
the background there are mono- or multinucleated stromal cells and scattered
mononuclear inflammatory cells, mainly lymphocytes. The stromal cells are
focally positive for actin and desmin.
Prepubertal vulval fibroma

Clinical features
This distinctive vulval lesion has been also described under the rubric child-
hood asymmetric labium majus enlargement.1,2 Lesions involve the labium
majus and present as a unilateral and exceptionally bilateral swelling. Patients
are girls between the ages of 3 and 13. A similar case in a postmenopausal
patient has been documented.3
The lesion is poorly circumscribed, lies within the dermis and subcutis and Fig. 12.271
consist of a poorly cellular mass with abundant collagen, edema and focal Angiomyofibroblastoma: low-power view showing a richly vascular tumor. In this
myxoid change. The cells within the tumor are positive for CD34. example, there is a strikingly myxoid stroma. By courtesy of M. Nucci, MD, and
C.D.M. Fletcher, MD, Brigham and Women’s Hospital and Harvard Medical School,
Angiomyofibroblastoma Boston, USA.
Clinical features
This is a distinctive benign soft tissue tumor of the external genitalia and
perineum that must be distinguished from aggressive angiomyxoma (see
below).1–5 Rare cases have been documented in the vagina, fallopian tube,
urethra and retroperitoneum.6–9 It most commonly affects females of repro-
ductive age but has also been described in the elderly.4 Cases in males are
exceptional.10 A tumor sharing many clinical and histological features with
angiomyofibroblastoma has been reported in the male genital tract as angio-
myofibroblastoma-like tumor. These are described in the scrotum and groin
and histologically show hybrid features between angiomyofibroblastoma and
spindle cell lipoma.11,12
Angiomyofibroblastoma presents as a slowly growing, small (usually less
than 5 cm diameter), asymptomatic subcutaneous mass in the vulva or, less
commonly, in the vagina. Polypoid morphology is exceptional.13 They are
frequently confused with a Bartholin’s gland cyst. In males, tumors occur
on the scrotum and rarely in the perineum, groin and spermatic cord.14–16
Behavior is generally benign with little or no tendency for recurrence
although a single malignant case has been reported.17,18 This tumor con-
sisted of typical areas of angiomyofibroblastoma with areas of high-grade
myxoid sarcoma. Fig. 12.272
Angiomyofibroblastoma: the tumor cells have eosinophilic cytoplasm and small
nuclei. Nucleoli are not apparent. By courtesy of M. Nucci, MD, and C.D.M. Fletcher,
Histological features MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Angiomyofibroblastoma is well circumscribed and surrounded by a fibrous
pseudocapsule. Scanning magnification reveals a tumor with hypo- and
hypercellular areas and a prominent vascular network composed of thin-
walled dilated vascular channels (Figs 12.271, 12.272). The hypocellular Differential diagnosis
areas display prominent myxoid change. Tumor cells are plump, epithelioid or Distinction from aggressive angiomyxoma is not usually difficult as the lat-
spindle-shaped with imperceptible to abundant pink cytoplasm, finely dispersed ter is larger (usually more than 5 cm), infiltrative, less cellular and vascu-
chromatin and inconspicuous nucleoli. They tend to concentrate around the lar and contains vessels with thicker walls. However, tumors with hybrid
vascular channels. Multinucleated forms are frequent. Epithelioid cells with features of angiomyofibroblastoma and aggressive angiomyxoma have been
hyaline cytoplasm often have a plasmacytoid appearance. Cytological atypia reported.21 Despite this, it is controversial whether both entities are related.
is absent and mitotic figures are usually rare or exceptionally more promi- Aggressive angiomyxoma has rearrangements of HMGA2, a member of the
nent.19 Scattered lymphocytes and mast cells are often present. Intratumoral high-mobility-group protein family involved in alteration of chromatin struc-
mature adipocytes are present in a number of cases and may represent most ture and in the transcription of many genes. The latter feature has not been
of the tumor (lipomatous variant of angiomyofibroblastoma).5,20 Degenerative found in angiomyofibroblastoma.22 The rare cases of hybrid tumors are best
nuclear hyperchromatism may sometimes be present. classified and treated as aggressive angiomyxoma, and, if possible, cytoge-
The tumor cells are diffusely and strongly positive for desmin but in only netic analysis or immunohistochemistry for HMGA2 should be performed.
occasional cases are they positive for either smooth-muscle actin or pan- By immunohistochemistry, nuclear staining for this protein is seen in the
muscle actin. Estrogen and progesterone receptor can be positive.5 CD34 majority of (but not all) aggressive angiomyxomas and it tends to be neg-
is only exceptionally positive. Epithelial markers, S-100 and myoglobin are ative in angiomyofibroblastoma.23,24 However, it is important to take into
negative. consideration that there is not always correlation between the translocation
Ultrastructural studies suggest myofibroblastic differentiation.1,3,4 and protein expression.
Aggressive angiomyxoma
Clinical features
This tumor presents as a slowly growing asymptomatic mass involving the
pelvis and perineum.1–6 Exceptionally, the lesion can present in the retroperi-
toneum.7 It mainly affects females in the third or fourth decade of life. Only a
single case has been reported in a child.8 Less than 5% of cases occur in males,
with predilection for the scrotum, perineum or groin.9–11 In males, lesions may
mimic a hydrocele or an inguinal hernia.12,13 Tumors are often 10 cm or more
in diameter and can sometimes attain a very large size. Genitourinary and
anorectal symptoms usually ensue due to external compression by the tumor.
In females, lesions present mainly in the vulva or perineum followed by the
vagina and the pelvis. Because of its extensive infiltrative growth, complete
surgical excision is often difficult; local recurrences are therefore frequent and
occur in up to 30% of cases. Metastasis are exceptional.14,15
Rare case reports have been published of tumors displaying prominent
reduction in size after treatment with gonadotrophin releasing hormone
agonists.16,17
Fig. 12.274
Histological features Aggressive angiomyxoma: in this view, a smooth muscle bundle is evident in the
upper field. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and
Macroscopic examination reveals a soft, ill-defined, lobulated tumor with Harvard Medical School, Boston, USA.
myxoid change. Microscopically, the lesion is infiltrative, with numerous
small- and medium-sized blood vessels and a small number of tumor cells in
a myxoid stroma (Figs 12.273–12.275). The blood vessels have thick walls,
which are often hyalinized. Tumor cells are small, spindle-shaped or stel-
late with ill-defined pale pink cytoplasm and vesicular nuclei. Cytological
atypia is absent and mitotic figures are rare. Bundles of smooth muscle are
frequently seen adjacent to blood vessels, a finding that can be highlighted
by a desmin stain.9 Residual normal structures including glands and smooth
muscle are often entrapped by the tumor. Scattered mast cells are often pres-
ent. Multinucleated giant cells similar to those found in stromal polyps are
occasionally found. Some cases overlap histologically with angiomyofibro-
blastoma (see above).
Immunohistochemically, tumor cells are positive for smooth-muscle actin
and desmin. Positivity for estrogen and progesterone receptors is also seen and
in men androgen receptors are positive.5,7,18 Cytogenetic analysis of a num-
ber of aggressive angiomyxomas has often shown rearrangements of chro-
mosome 12q13–15. The latter results in an aberrant expression of HMGA2
(a member of the high-mobility-group protein family previously known as
HMGIC).19–23 Interestingly, the area involved (12q14–15) is the same as that
reported in a number of other tumors including leiomyoma and lipomatous
neoplasms. Staining for HMGA2 may be useful to distinguish aggressive
Fig. 12.275
Aggressive angiomyxoma: high-power view showing a uniform cellular population.
There is no pleomorphism. By courtesy of M. Nucci, MD, Brigham and Women’s
Hospital and Harvard Medical School, Boston, USA.
angiomyxoma from potential mimics, mainly angiomyofibroblastoma (see

under the latter), but this marker, although sensitive, is not very specific.24,25
Electron microscopy shows cells with features of fibroblasts and
myofibroblasts.5
See angiomyofibroblastoma.
Chronic lymphedema of the vulva may give rise to a lymphedematous
pseudotumor that can mimic aggressive angiomyxoma.26 In the former, how-
ever, there is massive edema rather than myxoid change, and telangiectatic
lymphatics focally surrounded by lymphocytes. Identical changes may be seen
in massive localized lymphedema secondary to morbid obesity.
Cellular angiofibroma
Fig. 12.273
Aggressive angiomyxoma: there are conspicuous blood vessels dispersed in a
Clinical features
myxoid stroma. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Cellular angiofibroma is a distinctive tumor that occurs mainly on the vulva
Harvard Medical School, Boston, USA. of middle-aged women.1–7 Very rare cases occur in the vagina.6,7 Presentation
in males is less common, with lesions occurring in the inguinoscrotal region or

rarely in the perianal region.1,2,6,7 Exceptional cases have been reported in the
retroperitoneum and in the subcutaneous tissue of the chest, abdomen, knee,
retroperitoneum, urethra, anus, upper eyelid and oral mucosa.2,7–10 Tumors
tend to be small and behavior is benign, with almost no tendency for local
recurrence except very rarely.1,7,11 Sarcomatous change has been reported but
so far this has not been associated with aggressive behavior.7,12,13

Cytogenetic analysis of cellular angiofibroma has shown loss of chromosome
13q14, a feature also seen in spindle cell lipoma and mammary-type myofi-
broblastoma.7,14,15 In conjunction with histological similarities, this gives fur-
ther support to a link between these neoplasms.
Tumors are well circumscribed but unencapsulated, with only occasional
extension into the surrounding soft tissues (Figs 12.276–12.278).1 An infil-
trative pattern is rare.7 Most lesions are fairly cellular and composed of short,
bland, spindle-shaped cells with poorly defined pale eosinophilic cytoplasm
and vesicular nuclei. Nuclear grooves and intranuclear inclusions are com-
mon. The number of mitotic figures varies but sometimes they may be promi-
Fig. 12.278
nent. Thick-walled, medium-sized hyalinized blood vessels are frequent in Cellular angiofibroma: the tumor cells are small, uniform and have round to oval
vesicular nuclei. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and
Harvard Medical School, Boston, USA.
addition to slender collagen bundles and mast cells. Pseudovascular spaces

are sometimes seen. Mature adipocytes are frequently present (in up to 30%
of cases). Focal cytological atypia resembling symplastic changes seen in other
tumors are described and sarcomatous transformation can be identified.7,12,13,16
Malignant areas usually show high cellularity, cytologic atypia and multinu-
cleated cells.7 Tumors may rarely show features of a pleomorphic liposar-
coma or of an atypical lipomatous tumor.6,13
Tumor cells are positive for vimentin and are positive for CD34 in up
to 50% of cases. Staining for actin, desmin, caldesmon, S-100 protein and
epithelial markers is negative.1, 2
Distinction is mainly with angiomyofibroblastoma. The latter consists of
more epithelioid desmin-positive cells with a nested pattern and a tendency
for perivascular distribution. Cellular angiofibroma is negative for desmin
and is often positive for CD34.
Fig. 12.276
Cellular angiofibroma: the tumor is characterized by thick-walled, hyalinized blood
vessels associated with a densely cellular stroma. By courtesy of M. Nucci, MD, Genital leiomyoma
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Clinical features
Genital leiomyoma comprises those lesions arising from the vulva, scrotum
and nipple. Tumors arising in the vulva and scrotum are distinctive from
other cutaneous leiomyomas including pilar leiomyoma and angioleiomy-
oma.1 Leiomyomas arising in the nipple are similar to pilar leiomyoma.
Vulval leiomyomas are relatively rare and present mainly in women of
reproductive age or slightly older as an asymptomatic swelling.1–5 Clinical
features are not distinctive. Tumors are subcutaneous, well circumscribed and
are often clinically diagnosed as a cyst. The majority of benign lesions are
less than 5 cm in diameter and present in the labia. Rare cases arise in the
clitoris.6 Tumors may increase in size during pregnancy and also in association
with estrogen/progesterone replacement therapy.7 Benign tumors are typi-
cally circumscribed and small, but only histological examination allows for
distinction between benign, low-grade malignant and malignant tumors.
In the male8 it presents as a painless, slow-growing, palpable mass (pap-
ule or nodule), and/or difficulty with micturition9 if it affects the penis; or
swelling of the scrotum where it arises from the tunica dartos scroti.1,10–12
Scrotal tumors are less common and tend to be larger than their vulval
counterparts.13,14 They present as an asymptomatic mass that may occasion-
ally be polypoid.14 Rare cases are associated with prominent warty epidermal
Fig. 12.277 hyperplasia and resemble condyloma acuminatum.15 Other benign smooth
Cellular angiofibroma: note the associated collagen fibers. By courtesy of M. Nucci, muscle lesions of the scrotum such as hamartoma of the dartos muscle are
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. exceedingly rare.16
Tumors are well circumscribed and noninfiltrative with variable cellularity.1–3
They are composed of admixed spindled and epithelioid cells, often with a single
cell type predominating.4,17,18 Lesions with a spindled cell component are very
similar to those found in the uterus and consist of bundles of cells with well-
defined eosinophilic cytoplasm, vesicular cigar-shaped nuclei and an inconspicu-
ous nucleolus. Focal myxoid change and hyalinization are commonly seen and
sometimes this results in a plexiform appearance. Epithelioid tumor cells have
abundant eosinophilic or pale-staining cytoplasm.
Because of the rarity of vulval smooth muscle tumors, it is often difficult
to separate benign lesions from those with potential for local recurrence or
metastasis (see below). It has been suggested that a tumor with any evidence
of mitotic activity, nuclear pleomorphism or an infiltrative margin should be
regarded as having at least the potential for local recurrence.4 In such cases,
excision with a margin of at least 1 cm should be recommended.4
Because of their rarity, there is even less information relating to histo-
logical evaluation of scrotal leiomyoma. Degenerative cytological atypia
is accepted in these tumors but these changes occur in noncellular, well-
circumscribed lesions that lack mitotic activity.19 Fig. 12.279
Vulval leiomyosarcoma: this low-power view shows fascicles of tumor cells with
Leiomyosarcoma eosinophilic cytoplasm. By courtesy of C. Crum, MD, Brigham and Women’s
Hospital and Harvard Medical School, Boston, USA.
Clinical features
Vulval leiomyosarcoma is rare and presents in middle-aged to elderly patients
as an asymptomatic mass mainly affecting the labia.1–6 Malignancy is not usu-
ally suspected on clinical examination unless the mass is large and poorly cir-
cumscribed. Lesions may be confused with a Bartholin’s gland cyst.6,7
Scrotal leiomyosarcomas are exceptional and present as an asymptomatic,
rapidly growing mass in elderly patients.8,9
Wide local excision is the treatment of choice. It is difficult to predict the
outcome because of their rarity and the lack of large studies with adequate
follow-up information.
Accepted criteria for the histological diagnosis of leiomyosarcoma include
(Figs 12.279–12.281):1,2,10
• size larger than 5 cm in diameter,
• infiltrative margins,
• more than 5 mitoses/10 high-power fields (HPF),
• moderate to severe cytological atypia.
More recently, it has been suggested that tumor necrosis should also be
Fig. 12.280
regarded as evidence of malignancy.10 Vulval leiomyosarcoma: note the nuclear pleomorphism. By courtesy of C. Crum,
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Vulvar leiomyomatosis
Clinical features
This rare condition is characterized by multiple leiomyomas in the vulva associated
with esophageal leiomyomas.1–8 The vulval tumors may appear before, concomi-
tantly or after the development of esophageal lesions. Involvement of the clitoris is
sometimes noted. Patients can also present with Alport’s syndrome, characterized
by inherited glomerulonephritis, ocular abnormalities and deafness.5

The pathogenesis of the disease is unknown but deletions and mutations in
the COL4A6 and COL4A5 genes have been described.5,7 These genetic altera-
tions are associated with defects in type IV collagen in Alport’s syndrome.
Vulval and esophageal leiomyomas are identical to those occurring
sporadically.
Myointimoma
This is a rare, recently described tumor involving the corpus spongiosum of Vulval leiomyosarcoma: high-power view showing a mitotic figure in the center of
the glans penis.1 The original series consisted of adult patients, but a recent the field. By courtesy of C. Crum, MD, Brigham and Women’s Hospital and Harvard
small series in children and adolescents has been reported.1,2 Few single case Medical School, Boston, USA.
reports have been presented.3–5 Lesions are small (usually less than 1 cm) and
asymptomatic. It does not seem to be related to trauma. The behavior is
benign with no tendency for local recurrence.1,2
Low-power examination reveals a diffuse myointimal proliferation of the blood
vessels of the corpus spongiosum of the glans penis in a plexiform growth pattern
(Figs 12.282–12.284). The proliferating cells are bland and spindled with abun-
dant pink cytoplasm and vesicular nuclei. A minority of the cells display features
more reminiscent of fibroblasts. The background stroma is sclerotic and myxoid.
Focal degenerative changes may be seen and mitotic figures are absent.
The spindled cells are positive for smooth-muscle actin, muscle-specific
actin and calponin but negative for desmin.
This tumor must be distinguished from myofibroma, intravascular nodular
fasciitis and vascular leiomyoma.
Postoperative spindle-cell nodule Fig. 12.283

Myointimoma: the vascular lumina are compressed by the proliferation of spindle-
Clinical features shaped cells.
This rare reactive lesion presents as a small nodule at the site of a previous
surgical procedure on the genitourinary tract including the bladder, vulva
and the vagina.1–4 It grows rapidly and is usually asymptomatic.1–3 Local
recurrence is usually not seen.
Fig. 12.284
Myointimoma: areas of hyalinization may be seen.

The lesion is regarded as a non-neoplastic reparative phenomenon,
Interestingly, trisomy 7 has been reported in two cases.5 The nodule is poorly
circumscribed and resembles nodular fasciitis.1–3 It is composed of bundles
Fig. 12.282 of plump myofibroblast-like cells dispersed in a myxoid or edematous back-
Myointimoma: note the ground. Nuclei may be bland or hyperchromatic. Small blood vessels, foci of
multinodular and plexiform hemorrhage, lymphocytes and neutrophils are additional features. Mitotic
growth pattern. figures are common.
Degenerative and metabolic
13
Chapter
diseases
See
for references and
additional material
Nooshin Brinster and Eduardo Calonje
The hyperlipidemias 520 Porphyria 549 Lichen myxedematosus/scleromyxedema 574

Eruptive xanthomata 522 Congenital erythropoietic porphyria 550 Acral persistent papular mucinosis 578
Tendinous xanthomata 523 Erythropoietic protoporphyria 551 Cutaneous mucinosis of infancy 579
Tuberous xanthomata 525 Hereditary coproporphyria 553 Self-healing juvenile cutaneous mucinosis 579
Planar xanthomata 527 Porphyria cutanea tarda 553 Reticular erythematous mucinosis 580
Verruciform xanthoma 528 Hepatoerythropoietic porphyria 555 Scleredema 580
Variegate porphyria 555 Papular and nodular cutaneous mucinosis of
Angiokeratoma corporis diffusum 530 systemic lupus erythematosus 581
Pseudoporphyria 559 Myxoid cyst 582
The amyloidoses 532
Primary and myeloma-associated systemic Gout 562 Cutaneous focal mucinosis 582
amyloidosis 534 Mucinous nevus 583
Ochronosis 564 Neuropathia mucinosa cutanea 583
Secondary amyloidosis 536
Alkaptonuria 564 Self-healing infantile familial cutaneous
Hemodialysis-associated amyloidosis 536
Exogenous ochronosis 564 mucinosis 583
Heredofamilial amyloidoses 537
Amyloid elastosis 537 Hartnup disease 565 Localized mucinosis secondary to venous
Primary localized cutaneous amyloidosis, lichen insufficiency 583
and macular types 537
Pellagra 565 Secondary cutaneous mucinosis 583
Secondary localized cutaneous amyloidosis 541 Scurvy 566 Acanthosis nigricans 583
Familial primary cutaneous amyloidosis 541
Nodular amyloidosis 541 Calcinosis cutis 566 Acrodermatitis enteropathica 586
Dystrophic calcinosis cutis 566
Colloid milium 543 Metastatic calcinosis cutis 568 Necrolytic migratory erythema 587
Juvenile colloid milium 543 Idiopathic calcinosis cutis 568 Bullosis diabeticorum 589
Adult colloid milium 544
The mucinoses 571
Hyalinosis cutis et mucosae 546 Generalized myxedema 572
Localized (pretibial) myxedema 573
Cutaneous macroglobulinosis 548
The presence of xanthomata commonly represents a cutaneous manifesta-

The hyperlipidemias tion of systemic disease, and their recognition should therefore be followed
by an intensive investigation to exclude the latter (Table 13.1).2,4 Although
The hyperlipidemias may present as cutaneous xanthomata, which are local- not a hard and fast rule, xanthoma morphology and distribution can
ized aggregates of histiocytes containing accumulated lipid (primarily free sometimes point towards specific hyperlipidemia variants.
and esterified cholesterol), in the form of five main clinical types: The plasma lipids are composed of triglycerides and cholesterol; these are
• eruptive, insoluble and their transport is facilitated by their aggregation into lipopro-
• tendinous, teins. The latter are macromolecular complexes composed of an outer shell of
• tuberous, hydrophilic phospholipids, nonesterified cholesterol and apo(lipo)proteins,
• planar, which emulsify the associated hydrophobic core of triglycerides and choles-
• disseminated.1 terol ester.5 There are a large number of apoproteins, with variable structure
The last, xanthoma disseminatum, in which serum lipid levels are normal, and function (e.g. ApoB-48, which is required for the secretion of chylomi-
is discussed in Chapter 29 (see xanthogranuloma). Xanthoma cells express crons into the thoracic duct).3 In addition to giving structure to the lipopro-
CD4, CD11c, CD14b, and CD68 in addition to human leukocyte antigen tein, apoproteins also represent ligands for specific receptors (e.g. ApoE is a
(HLA) class II antigens.2 ligand for liver chylomicron receptors). They also act as cofactors for a
Hyperlipidemias may be primary, or secondary to conditions such as dia- number of lipid-modifying enzymes (e.g. ApoCII activates lipoprotein lipase).5
betes mellitus, obesity, pancreatitis, renal disease (the nephrotic syndrome or Lipoprotein metabolism, which is summarized in Figure 13.1, involves both
chronic renal failure), hypothyroidism, alcohol consumption, pregnancy, exogenous (dietary) and endogenous pathways.6 For more detailed informa-
cholestatic liver disease (e.g. primary biliary cirrhosis) and paraproteinemias. tion the reader is particularly referred to references 1 and 6.
Drug-induced hyperlipidemia also occurs as a result of administration of The classification of hyperlipidemias is based upon the electrophoretic
estrogens, corticosteroids or 13-cis-retinoic acid. It is often associated with separation, on paper or agarose gel, of abnormal quantities of lipoprotein in
serious, potentially life-threatening disorders such as atherosclerosis (low the plasma (Fig. 13.2). There are seven main classes of lipoprotein, with
density lipoproteins) and pancreatitis (hypertriglyceridemia).3 differing electrophoretic mobilities:
The hyperlipidemias 521
Table 13.1
Classification of xanthomatous disorders
Hyperlipidemic xanthomatoses: disorders characterized by elevated Normolipidemic xanthomatoses: disorders characterized by normal plasma
plasma triglycerides or cholesterol triglycerides and cholesterol
Primary Elevated plasma triglycerides Disorders characterized by Accumulation of unusual sterols in LDL
hyperlipoproteinemias lipoprotein lipase deficiency altered lipoprotein content cerebrotendinous xanthomatosis(cholestanol)
familial hyperlipoproteinemia, type V or structure sitosterolemia (sitosterol, campesterol,
familial hypertriglyceridemia stigmasterol, etc.)
Elevated plasma triglycerides and Deficiency of HDL
cholesterol plantar and buccal mucosal xanthomas
familial dysbetalipoproteinemia, type III diffuse plane xanthomas
Elevated plasma cholesterol Normocholesterolemic dysbetalipoproteinemia
familial hypercholesterolemia tuberous
xanthelasmas
Hyperapobetalipoproteinemia
tendon xanthomas
xanthelasmas
Secondary Elevated plasma triglycerides Disorders associated with Multiple myeloma
hyperlipoproteinemias diabetes mellitus antibodies directed against Other paraproteinemias
drug-induced chylomicronemia lipoprotein components
alcohol
States with no demonstrated Underlying lymphoproliferative disease
estrogens
lipoprotein abnormalities multiple myeloma
retinoids
cryoglobulinemia
hypothyroidism
Waldenström’s macroglobulinemia
nephrotic syndrome
leukemia
type I glycogen storage disease (von
lymphoma
Gierke’s disease)
other
Elevated plasma cholesterol
Xanthomatosis antedated by local tissue alterations
hepatic cholestasis
normolipemic eruptive xanthomas (after erythema)
primary biliary cirrhosis
xanthelasmas and planar xanthomas (after
biliary atresia
erythroderma)
hypothyroidism
fiverruciform xanthomas (in areas of dystrophic
dysglobulinemias or
epidermolysis bullosa)
paraproteinemias
Other
multiple myeloma
hereditary tendinous and tuberous
xanthomas
normolipemic tendon and tuberous
xanthomas
normolipemic subcutaneous xanthomatosis
HDL, high density lipoprotein; LDL, low density lipoprotein.

Reprinted from Cruz, P.D., East, C., Bergstresser, P.R. (1988) Journal of the American Academy of Dermatology, 19, 95–111 with permission from the American Academy of
Dermatology, Inc.
• chylomicrons, which are composed predominantly of exogenous The lipid content of xanthomata is probably mostly derived from the plasma,
triglycerides produced by small intestinal mucosal epithelium in response presumably by lipoprotein (particularly LDL and VLDL) permeation of blood
to dietary lipid, vessel walls with the release of lipid and its subsequent phagocytosis by histio-
• very low density (pre-beta) lipoproteins (VLDL) of hepatic derivation, cytes, although localized lipogenesis may also be of importance.10–13 The sub-
which are particularly involved in the transportation of endogenous groups and proportions of lipid deposited within xanthomata are similar to those
triglyceride, found in atheromatous plaques, raising the possibility of a shared pathogenesis.1
• intermediate density lipoproteins (IDL), which are thought to be VLDL Xanthomata are, however, not always associated with hypercholester-
remnants, olemia or hyperlipoproteinemia.14 Under such circumstances, they may evolve
• low density (beta) lipoproteins (LDL), which are mainly involved in as a consequence of altered lipoprotein content or structure, represent local
cholesterol transport and derived from IDL or else produced by the liver, tissue changes or develop as a consequence of systemic disease including lym-
• high density (alpha) lipoproteins (HDL) composed predominantly of phoma, multiple myeloma, and Waldenström's macroglobulinemia.15
lipoprotein and equal quantities of cholesterol and phospholipid, Normocholesterolemic xanthomata can therefore arise as a consequence of
• high density lipoprotein variant HDL2,1,5 the accumulation of cholesterol-like substances within histiocytes (e.g.
• high density lipoprotein variant HDL3.1,5 cerebrotendinous xanthomatosis and β-sitosterolemia).
The hyperlipidemias are classified into six types according to the lipopro- Cerebrotendinous xanthomatosis represents an abnormality of bile acid
tein anomaly present (Table 13.2). However, it should be noted that each of metabolism inherited in an autosomal recessive pattern.16–18 As a consequence of
these six types may result from a variety of pathogeneses, including those of mitochondrial enzyme sterol 27-hydroxylase deficiency and resultant impaired
a known or presumed genetic basis and others that complicate a diverse group oxidation of the cholesterol side chain during the production of cholic acid,
of disease processes (secondary hyperlipidemia).7–9 High density lipoproteins cholestanol (and cholesterol) accumulates in the tissues, especially the tendons,
are not atherogenic.3 Indeed, their function is to remove cholesterol from the lungs, and brain. The xanthomata particularly affect the Achilles tendons and
tissues and high levels serve to protect against vascular disease.5 Conversely, the tendons of the knees, elbows, and the interphalangeal joints.19 In addition to
HDL deficiency (e.g. Tangier disease) is associated with cholesterol tendinous xanthomata, patients develop juvenile cataracts and progressive neu-
accumulation.10 rological dysfunction including mental retardation, dementia, pyramidal signs,
522 Degenerative and metabolic diseases
Fig. 13.1
Lipoprotein metabolism. (LDL, low density lipoprotein;
VLDL, very low density lipoprotein.) Reproduced with
permission from Cruz, P.D., East, C., Bergstresser,
P.R. (1988) Journal of the American Academy of
Dermatology, 19, 95–111.
Eruptive xanthomata
Clinical features
Eruptive xanthomata are small (1–4 mm) yellowish papules with a red halo
that have a predilection for the buttocks, shoulders, and extensor surfaces of
the limbs (Fig. 13.3).1 They may also present in the antecubital and popliteal
fossae, axillae, lips, eyelids, and ears.2 They often appear in crops and may
wax and wane with plasma lipoprotein levels.3 Lesions usually resolve spon-
taneously over a period of weeks. Pruritus is frequently present and the pap-
ules are sometimes tender.2 Eruptive xanthomata may rarely display a Koebner
phenomenon.4,5 Healing is occasionally associated with the development of
hyperpigmented scars.2 Cutaneous lesions of Langerhans cell histiocytosis
may mimic eruptive xanthoma.6
Eruptive xanthomata are associated with hypertriglyceridemia and most
Fig. 13.2 often occur in hyperchylomicronemic states. Sometimes their presence
Hyperlipidemia: electrophoretic separation of serum lipids. (Chylo, chylomicron; correlates with increased levels of very low density lipoproteins. The most
HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low density common cause, however, is secondary hyperlipoproteinemia, especially in
lipoprotein.) By courtesy of B. Lewis, MD, St Thomas’ Hospital, London, UK.
those cases associated with diabetes mellitus and alcohol ingestion, or in
those that are drug induced (e.g. due to exogenous estrogens, corticoster-
oids or retinoids).2,7 They may also develop as a consequence of decreased
cerebellar ataxia, spinal cord paresis, and sensory changes due to dysmyelina- lipoprotein lipase activity, ApoCII deficiency or increased synthesis of
tion.18,20,21 Coronary atherosclerosis, endocrine abnormalities, and diarrhea may VLDL, which effectively blocks chylomicron access to lipoprotein lipase.2,8
also be present. In addition to cholestanol accumulation, cerebrotendinous xan- Eruptive xanthomata are therefore often accompanied by other features of
thomatosis has been shown to be characterized by abnormal high density hyperlipidemia, including lipemia retinalis, hepatosplenomegaly, abdomi-
lipoproteins, which result in impaired cholesterol (and cholestanol) transport nal pain, and pancreatitis. They may also rarely develop as a manifestation
and contribute to the consequent xanthomatization.16 The mortality is high, of primary hyperlipoproteinemia (HPL), particularly autosomal recessive
patients usually dying in the fourth to sixth decades, most often from progres- lipoprotein lipase deficiency (HLP type I) in children and familial HPL type
sive neurological dysfunction, pseudobulbar paralysis or myocardial V in adults.9,10 An exceptional association with β-sitosterolemia, a condi-
infarction.21 tion usually presenting with tuberous or tendinous xanthomata, has been
Tendinous and tuberous xanthomata may also represent a manifestation documented.11 Much rarer associations include familial hypertriglyceri-
of β-sitosterolemia. This is an autosomal recessive condition in which demia, the nephrotic syndrome, chronic pancreatitis, von Gierke's disease,
increased intestinal absorption of the plant sterols β-sitosterol, campesterol, and hypothyroidism.7,12,13 An association with acanthosis nigricans has also
and stigmasterol results in tissue deposition along with cholesterol and subse- been reported.14
quent xanthoma formation.22–24 Normally these sterols are almost completely
unabsorbed from the gastrointestinal tract. β-Sitosterolemia is associated
with an increased risk of atherosclerosis.3
Xanthomata may occur in extracutaneous locations mimicking tumors Histological features
in patients with hyperlipidemia. Sites include deep soft tissues and The histological features are seen predominantly within the superficial reticu-
mediastinum.25 lar dermis. In early lesions histiocytes are numerous and the fully developed
Table 13.2
Classification of hyperlipidemias
Type Anomaly Primary cause Secondary cause Atherogenesis Xanthoma Associations

I Raised chylomicrons Familial lipoprotein lipase deficiency − − Eruptive Hepatomegaly
Apoprotein Cll deficiency Pancreatitis
Lipemia retinalis
Abdominal pain
IIA Raised LDL Familial hypercholesterolemia Hepatoma + Tendinous −
Familial multiple type hyper Porphyria Xanthelasma
lipoproteinemia Myxoedema Arcus
Common hypercholesterolemia Anorexia nervosa Tuberous (rare)
Nephrotic syndrome
Cushing’s syndrome
IIB Raised LDL and VLDL Familial hypercholesterolemia Nephrotic syndrome + Tendinous −
Familial multiple type hyperlipidemia Cushing’s syndrome Xanthelasma
Arcus
Tuberous
III Raised IDL Familial dysbetalipoproteinemia Paraproteinemia + Palmar Diabetes
Tendinous Gout
Tuberous Obesity
IV Raised VLDL Familial multiple type hyperlipidemia Diabetes + Eruptive −
Familial hypertriglyceridemia Uremia Tendinous
Sporadic hypertriglyceridemia Paraproteinemia Tuberous
Alcoholism
Lipodystrophy
Obesity
V Raised chylomicrons Familial multiple type Diabetes + Eruptive Hepatomegaly
and VLDL hyperlipoproteinemia Obesity Pancreatitis
Familial lipoprotein lipase deficiency Pancreatitis Lipemia retinalis
Apoprotein Cll deficiency
Familial hypertriglyceridemia
Famial type V hyperlipoproteinemia
IDL, intermediate density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein.
Eruptive xanthomata often develop rapidly over the course of several days
and occasionally are associated with spontaneous resolution. The quantity of
intracytoplasmic lipid (predominantly triglyceride in contrast to other xan-
thomata, which contain mostly cholesterol) is in a state of flux and may be
associated with extracellular deposition, a phenomenon that is rare or absent
in the other types of xanthomata. In all xanthomata the lipid within the mac-
rophage stains positively with fat stains such as oil red O, scarlet or Sudan red
(Fig. 13.7).
There can be confusion with granuloma annulare histologically as both con-
ditions have certain features in common, namely a dermal interstitial
histiocytic infiltrate with variably increased mucin.12,17 Although extracellular
lipid may disrupt dermal collagen, necrobiosis is not characteristic of eruptive
xanthoma. Additionally, it contains few giant cells and the perivascular infil-
trate is lymphocytic, in contrast to the histiocytes seen in granuloma
annulare.12
Fig. 13.3
Eruptive xanthoma: numerous small yellow papules are present on the buttocks.
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Tendinous xanthomata
Clinical features
‘foam cells’, which characterize xanthomata, are sometimes few in number. Tendinous xanthomata, which are associated with raised low density lipo-
The infiltrate may also contain an admixture of lymphocytes and protein levels, are slowly enlarging subcutaneous tumors that occur in ten-
neutrophils.15,16 In an established papule, xanthoma cells with characteristic dons (especially those of the hands, knees, elbows, and the Achilles tendon),
clear or foamy cytoplasm form the predominant cell type (Figs 13.4–13.6). ligaments, fascia, and periosteum (Figs 13.8, 13.9).1 The overlying skin,
Fig. 13.6
Eruptive xanthoma: the histiocytes express CD68.
Fig. 13.4
Eruptive xanthoma: biopsy
of an established lesion.
The histiocytes have
abundant vacuolated
cytoplasm.
Fig. 13.7
Eruptive xanthoma: the lipid within the macrophages stains positively with oil red O.
Fig. 13.5
Eruptive xanthoma: high-power view showing an admixture of vacuolated xanthoma
cells and nonlipidized variants with abundant eosinophilic cytoplasm.
which appears normal, is freely moveable over the surface and small tendon
xanthomata may be difficult to palpate.1 The lesions characteristically
‘move with the tendons’ and are thought to be trauma related.2 The presence
of these xanthomata is most frequently a feature of heterozygous familial
(LDL receptor deficiency) hypercholesterolemia.2–4 There is a high risk of
associated coronary atherosclerosis. A recent meta-analysis demonstrated a
threefold increased risk of cardiovascular disease in patients with familial
hypercholesterolemia and tendinous xanthomata compared to those with-
out cutaneous lesions.5 Tendinous xanthomata are also seen in familial
combined hyperlipidemia, normocholesterolemic states such as cerebroten-
dinous xanthomatosis (cholestanolosis) and β-sitosterolemia, and the neph-
rotic syndrome.2,6–10 Fig. 13.8
Clinically, the lesions, which may be mistaken for gouty tophi and rheu- Tendinous xanthoma: typical nodules on the heels. These lesions are often related
matoid nodules, are sometimes found in association with tuberous xan- to trauma; the Achilles tendon is a classical site. By courtesy of A.F. Lant, MD,
thomata and xanthelasmata. and J. Dequeker, MD, London, UK.
Four other conditions may also be characterized by tuberous

xanthomatosis:
• homozygous familial hypercholesterolemia,
• cerebrotendinous xanthomatosis,
• β-sitosterolemia,1
• type IV hyperlipoproteinemia.4
Tuberous xanthomata also occur in secondary hyperlipidemia (e.g. due to
the nephrotic syndrome or hypothyroidism). Protease inhibitors may cause
hyperlipidemia, and ritonavir has been reported to induce tuberous and tendi-
nous xanthoma lesions.5 Clinically, tuberous xanthomata occasionally resem-
ble the lesions of erythema elevatum diutinum. Tuberous and tendinous
normolipemic xanthomata have been described but it seems that, with ade-
quate follow-up, patients usually develop some form of hyperlipidemia.6
Fig. 13.9
Tendinous xanthoma: xanthomata are present overlying the knuckles. By courtesy
Tendinous xanthomata are composed of multiple nodules containing
anthoma cells, accompanied in early lesions by an admixture of inflam-
x
matory cells including histiocytes, lymphocytes, and neutrophil poly-
morphs. The deposits in tendinous xanthoma are doubly refractile to
polarized light (Fig. 13.10). Older lesions are characteristically associated
with fibrosis.
Tuberous xanthomata
Tuberous xanthoma: firm
Tuberous xanthomata are firm yellow–red papules and nodules, which are erythematous nodules
found most frequently on the extensor aspect of the knees, elbows, and but- over the elbow. By
tocks (Figs 13.11–13.13).1 Lesions sometimes also occur on the hands and courtesy of R.A. Marsden,
palms.2 They are most characteristically seen in familial dysbetalipoproteine- MD, St George’s Hospital,
mia type III, and there is a particular risk of peripheral vascular disease.3 London, UK.
Fig. 13.12
Fig. 13.10 Tuberous xanthoma: erythematous nodule on the back of the arm. By courtesy of
Tendinous xanthoma: intense birefringence of deposits in polarized light (oil red O). the Institute of Dermatology, London, UK.
Fig. 13.13
Tuberous xanthoma: in this example, eruptive lesions are present on the elbows.
Cholesterotic fibrous histiocytomas may be associated with hyperlipidemia and

often simulate a tuberous xanthoma clinically and histologically.7 A rare case of
malignant fibrous histiocytoma clinically presenting as a tuberous xanthoma in
a patient with type IIA hyperlipoproteinemia has been documented.8
Tuberous xanthomata consist of multiple nodules in the reticular dermis and
sometimes the subcutaneous fat (Fig. 13.14). Their appearance varies,
depending upon their stage of evolution (Fig. 13.15). Xanthoma cells pre-
dominate in early lesions, but with maturity fibrosis supervenes (Fig. 13.16).
On occasion, foreign body giant cell granulomata containing cholesterol
clefts are seen and a perivascular chronic inflammatory cell infiltrate is
B
sometimes evident (Fig. 13.17).
Fig. 13.15
Differential diagnosis Tuberous xanthoma: (A) the infiltrate is composed of uniform xanthoma cells
Heavily lipidized fibrous histiocytomas that tend to occur mainly around the characterized by pale, foamy cytoplasm and small central vesicular nuclei;
ankle may histologically mimic tuberous xanthoma.9 (B) occasional normal mitoses are commonly present.
Fig. 13.14 Fig. 13.16

Tuberous xanthoma: several nodules are present in the reticular dermis. Tuberous xanthoma: there is marked scarring.
A B
Fig. 13.17
(A, B) Tuberous xanthoma: in addition to xanthoma cells, occasionally there are foreign body giant cells containing cholesterol clefts. The lipid has been dissolved out during
processing.
Planar xanthomata
Clinical features
Planar xanthomata are typically soft yellow dermal macules or plaques that
occur most frequently around the eyes, where they are known as xanthelas-
mata (Fig. 13.18).1,2 About 50% of patients with xanthelasmata have associ-
ated hyperlipidemia (hypercholesterolemia or hyperlipoproteinemia type III)
which is often accompanied by a cholesterol corneal arcus.3–5 Many of those
who appear biochemically normal on routine testing, however, are shown to
have subtle abnormalities of lipid metabolism on more detailed analysis.6
There is a particularly increased risk of coronary artery atherosclerosis in
younger patients.1 When very extensive (diffuse or generalized plane xan-
thomatosis) and associated with orange–yellow planar xanthomata around
the head and neck, and occasionally the upper trunk and arms, there may be
an associated systemic disorder such as multiple myeloma with paraproteine-
mia, cryoglobulinemia, benign paraproteinemia or, less commonly, leukemia
and rheumatoid arthritis (necrobiotic xanthogranuloma) (Fig. 13.19).1,3,7–13 A
More exceptional associations include idiopathic Bence Jones proteinuria,
Fig. 13.19
Planar xanthoma: (A) widely distributed lesions over the forehead, eyelids, and
Fig. 13.18 cheeks; (B) extensive yellow plaques on the scalp. This appearance should prompt
Xanthelasmata: note the yellow, periorbital plaques. These are a common manifestation a search for an associated paraproteinemia. By courtesy of R.A. Marsden, MD,
of hypercholesterolemia. By courtesy of the Institute of Dermatology, London, UK. St George’s Hospital, London, UK.
Sézary's syndrome, Castleman's disease, relapsing polychondritis, acquired Histological features

palmoplantar keratoderma, adult T-cell leukemia/lymphoma, and Takayasu's
In planar xanthomata, the characteristic lipid-laden foam cells are situated
disease.14–20 A patient with monoclonal gammopathy and cutaneous lesions
within the superficial dermis (Figs 13.21–13.23). There is minimal fibrosis.
with features of both plane xanthoma and amyloidosis has been documented.21
In rare cases, the histology may overlap with that of necrobiotic
The latter case was also associated with myeloma.
xanthogranuloma.33
In cases of myeloma and plane xanthoma, it has been demonstrated that
complexes form between serum lipoproteins and paraprotein, suggesting
that this interaction may induce a hyperlipidemia and xanthoma forma- Verruciform xanthoma
tion.22,23 The serum lipid levels of patients with diffuse plane xanthomata
are normal or raised. Plane xanthomata may present in the gingiva and, in Clinical features
this location, are usually associated with hyperlipidemia.24 An exceptional The verruciform xanthoma is an uncommon, asymptomatic lesion, which
case has been described in an infant presenting with normolipemic papular occurs predominantly in the oral cavity of adults in their fifth or sixth decade
and nodular lesions progressing to plane xanthomata and resulting in spon- and shows a male predilection (1.7:1).1–5 It is most often found on the
taneous resolution.25 Diffuse plane normolipemic xanthomata with mucosal premolar gingiva of the mandible or maxilla.1 At this site it usually produces
and conjunctival involvement and aortic valve xanthomatosis may occur a solitary, well-circumscribed, asymptomatic, erythematous or yellow–tan
exceptionally.26 Lesions have been reported that clinically resembled plane lesion, 3–20 mm in diameter, which may be papillomatous or ulcerated. The
xanthomata in a patient with systemic lupus erythematosus but histologi- patients are normolipidemic. The clinical differential diagnosis includes viral
cally showed degeneration of collagen bundles with secondary fat warts, leukoplakia, and squamous cell carcinoma.
deposition.27 Verruciform xanthomata of the skin, which are extremely rare, have been
Intertriginous xanthomata seen in patients with raised low density lipo- described at a variety of sites including the ear, nose, and digits.6–9 Most cases
proteins and pathognomonic of homozygous familial hypercholesterolemia described, however, have arisen on anogenital skin (Fig. 13.24).10–16 It may
present as yellow papules and plaques, often with a cobblestone appearance. also develop as a reactive phenomenon within epidermolytic acanthoma,
These occur in the finger webspaces and to a lesser extent in the axillae and
antecubital and popliteal fossae.2,28 They have a particularly high association
with early and severe atherosclerosis. Intertriginous xanthomata may also
rarely be seen in heterozygous familial hypercholesterolemia.29
Planar xanthomata presenting as yellow–orange macules in the skin creases
of the palm and fingers (xanthoma striatum palmare) are diagnostic of famil-
ial dysbetalipoproteinemia (HLP type III, broad beta disease) (Fig. 13.20),
which is due to an abnormality of the apoprotein ApoE (homozygous ApoE2/
E2).1,2,30 This results in impaired uptake of lipoprotein remnant particles by
the liver and macrophages with resultant hyperlipoproteinemia and increased
atherogenesis.29 Interestingly, the tendency to familial dysbetalipoproteinemia
is present in 1% of the population, but a second lipid abnormality appears to
be necessary to induce symptoms.29
Plane xanthomata of cholestasis, for example due to primary biliary cirrho-
sis and biliary atresia, present as well-demarcated, beige–orange plaques that
are particularly found on the hands and feet, but may occur elsewhere.2 They
can also develop in patients with diabetes mellitus and have been described in
the setting of cholestasis resulting from chronic graft-versus-host disease.31
Planar xanthomata have also been described as a feature of HDL
deficiency.32
Fig. 13.21
Planar xanthoma: a dense infiltrate is present in the upper dermis.
Fig. 13.20
Planar xanthoma: palmar lesions presenting as discrete macules with accentuation
in the skin creases. By courtesy of R.A. Marsden, MD, St George’s Hospital, Fig. 13.22
London, UK. Planar xanthoma: there is an admixture on nonlipidized and lipidized histiocytes.
Although most studies have not demonstrated definitive evidence to support

this hypothesis, there are isolated reports demonstrating HPV DNA by poly-
merase chain reaction (PCR) in the lesions.32–35 Additionally, it has been sug-
gested that keratinocyte necrosis may lead to the release of intracellular lipids,
with resultant macrophage influx and xanthomatization.3,34,36 The inciting
event leading to keratinocyte necrosis has not been identified.
Immunohistochemical and electron microscopic studies tend to give support
to this latter hypothesis (see below).
Verruciform xanthoma is an exophytic lesion characterized by massive
but regular epidermal proliferation, parakeratosis, and hyperkeratosis (Fig.
13.25).32 Neutrophils, neutrophilic debris, and bacterial colonies may be
evident in the parakeratotic stratum corneum. The acanthosis is associated
with uniform, bulbous epidermal ridges, all of which penetrate to the same
depth, giving a characteristically level lower border. The expanded ridges
are associated with marked central keratinocyte necrosis and a heavy
neutrophil polymorph inflammatory cell infiltrate (Fig. 13.26). There is no
Fig. 13.23
Planar xanthoma: in addition to xanthoma cells, there are scattered lymphocytes.
Fig. 13.25
Verruciform xanthoma: there is marked acanthosis, hyperkeratosis, and a level
lower border.
Fig. 13.24
Verruciform xanthoma: in this unusual gross example, there are numerous warty
and polypoid lesions showing extensive involvement of the vulva, perineum, and
thighs. A viral etiology was initially suspected clinically.
seborrheic keratoses, and epidermal nevi (including patients with inflamma-

tory linear verrucous epidermal nevus or with the epidermal nevus syndrome)
and has been recorded as a complication of lymphedema.9,17–22 It has been
described in association with longstanding discoid lupus erythematosus, com-
plicating ulceration in epidermolysis bullosa, and in association with squamous
cell carcinoma of the penis.23–27 Occasionally, verruciform xanthomata are
multifocal.6 Such a case has been described as multiple lesions in the upper
aerodigestive tract of a child with a systemic lipid storage disease.28 Multiple
verruciform xanthomata have also been reported in the anogenital region sev-
eral years following necrotizing fasciitis of the perineum and in the oral mucosa
in a patient with chronic graft-versus-host disease.29,30 A rare case of dissemi-
nated lesions has been described on the hands, feet, and anogenital region.31
In the skin, verruciform xanthoma usually presents as a gray or pink nod-
ule or as a plaque with a variably warty surface. Untreated, the lesions have
a long duration and behave in a benign fashion, recurrence being very uncom-
mon after local excision. Fig. 13.26
Verruciform xanthoma:
there is extensive
Pathogenesis and histological features keratinocyte necrosis
The etiology and pathogenesis of the verruciform xanthoma are unknown. associated with a
Originally, a viral infection by human papillomavirus (HPV) was suspected. polymorph infiltrate.
epithelial atypia and viral inclusions are invariably absent. The accentuated • Viral warts: verruciform xanthoma lacks the vacuolation, clumped
papillary dermis between the elongated epidermal ridges contains large keratohyalin granules and tiers of parakeratosis seen in a viral wart.
numbers of eosinophilic foamy to granular xanthoma cells, which stain pos- Inclusions are not a feature.
itively with lipid stains, but not usually with the diastase–periodic acid- • In granular cell tumor the hyperplastic overlying squamous epithelium
Schiff (PAS) technique (Fig. 13.27). No foreign body or Touton giant cells often shows an infiltrative growth pattern, in contrast to the exophytic
are present. At the base of the lesion the epidermis may show focal basal cell nature of verruciform xanthoma. The granular cells are larger, often have
hydropic degeneration associated with patchy loss of basement membrane. a syncytial appearance, and typically stain positively with the PAS
The reticular dermis deep to the lesion often contains a moderately dense reaction.
lymphocyte–plasma cell infiltrate, which at the edge of the lesion sometimes • Verrucous carcinoma has both exophytic and endophytic components,
adopts a lichenoid distribution. Typically,vascular ectasia is seen beneath the latter appearing as deeply penetrating bulbous epithelial processes.
the lesion. The epithelium often has a ‘watery’ appearance and xanthoma cells are
By immunohistochemistry, fully formed foamy cells are negative for histio- not a feature.
cytic markers including factor XIIIa, Mac 387, Ham-56, and KP1.34,37 Cells
with incompletely lipidized cytoplasm show diffuse positivity for KP1 and
weak positivity for FXIIIa and keratin. Cells with little cytoplasmic lipid are Angiokeratoma corporis diffusum
diffusely positive for FXIIIa and weakly positive for keratin. Nonlipidized
cells located in the periphery of the infiltrate are diffusely positive for FXIIIa Clinical features
only. This staining pattern has led to the suggestion that FXIIIa-positive der- Angiokeratoma corporis diffusum (Anderson-Fabry's disease) is a sex-linked
mal dendritic cells play an active role in the formation of the lipid cells seen recessive disorder of glycosphingolipid metabolism with a high mortality. It is
in this condition.34 It also tends to give further support to the role of damaged very rare with an approximate incidence of 1 in 200 000.1 Deficiency of the
keratinocytes in the pathogenesis of verruciform xanthoma.34 The mechanism lysosomal enzyme α-galactosidase A leads to the widespread accumulation of
of keratinocyte damage is not fully elucidated. One theory proposes that the neutral glycolipids, mainly globotriaosylceramide (GB3, ceramidetrihexo-
macrophages play an active role in keratinocyte cleavage and keratinolysis side), and elevated urinary trihexoxylceramide levels.1–6
with secondary release of epithelial lipid. Macrophage recruitment is postu- Globotriaosylceramide is normally broken down by α-galactosidase A to
lated to occur as a consequence of CD8-positive T cells present in the produce galactose and lactosylceramide. The full-blown syndrome is nor-
submucosa.38,39 mally seen only in men, since female carriers have 15–40% greater enzyme
Ultrastructural studies have revealed histiocytes containing numerous activity than their male siblings or offspring. Heterozygotes, however, usually
nonmembrane-bound lipid droplets, lysosomes, and myelin figures.11,40 display abnormal ophthalmological and ultrastructural features.7 Occasionally,
Smaller numbers of these lipid inclusions may be found in the overlying kera- heterozygous females may manifest signs and symptoms due to extreme X
tinocytes and in the intercellular space. In one report, basal melanocytes were inactivation (lyonization) of the healthy X chromosome.7,8 Cutaneous lesions
found to contain conspicuous lipid droplets.41 This was accompanied by evi- are believed to occur in about 20% of heterozygous females.9
dence that the latter had been released into the basal intercellular space in In males, the disease normally presents in childhood as episodes of excru-
association with disruption of the basal lamina, thereby providing a source ciating intermittent pain, frequently in the fingers and toes.10 The attacks may
for the lipid within the dermal macrophages. be accompanied by fever, edema, and malaise. Patients may also have hypo-
hidrosis, acroparesthesiae, and peripheral vasomotor disturbance affecting
the heart, kidney, and central nervous system. Heat intolerance and telangi-
Differential diagnosis ectases of the ears are often present early in the course of the disease.11
Verruciform xanthoma must be distinguished from viral warts, granular cell The characteristic angiokeratomata develop after puberty and present as
tumor, and verrucous carcinoma: tiny red–black bilaterally symmetrical papules, 0.5–2 mm in diameter, with
slight hyperkeratosis.10 Lesions are typically seen in the bathing trunk
distribution including the thighs, buttocks, lower back, penis, and scrotum,
although occasional lesions may also be seen on the trunk or buccal mucosa
(Figs. 13.28, 13.29). The number of angiokeratomata is highly variable.
Atypical cases can present with an oligosymptomatic phenotype which
includes only very few cutaneous angiokeratomata and asymptomatic involve-
ment of organs such as the kidney and the heart.12 A female heterozygote with
multiple nonkeratotic cutaneous angiomas has also been described.13
Nonvascular proliferations have been reported in patients with Fabry's
disease, including polyarteritis nodosa and leg ulcers.14,15 Telangiectasias
develop in up to one-fourth of affected males.16,17 A recent study correlated
the presence of angiokeratomas and telangiectasias with disease severity.16
In a patient in whom the diagnosis is suspected, confirmation can usually
be obtained by an ophthalmic examination. The conjunctival vessels may be
tortuous or aneurysmal, as may the retinal vessels, and slit-lamp examination
of the eyes reveals characteristic whorled, corneal linear opacities (verticillate
cornea) (Fig. 13.30). Enzyme assay of α-galactosidase A can be performed
using peripheral leukocytes or cutaneous fibroblasts. Hair root analysis has
been recommended for the detection of heterozygotes.18
Affected males can develop transient cerebrovascular accidents, but one of
the most common causes of death is renal failure.19,20 In the early stages, pro-
teinuria is seen and microscopy of the urinary sediment sometimes reveals
characteristic lipid-laden cells even before proteinuria develops (Fig. 13.31).
Fig. 13.27 Electron microscopy may reveal the typical inclusions (Fig. 13.32).
Verruciform xanthoma: in Cardiac involvement is found in approximately 20% of patients.21
the papillary dermis there Glycosphingolipid deposits in the conducting system, myocardium, endocar-
is an infiltrate of uniform dium, and valves may give rise to angina, electrocardiographic abnormalities,
xanthoma cells. hypertrophic cardiomyopathy, hypertension, mitral valve incompetence, and
Angiokeratoma corporis diffusum 531
Fig. 13.28
Angiokeratoma corporis
diffusum: tiny grouped red
papules are present on the
buttocks, a characteristic
site. By courtesy of the
London, UK.
Fig. 13.30
Angiokeratoma corporis diffusum: (A) tortuous conjunctival vessels; (B) tortuous
retinal vessels. By courtesy of S. Parker, MD, St Thomas’ Hospital, London, UK.
Fig. 13.29
diffusum: conspicuous
angiokeratomata on
the penis, a commonly
affected site. By courtesy
London, UK.
aortic medial degeneration.22–25 Cardiovascular disease was found to be the most

common cause of death in patients in a recent study of the Fabry registry.26
Oral and dental abnormalities are more common than previously realized
and include the presence of cysts/pseudocysts of the maxillary sinuses and
maxillary prognathism.27

A variety of genetic defects has been identified including point mutations, Fig. 13.31
gene rearrangements, and deletions.28–31 A symptomatic heterozygous female Angiokeratoma corporis diffusum: urinary sediment stained with toluidine blue.
Fabry's disease patient without detectable mutation in the α-galactosidase The metachromasia (purple coloration) is due to the presence of intracytoplasmic
gene has recently been described.32 sulfatides.
Fig. 13.32
Angiokeratoma corporis diffusum: electron micrograph of urine sediment, showing
typical concentrically lamellated inclusions.
Fig. 13.34
diffusum: close-up view.
Fig. 13.33
Angiokeratoma corporis diffusum: ectatic blood-filled vascular channels expand the
papillary dermis. Note the hyperkeratosis.
The skin lesions are composed of ectatic blood-filled vessels in the papillary
dermis, associated with slight hyperkeratosis (Figs. 13.33, 13.34). A characteris- Fig. 13.35
tic feature is vacuolation of endothelial cells due to lipid deposits. The latter are Angiokeratoma corporis diffusum: the endothelial cells of this small blood vessel
doubly refractile and can usually be demonstrated in frozen material tissue sections. contain typical inclusions (L, lumen; E, endothelial cell).
They may also be identified in toluidine blue-stained material. On electron micros-
copy, lamellar electron-dense inclusion bodies are present within endothelial cells,
pericytes, smooth muscle cells, fibroblasts, sweat gland epithelium, and
macrophages. It is believed that these are due to lipid deposition within lysosomes
The amyloidoses
(Fig. 13.35). Lamellar bodies have also been identified in the endothelial cells of Amyloidosis is characterized by the extracellular deposition of a protein
affected vessels with polyarteritis nodosa in a patient with Fabry's disease.14 associated with particular tinctorial and ultrastructural properties. The amy-
loidoses are classified according to whether the amyloid deposition is systemic
Differential diagnosis or localized (Table 13.3).
Other forms of angiokeratomata, for example those of Mibelli or Fordyce, The most characteristic staining patterns of amyloid are seen with Congo
should be clinically distinguishable by their site and distribution although their red or Dylon (cotton dye pagoda red No. 9), which show apple-green
histopathological appearances are identical. It should be noted, however, that birefringence under polarized light (Fig. 13.36).1 Unfortunately, this is not
diffuse angiokeratomata may also be seen in fucosidosis, α-galactosidosis, specific, and green birefringence may also be seen with collagen and in colloid
sialidosis, aspartylglycosaminuria, α-N- acetylgalactosaminidase deficiency milium, porphyria, and lipoid proteinosis. Amyloid deposits, which are PAS
(Kanzaki disease), human beta-mannosidosis, adult-onset GM1 gangliosido- positive, may also be identified by the cotton dye Sirius red, or metachromatically
sis, and indeed, diffuse angiokeratomata of a benign type may occur in patients using methyl or cresyl violet.2 Further confirmatory evidence can be obtained
with normal enzyme activities.33–38 Widespread angiokeratomata have also by staining with thioflavine-T and examination using fluorescence microscopy
been described as an exceptional finding in tuberous sclerosis.39 or by immunocytochemistry (see below) (Fig. 13.37).
The amyloidoses 533
Table 13.3
Classification of the amyloidoses
Systemic amyloidosis Localized amyloidosis

Primary (due to an occult plasma Organs other than the skin*
cell dyscrasia)
Myeloma associated Primary cutaneous
Secondary Lichen, macular and biphasic
Hemodialysis associated Secondary cutaneous
Heredofamilial † Associated with neoplasms,
porokeratosis and PUVA therapy
Amyloid elastosis Familial cutaneous Nodular
*Not discussed further in this chapter.

†Including familial Mediterranean fever, Muckle–Wells syndrome, familial amyloidotic
polyneuropathy.
Fig. 13.37
Cutaneous amyloidosis: positive immunofluorescence just beneath the epidermis
in a case of macular amyloid (thioflavine-T).
Fig. 13.38
Cutaneous amyloidosis:
(A) electron micrograph
of macular amyloidosis
showing nodular deposits
in the superficial dermis;
(B) the characteristic
randomly orientated,
straight, nonbranching
A appearance of amyloid
filaments.
Fig. 13.36
Cutaneous amyloidosis: (A) positive staining with Congo red; (B) there is intense
apple-green birefringence when viewed with polarized light.
Amyloid shows characteristic and specific electron microscopic features of

rigid, straight, nonbranching amyloid filaments with a diameter of 6–10 nm
showing a hollow core on cross-section (Fig. 13.38).3 They are haphazardly
distributed, lack the cross-banding of collagen, and are embedded in an
electron-dense amorphous ground substance, which is probably composed of
B
polysaccharides.
X-ray diffraction and infrared spectroscopy reveal a beta-pleated

a ntiparallel configuration.4,5 Fibrils with a beta-pleated configuration are
insoluble and highly resistant to proteolysis. This, combined with a lack of
immunogenicity, results in their persistence at the site of deposition and
subsequent tissue-damaging effects.
All forms of amyloid contain up to 14% by dry weight of a nonfibrillary
protein, the serum amyloid P (SAP) component.2,6 The function of SAP is
unknown, but it has been suggested that it may be primarily involved in the
deposition and maintenance of the fibrillary components.2 Its presence, iden-
tified immunohistochemically, is a useful adjunct to the diagnosis of amyloi-
dosis.7 However, it should be appreciated that the antibody also labels
degenerate elastic fibers. The fibrillary component, however, may be derived
in very different ways in each of the recognized types of amyloidosis: 8
• In primary and myeloma-associated amyloidoses it consists of
immunoglobulin light chains (most often of lambda type, or a part
thereof).
• In the secondary form the fibrillary component is composed of amyloid
A protein, which is derived from a normal serum constituent known as
serum amyloid A protein. This serum protein, which is an HDL3-associated
apolipoprotein, is an acute phase reactant.2,8 Fig. 13.39
• Primary cutaneous amyloidosis is derived from filamentous degeneration Primary systemic
of keratin filaments (amyloid-K) (see below).9,10 amyloidosis: a waxy
nodule is present behind
The capacity to form amyloid in the primary and myeloma-associated
the ear. Note the purpura.
variants appears to be dependent upon the inherent ability of a segment of the
By courtesy of R.A.
variable region of the light chain to adopt a beta-pleated configuration.3 This Marsden, MD, St George’s
capability is only evident in a proportion of (so-called amyloidogenic) Bence Hospital, London, UK.
Jones proteins, which explains why not all patients with multiple myeloma
develop amyloidosis. Primary and myeloma-associated amyloidoses can be
distinguished histochemically from secondary amyloidosis using the potas-
sium permanganate reaction.11 The former are potassium permanganate resis-
tant whereas the latter is sensitive and loses its affinity for Congo red following
exposure. ‘Endocrine’ amyloid is also resistant to the effects of potassium per-
manganate solution, as is senile cardiac amyloid. Therefore, although the
amyloidoses all include, by definition, amyloid deposition, they in fact
represent a very diverse group of conditions.
Primary and myeloma-associated systemic

amyloidoses
Cutaneous disease occurs in up to 40% of patients with primary (due to occult
plasma cell dyscrasia) and myeloma-associated systemic amyloidosis.1–5
Clinical features
Primary and myeloma-associated systemic amyloidoses predominantly affect
the elderly (mean onset at 65 years of age) and show a slight predilection for
males.2 Up to 15% of patients with myeloma have coexisting primary amy-
loidosis. Occasional patients present with primary systemic amyloidosis and
only develop multiple myeloma later.6
Fig. 13.40
The early clinical changes, which are often mild, non-specific, and very dif- Primary systemic
ficult to diagnose, include weight loss, hoarseness, dyspnea, fatigue, paresthesia, amyloidosis: hemorrhagic
and lightheadedness.7 Subsequently, the most frequent features are development bullous lesion on wrist.
of the carpal tunnel syndrome and edema due to renal and cardiac involvement. By courtesy of the
Bilateral carpal tunnel syndrome may be the first symptom of the disease.8 Institute of Dermatology,
The commonest cutaneous manifestation is hemorrhage (purpura, London, UK.
petechiae, and frank ecchymoses) due to deposition of amyloid within blood
vessel walls, with resultant fragility (Figs 13.39–13.42). It occurs most typi- dorsal surfaces of the hands and fingers and the extensor aspect of the fore-
cally on the hands (often posttraumatic) and around the eyes, when the pur- arms and epidermolysis bullosa acquisita then enters the differential diagno-
pura may follow proctoscopy or vomiting (Fig. 13.43). Lesions are sometimes sis (Fig. 13.44). Healed lesions are sometimes associated with the development
also evident in the nasolabial folds, the neck, axillae, umbilicus, anogenital of milia.19 Bullous amyloidosis most often develops in patients with systemic
region, and within the oral cavity.4,9–11 Prominent hemorrhagic bullae may be disease, particularly myeloma associated.16 Rarely, however, it may compli-
present.11 Rarely, systemic amyloidosis presents with solitary vulval lesions cate primary cutaneous amyloidosis.14 Rare cases present an elastolytic
which may mimic a condyloma acuminatum.12,13 appearance and development of cordlike indurations associated with inter-
Blistering is sometimes an additional feature, which occurs due to cleavage mittent claudication. Prominent perivascular deposition of amyloid has been
developing within the amyloid deposits as a consequence of shearing documented in these patients.24,25
stresses.14–23 The blisters are often hemorrhagic, and occur most often on the In more advanced cases, waxy, smooth, shiny papules, plaques, and even
tongue, buccal or labial mucosa although they may be more widespread and nodules develop. Cystic nodular lesions have also been reported.26 The pap-
thus mimic those of bullous pemphigoid.14 Blisters can sometimes arise on the ules are skin-colored or yellow and have a dome-shaped appearance.9,27 They
The amyloidoses 535
Fig. 13.41 Fig. 13.44

Primary systemic amyloidosis: papular mucosal lesions with hemorrhage on the Primary systemic amyloidosis: blood-filled blisters on the dorsal aspect of the
inner aspect of the lower lip. By courtesy of R.A. Marsden, MD, St George’s fingers. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
Fig. 13.42 Fig. 13.45

Primary systemic amyloidosis: erythematous and purpuric lesions on the face of an Primary systemic amyloidosis: nail dystrophy as seen in this example is a very
elderly male. By courtesy of the Institute of Dermatology, London, UK. rare manifestation. By courtesy of R.A. Marsden, MD, St George’s Hospital,
London, UK.
are found predominantly on the face (especially the eyelids), head and neck,
axillae, umbilicus, inguinal region, and the perineum.4,9 In severely affected
patients the clinical appearances with taut skin, particularly affecting the
face, hands, and digits, may mimic scleroderma.9,27 Alopecia and nail dystro-
phy are sometimes evident (Fig. 13.45). Chronic paronychia, palmodigital
erythematous swelling, and induration of the hands have been described.28
The presence of these features in conjunction with macroglossia and the car-
pal tunnel syndrome is highly suggestive of primary or myeloma-associated
systemic amyloidosis (Fig. 13.46). In addition to macroglossia, the tongue
may be covered with waxy papules, nodules, and plaques and occasionally it
is ulcerated or fissured.4 As a consequence, speaking and swallowing diffi-
culties are not infrequently encountered. The sicca syndrome may also be a
manifestation of primary systemic amyloidosis.29 Exceptionally, association
with normolipemic xanthoma has also been documented.30
Hepatomegaly is found in about 50% of cases and there may also be evi-
dence of cardiomyopathy with arrhythmia or heart failure, peripheral neuropa-
Fig. 13.43 thy, and renal failure or the nephrotic syndrome. Splenomegaly is a feature in
Primary systemic amyloidosis: small macular purpuric lesions at a classical site. less than 10% of cases.5 Intestinal involvement can lead to malabsorption or an
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. ulcerative colitis-like picture, sometimes with hemorrhage.4 Pseudo-obstruction,
Fig. 13.46
Primary systemic Fig. 13.48
amyloidosis: macroglossia. Primary systemic
By courtesy of R.A. amyloidosis: high-power
Marsden, MD, St George’s view of Figure 13.47. Note
Hospital, London, UK. the red cell extravasation.
diarrhea, and constipation can also occur.7 There is no effective treatment for In those cases associated with blistering, the vesicle appears in an
systemic primary amyloidosis and the prognosis is therefore grave. Mortality intradermal or less commonly subepidermal location. The dermis, in addition
relates primarily to cardiac and renal involvement.2,3 to showing amyloid deposits, often in association with blood vessel walls,
also shows a fragmented appearance due to the presence of cleftlike spaces.13
Histological features Purpura is frequently marked.
Masses of eosinophilic, amorphous, fissured material are present in the Clinically normal skin shows histological evidence of amyloid deposition
ermis and subcutaneous tissues.9,31 The overlying epidermis is often
d in up to 50% of patients.27
stretched and flattened, but – in contrast to the macular and lichenoid vari-
ants – shows no evidence of amyloid deposition. In mild cases the changes Secondary amyloidosis
may be limited to the perivascular tissues, but in more extensive disease large
Secondary amyloidosis develops as a consequence of chronic inflammatory
aggregates are usually evident. Involvement of blood vessel walls, arrector
conditions or infections. Cutaneous involvement has not been recognized as
pili muscles, skin adnexa, and subcutaneous fat (amyloid rings) is frequently
a clinical feature of secondary systemic amyloidosis. Yet in one publication it
present (Figs. 13.47, 13.48).4,9,27 Amyloid deposits around the piloseba-
was described in eight out of nine patients with amyloidosis complicating
ceous units may be accompanied by follicular atrophy with resultant hair
rheumatoid arthritis.1 It is of interest to note that a considerable number of
loss.9 There is usually little secondary inflammatory cell infiltration.
chronic dermatoses may be associated with the development of secondary
amyloidosis including psoriasis, lepromatous leprosy, hidradenitis suppura-
tiva, chronically infected burns, and dystrophic epidermolysis bullosa.2–4 In
patients with no cutaneous lesions and symptoms suggestive of systemic amy-
loidosis, the diagnosis can be confirmed by Congo red staining of abdominal
fat aspirates.5
Although frank clinical lesions are not commonly a feature of secondary
amyloidosis, sometimes small deposits are found in specimens of normal
skin.1,6 Usually these are present in a perivascular location, but may
occasionally be present elsewhere in the dermis or even in subcutaneous
fat.7 Deposition of amyloid around sweat glands may also be seen. Deposits
are said to be focal and abdominal subcutaneous fat has been recommended
as the site that is most likely to be positive.1,5,8 Hemodialysis-associated
amyloidosis is a distinctive form of secondary amyloidosis and is described
below.
Hemodialysis-associated amyloidosis
Clinical features
This variant of amyloidosis, induced by beta-2-microglobulin, occurs in
Fig. 13.47 patients on long-term hemodialysis.1–5 Exceptionally, cases may present after
Primary systemic amyloidosis: the superficial blood vessels are thickened due to short-term hemodialysis.6 The most commonly involved organs are the heart,
amyloid deposition. gastrointestinal tract, and lungs.1 Interestingly, the disease does not seem to
The amyloidoses 537
involve the spleen.1 Carpal tunnel syndrome, polyarthralgia, and destructive sensory then motor peripheral neuropathy predominantly affecting the limbs
spondyloarthropathy have also been documented.4,7 The walls of blood and autonomic dysfunction manifesting as alternating diarrhea and constipa-
vessels are often involved whereas bone lesions are relatively rare, although tion, urinary incontinence, orthostatic hypotension, and sexual dysfunction.3
pathological fractures may occur.7,8 Cutaneous involvement, which is very The cutaneous manifestations comprise nonhealing ulcers, multiple atrophic
uncommon, has been reported to present as subcutaneous masses in the but- scars, and anhidrosis of the lower limbs.4,5 In some patients petechiae can be
tocks and shoulder, lichenoid papules and a wrinkled appearance of the skin induced by gentle stroking of the skin.
of the palmar aspect of the fingers. 6–11
Histological features Histologically, biopsies from clinically normal skin reveal the presence of
In cases with skin involvement, the amyloid deposits have been found either amyloid in blood vessel walls, sweat glands, and arrector pili muscle.4
in the subcutaneous tissue or in the papillary and reticular dermis, around
sweat glands and hair follicles.6–11 Occasionally, special stains are unhelpful in
demonstrating amyloid and confirmation of the diagnosis by electron micros-
Amyloid elastosis
copy is necessary.
Clinical features
Heredofamilial amyloidoses Amyloid elastosis is a very rare disease, characterized by systemic and cutane-
ous deposits of amyloid. Only three cases have been reported to date. Two
Familial Mediterranean fever patients presented with papular and nodular lesions, a sclerodermatous facial
appearance, a pseudoxanthoma-like appearance of the neck, cordlike thick-
Clinical features ening of superficial blood vessels, livedo reticularis-like changes on trunk,
This is a rare variant of autosomal recessive inherited systemic amyloidosis. It Raynaud's phenomenon, venous and arterial thrombosis, and the nephrotic
is characterized by episodes of fever associated with pleuritis, peritonitis, and syndrome.1,2 One of the patients had a lambda light chain paraprotein.2 The
synovitis.1–4 Cutaneous lesions are rare and consist of Henoch-Schönlein pur- third patient developed xanthomatous, yellow macules and patches in the
pura and erythema of the lower limbs mimicking erysipelas.1,5 Panniculitis and intertriginous areas of the axilla, neck, submammary, and abdomen. She was
recurrent urticaria may also occur.6,7 Nail fold capillary abnormalities consist- subsequently diagnosed with systemic AL amyloidosis.3
ing of increased tortuosity and enlargement of capillary loops have also been
documented.8 Cutaneous amyloid deposition has not been described. Histological features
Amyloid is seen in the dermis, around adnexal structures, surrounding elastic
Pathogenesis and histological features fibers, sometimes forming small globules, and in blood vessel walls, together
A serum precursor protein forms the amyloid in this condition. This precur- with striking deposits in the dermal, subcutaneous, and serosal elastic
sor is a high density lipoprotein known as serum amyloid A. tissue.1–3
The erysipelas-like lesions are characterized by a perivascular mixed infil-
trate of lymphocytes, histiocytes, and neutrophils with leukocytoclasia.5
Vasculitis is not seen, although on direct immunofluorescence perivascular Primary localized cutaneous amyloidosis,
C3 and, less consistently IgM and fibrinogen, have been reported.5 lichen and macular types
Muckle-Wells syndrome and familial cold
Clinical features
autoinflammatory syndrome
Lichen and macular amyloidoses (skin-limited amyloidoses) represent differ-
Muckle-Wells syndrome is an autosomal inherited disease with variable pen-
ent manifestations of the same process and both entities may coexist (biphasic
etrance. It is characterized by urticaria, deafness, conjunctivitis, and systemic
amyloidosis) or one may transform into the other.1–4 A recent large study of
amyloidosis.1,2 The disease has been mapped to chromosome 1q44. The gene
primary localized cutaneous amyloidosis found that 67% of cases represented
is called CIAS1 and encodes a pyrin-like protein that appears to play a role in
lichen amyloidosis, 8% macular amyloidosis, and 25% biphasic variants.5
regulation of inflammation and apoptosis.3,4 Familial cold autoinflammatory
Although most cases are sporadic, up to 10% of patients demonstrate an
syndrome (familial cold urticaria) is very similar to Muckle-Wells syndrome
autosomal dominant inheritance pattern (see familial primary cutaneous
but, in the former, there is no deafness and the episodes of urticaria are pre-
amyloidosis).6,7
cipitated by cold. The same serum precursor protein (serum amyloid A) pro-
duces the amyloid in both conditions. Cutaneous amyloidosis is not typically Macular primary cutaneous amyloidosis
seen in Muckle-Wells syndrome. Recently, six patients with this syndrome This is most commonly seen in patients from the Middle East, Asia, and
were described as having sclerotic, hyperpigmented plaques with hypertricho- Central and South America.1,8 It affects females more often than males (3:1),
sis on the extremities and abdomen.5 is seen in younger age groups, and is usually a chronic condition.9,10 Patients
Cold-induced urticarial lesions are characterized by an upper to mid-der- present with a macular, dark brown or grayish, symmetrical pigmentation,
mal infiltrate of neutrophils with a few eosinophils and dermal edema.6 which occurs most frequently on the upper chest and back, although the
Neutrophils are seen intravascularly and in vessel walls. Although vasculitis extremities and face may also be affected (Fig. 13.49).1,9 The lesions some-
has not been described, some vessels may contain fibrinoid deposits. times have a very characteristic reticulated or rippled appearance, which can
Histological features of the sclerotic lesions include dermal thickening with be quite subtle, and they are usually moderately pruritic (Fig. 13.50). More
sclerosis of collagen bundles, fragmentation and thickening of elastic fibers, commonly, however, macular amyloid appears as small, 2–3 mm diameter
focal calcification of degenerated elastic fibers, superficial and deep perivas- lesions or else as confluent macular foci, which sometimes have superimposed
cular and interstitial infiltrate of lymphocytes and histiocytes, numerous micropapules.8 Lesions sometimes follow Blaschko's lines, resembling incon-
plasma cells and admixed eosinophils and mast cells. tinentia pigmenti.11,12 Exceptionally, widespread diffuse pigmentation occurs.13
Predominantly hypopigmented macules have been described, mimicking gut-
Familial amyloidotic polyneuropathy tate morphea and vitiligo.14
Clinical features Papular or lichen amyloidosis
Familial amyloidotic polyneuropathy is an autosomal dominant disease in In papular or lichen amyloidosis, discrete papules and/or plaques occur, which
which the deposition of amyloid occurs predominantly in peripheral nerves. are often scaly, persistent, and pigmented. They are usually severely pruritic
The amyloid deposits in this disease consist in most cases of variant transthy- (Fig. 13.51). Excoriations, lichenification, and nodular prurigo-like lesions
retin with single amino acid substitutions.1–3 Clinical manifestations include due to chronic scratching are sometimes evident.10 Lesions are especially
c ommon on the front of the shins and extensor aspect of the forearms
(Figs 13.52, 13.53).15,16 The calves, ankles, dorsa of the feet, thighs and
trunk may also be affected.17–19 Presentation is most often in young adults.
The sex incidence is equal.1,20 Lichen amyloidosis shows a predilection for the
Chinese race and familial cases have been recorded.18,19 An association with
Epstein-Barr virus infection has been reported in a single case but this was not
confirmed in a larger study.21
Association with systemic disease is probably coincidental but there have
been a number of cases described with progressive systemic sclerosis.22,23
Other primary cutaneous amyloidoses
These include anosacral and poikilodermatous variants:
• Anosacral amyloidosis presents as scaly hyperpigmented macules and
lichenoid papules spreading out from the perianal skin.24,25 It is seen in
patients from Japan and China and is very rare. The disease may present
early in life and its cause has not been established, although a
relationship to keratinocyte apoptosis has been suggested.25 Clinically,
lesions can be confused with lichen simplex chronicus, a dermatophyte
infection or even postinflammatory hyperpigmentation.
Fig. 13.49
Macular amyloid: hyperpigmented lesion in a characteristic site. By courtesy of R.A.
Fig. 13.50
Macular amyloid: close-up view of a lesion showing the typically rippled
appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Fig. 13.52
Lichen amyloidosis: scaly
lichenoid papules on the
shin. By courtesy of R.A.
Fig. 13.53
Fig. 13.51 Lichen amyloidosis: grouped, erythematoviolaceous papules, with a lichenoid
Lichen amyloidosis: pigmented papules on the chest. By courtesy of R.A. Marsden, surface and showing excoriations in some areas. By courtesy of R.A. Marsden, MD,
MD, St George’s Hospital, London, UK. St George’s Hospital, London, UK.
The amyloidoses 539
• Poikiloderma-like cutaneous amyloidosis is an extremely rare

manifestation of localized cutaneous amyloidosis.26,27 Patients present
with poikilodermatous skin lesions and lichenoid papules. It may be
associated with photosensitivity, short stature, and palmoplantar
keratoderma.27 Blisters are rarely seen. The condition presents early in
life or in young adults. Confusion with other conditions associated with
poikiloderma including poikiloderma atrophicans vasculare is possible.

Chronic irritation to the skin has been proposed as the cause of amyloid
deposition in the macular and lichenoid variants although this has never
been proven.28,29 The documentation, however, of friction amyloidosis due to
nylon brush skin massage and towels does offer some support to this hypoth-
esis.30–33 It may be that chronic trauma in a susceptible or ‘primed’ individual
may be associated with an increased risk of developing cutaneous amyloido-
sis. It has been suggested that amyloid deposition in lichen amyloidosis is a
consequence of scratching, as pruritus tends to be the presenting symptom
even before amyloid is detected in skin biopsies.34 The chronic damage to the
Fig. 13.55
epidermis induces apoptosis of keratinocytes and this leads to amyloid depo- Macular amyloidosis: close-up view of faceted deposits.
sition in the papillary dermis. A similar mechanism has been proposed in
notalgia paresthetica. This is a condition characterized by pruritus, a burn-
ing sensation, and paresthesia or hyperesthesia in an area of the back between
dermatomes D2 and D6.35,36 The resultant irritation and scratching induce
cutaneous hyperpigmentation and amyloid deposition. It has even been sug-
gested that the cutaneous amyloidosis observed in patients with multiple
endocrine neoplasia type 2A is secondary to notalgia paresthetica (see
below).37
In both variants the amyloid is deposited high in the papillary dermis,
often immediately adjacent to the epidermis.8,9,17,38,39
In the macular type, the amount of amyloid present is often very small
and focally distributed. It frequently has a faceted appearance (Figs
13.54–13.56).2,9 Special stains and/or immunocytochemistry are some-
times necessary as the deposits can easily be missed. Intraepidermal cytoid
bodies are present in about 33% of cases.8 Typically, there is associated
pigmentary incontinence, but only minor epidermal changes of hyperkera-
tosis and acanthosis are generally evident. Melanin pigment may be pres-
ent in the stratum corneum. A slight perivascular chronic inflammatory
cell infiltrate is often found in the superficial dermis.9 Mild vacuolar inter-
face alteration can be present.14
Fig. 13.56
Macular amyloidosis:
pigmentary incontinence
is typically present.
In papular or lichen amyloidosis, the histopathological changes are similar

and cannot be reliably distinguished from those of the macular variant, except
that the quantities deposited are greater and there is often more marked epi-
dermal acanthosis, hypergranulosis, and hyperkeratosis. Basal cell hydropic
degeneration may be evident and colloid bodies are usually visible (Figs
13.57, 13.58).1 Satellite cell necrosis is sometimes a feature.1 A superficial
perivascular chronic inflammatory cell infiltrate is typically present.
When special stains fail to demonstrate the presence of amyloid, ultrastruc-
tural studies are usually successful in detecting the presence of the protein.40
In contrast to skin involvement in systemic disease, blood vessel deposits
are not a feature of primary cutaneous localized lesions.
In earlier literature it was postulated that the amyloid might have been
derived from mast cells or fibroblasts. The application of newer technology,
Fig. 13.54 however, has shown that it is indisputably of keratinocyte derivation, and
Macular amyloidosis: typical eosinophilic faceted deposits are present in the amyloid deposits have been shown to contain disulfide bonds and bullous
papillary dermis. pemphigoid antigen.8 Numerous recent publications confirm the presence of
Fig. 13.59
Lichen amyloidosis:
(A) early filamentous
degeneration is seen in
this basal keratinocyte
Fig. 13.57 (K), lamina densa is
Lichen amyloidosis: there is hyperkeratosis, acanthosis, and basal cell hydropic arrowed; (B) compare the
degeneration; small eosinophilic globules are present in the papillary dermis. A mild organized appearance of
chronic inflammatory cell infiltrate is present. Note the pigmentary incontinence. the tonofilaments with
the haphazardly orientated
amyloid immediately
A adjacent to the lamina
densa.
Fig. 13.58 B
Lichen amyloidosis: in this view, there is interface change and a lymphocytic infiltrate.
epidermal keratin in the deposits in both macular and lichenoid forms using It is thought that on entering the dermis, fibroblasts and macrophages convert
monoclonal immunocytochemistry.3,41–49 The amyloid of the skin-limited the degenerate keratin into amyloid filaments (Fig. 13.59).52 The precise
variants, so-called amyloid-K, has been shown to contain 50 and 67 kD kera- mechanism is unknown, but it must involve the conversion of the normal
tin filaments.28,48 Apolipoprotein E, one of the proteins found in the amyloid alpha tertiary structure of tonofilaments into the beta-pleated configuration
plaque of Alzheimer's disease and in systemic amyloidosis, has also been of amyloid. The filaments of amyloid and cytoid bodies show ultrastructural
demonstrated in the amyloid present in localized cutaneous amyloidosis.50,51 differences. Amyloid fibrils are irregularly distributed whereas the filaments
Electron microscopic studies have provided further evidence that amyloid-K in cytoid bodies are arranged in bundles or whorls.53
is of keratinocyte origin by showing tonofilament filamentous (apoptotic) It is postulated that the development of localized cutaneous amyloidosis is
degeneration into amyloid filaments both within the epidermis and in the dependent upon mild chronic trauma resulting in excessive production of
immediately adjacent dermis.52 Under normal circumstances apoptotic kera- cytoid bodies and their subsequent conversion into amyloid deposits. It would
tinocytes (cytoid bodies) are either shed as a consequence of epidermal seem that despite a normal humoral response as shown by the presence of
upward migration or are released into the dermis where they are removed by IgM and IgG in association with complement fixation, the normal cellular
an inflammatory response as is seen, for example, in lichen planus. In macu- response whereby apoptotic keratinocytes are removed is lacking.28,54–56
lar and lichenoid cutaneous amyloidosis it appears that the above disposal Amyloid deposits are frequently found in intimate association with dermal
mechanism is either overwhelmed or nonfunctioning. elastic fibers and the deposits in macular amyloidosis have been shown to
Early ultrastructural changes consist of loss of tonofilament electron den- contain fibrillin.57 Whether this is of pathogenetic significance or is merely a
sity and development of a wavy morphology accompanied by internalization secondary phenomenon is uncertain.
of desmosomes, thickening of the keratinocyte cell membrane, and the acqui- The apoptotic theory of amyloidogenesis in the cutaneous variants has, how-
sition of hemidesmosome-like attachments to neighboring cells.28 Cytoplasmic ever, been challenged. On the basis of finding amyloid deposits immediately
and nuclear remnants are frequently present in the more superficial deposits. below the basal keratinocyte, separating its cell membrane from the lamina
The amyloidoses 541
densa in the absence of any evidence of filamentous degeneration, it has been Amyloidosis cutis dyschromica (vitiliginous) is another familial variant
suggested that cutaneous amyloid deposits may also be a direct secretory product of primary cutaneous amyloidosis characterized by reticulate hyper- and
of keratinocytes.58,59 It could be that both mechanisms are in operation. hypopigmentation of the trunk and limbs, with onset typically in
childhood.14–19 Papules, atrophy, and telangiectasia are usually not present.
One patient with concomitant morphea has been described.18 It has been
Secondary localized cutaneous amyloidosis suggested that the disease is caused by hypersensitivity to ultraviolet B
Microscopic foci of amyloid have been described in a number of cutaneous light with possible DNA repair defects.16 Histologically, the amyloid is
neoplasms including basal cell carcinoma, sweat gland tumors, syringocysta- present in the papillary dermis. Amyloidosis cutis dyschromica may repre-
denoma papilliferum, pilomatrixoma, trichoepithelioma, trichoblastoma, intra- sent the same disease described as X-linked reticulate pigmentary disorder
dermal nevus, dermatofibroma, seborrheic keratosis, solar keratosis, and in which cutaneous amyloidosis occurs as a secondary phenomenon in
Bowen's disease (Fig. 13.60).1–7 The amyloid in most cases appears to be patients with a disease characterized by failure to thrive, chronic respira-
derived from tumor cells. Porokeratosis has also been reported in association tory disease, photophobia with corneal dystrophy, and gastrointestinal
with dermal amyloid deposition as a result of apoptosis of keratinocytes.8,9 disease.20,21
Mycosis fungoides and discoid lupus erythematosus may exceptionally be
seen associated with localized cutaneous amyloidosis.10,11
Cutaneous amyloid deposition may also rarely be seen as a consequence of Nodular amyloidosis
chronic epidermal damage following PUVA therapy.12,13 So-called concha amy-
loidosis due to chronic actinic damage to the ear has also been Clinical features
documented.14,15 In this rare variant, which is more common in females, pink–brown single
Repeated insulin injections at the same site have been reported as inducing or multiple nodules develop on the trunk, extremities, genitalia, face or
amyloid in the skin.16 scalp (Fig. 13.61).1–7 Bilateral nodular amyloidosis of the eyelids in the
absence of systemic amyloidosis has rarely been documented.8 The lesions
Familial primary cutaneous amyloidosis often have a waxy appearance and the surface may be atrophic or ulcer-
ated. Most cases of nodular amyloidosis are limited to skin and only 7%
Familial primary cutaneous amyloidosis is a very rare autosomal dominant show progression to systemic amyloidosis.7,9 Occasional reports have doc-
variant of amyloidosis that presents with manifestations of either macular umented monoclonal paraproteinemia, lymphoplasmacytoid lymphoma,
and/or lichenoid amyloidosis.1–5 Lichen amyloidosis is also seen in patients Sjögren's syndrome, proteinuria, bone marrow abnormalities, and a posi-
with multiple endocrine neoplasia type 2A (Sipple's syndrome).6–8 Germline tive rectal biopsy.10–15 Nodular cutaneous amyloidosis has also been
mutations of the RET proto-oncogene on chromosome 10 involving cysteine described in association with carpal tunnel syndrome induced by the amy-
residues have been consistently described in Sipple's syndrome. However, loidogenic transthyretin His 114 variant.16 An unusual variant of nodular
familial primary cutaneous amyloidosis without Sipple's syndrome does not amyloidosis with bilateral plantar involvement is very occasionally
show RET mutations, clearly indicating that they are different conditions.6,9 encountered.17
Recent genetic studies in a small subset of patients with familial primary
cutaneous amyloidosis have isolated a mutation in the OSMR gene on chro- Histological features
mosome 5.10,11 This encodes the oncostatin M receptor beta which is expressed
The histological appearances cannot be distinguished from those of systemic
in various tissues including keratinocytes, cutaneous nerves, and in the dorsal
amyloidosis and, indeed, as in primary amyloidosis, the amyloid consists of
root ganglion. This is a cytokine receptor complex, and it is speculated that
light chain-derived AL protein.18–21 It is thought likely that this nodular vari-
mutations in it lead to dysfunctional cell signaling resulting in apoptosis of
ant results from local production of light chains by a localized group of
keratinocytes, amyloid deposition, and reduction of nerve fibers, which
plasma cells.1 PCR studies have demonstrated that the infiltrating plasma
causes pruritus.10,12 Not all patients with familial primary cutaneous
amyloidosis have been shown to have the same mutation in chromosome 5,
indicating genetic heterogeneity in this disease.13
The histopathological findings are identical to those described in the
primary nonfamilial variants of localized cutaneous amyloidosis.
Fig. 13.61
Nodular amyloidosis: an
Fig. 13.60 irregular infiltrated plaque
Tumor-associated amyloid: amyloid deposits in a basal cell carcinoma. limited to the nose.
cells in cases of nodular amyloidosis are usually monoclonal.22,23 Polyclonality,

however, has also been reported.11 In all patients with nodular amyloidosis, it
is important to exclude systemic disease.2,7
The deposits of amyloid are present in both the papillary and reticular
dermis and may involve the subcutaneous fat (Figs 13.62–13.64). Sometimes
the vasculature and nerve sheaths are affected (Figs 13.65–13.67).2
Fig. 13.64
Nodular amyloid: the
A amyloid deposits fill the
papillary dermis.
Fig. 13.62
Nodular amyloidosis: (A) massive deposits of amyloid are present in the dermis; Fig. 13.65
(B) there is a heavy associated plasma cell infiltrate. Nodular amyloidosis: amyloid deposits have thickened the blood vessel walls.
Fig. 13.63 Fig. 13.66

Nodular amyloidosis: in this example there is a broad bandlike deposit in the upper dermis. Nodular amyloid: the deposits are strongly Congo red positive.
Colloid milium 543
Fig. 13.69
Juvenile colloid milium:
Fig. 13.67 there is papular thickening
Nodular amyloid: in this example, vessels in the subcutaneous fat showing striking of the skin, particularly
involvement. involving the cheeks,
nose, and forehead.
By courtesy of
S. Hendfield-Jones, MD,
London, UK.
Fig. 13.70
Fig. 13.68 this less severely affected
Nodular amyloidosis: there is a conspicuous plasma cell infiltrate. child shows typical
yellow–brown translucent
papules on the nose and
upper lip. By courtesy of
Characteristically, plasma cells are seen around blood vessels and at the S. Hendfield-Jones, MD,
margin of the amyloid deposits (Fig. 13.68).4,24 Rarely, an associated for- Institute of Dermatology,
eign body giant cell reaction and/or calcification are evident.4,6 London, UK.
Colloid milium
unctured characteristically express gelatinous material. The underlying
p
Colloid milium, which is characterized by the deposition of amorphous,
tissues often feel indurated. Juvenile colloid milium predominantly affects
eosinophilic granular deposits in the superficial dermis, has a number of sub-
the face, in particular the cheeks, nose, and around the mouth (Figs 13.69–
types including the juvenile and adult variants. It may also develop as a
13,71). Induction of purpura after stroking has been described in both
manifestation of ochronosis due to use of the skin bleaching agent hydroqui-
juvenile and adult colloid milium.8 This phenomenon has been attributed to
none.1 Two other variants – nodular colloid degeneration and paracolloid of
vascular fragility due to infiltration of the blood vessel walls by colloid mate-
the skin – are probably variants of nodular amyloidosis.2–4 An alternative
rial. Exceptionally, juvenile colloid milia may present with gingival deposits
name proposed for adult colloid milium is that of papular elastosis.5
and ligneous conjunctivitis as a result of infiltration of these tissues by
colloid-like material.9–11
Juvenile colloid milium
Clinical features Although the etiology remains unknown, in some cases at least, sunlight plays
The juvenile variant, which is exceedingly rare, develops in children before an important role. The pathogenesis, however, shows considerable overlap with
puberty and sometimes has a familial incidence.6 Patients present with macular and lichenoid amyloidosis. Juvenile colloid milium represents a primary
discrete, or sometimes confluent, papules measuring 0.2–1.5 cm in diame- degenerative disorder of epidermal keratinocytes, which through the process of
ter.7 Lesions, which are yellow–brown in color, appear translucent and when apoptosis are transformed into colloid bodies within the superficial dermis.
Fig. 13.71 Fig. 13.73

Juvenile colloid milium: close-up view from the brother of the patient shown in Juvenile colloid milium: internalized desmosomes are evident within this degenerate
Figure 13.70. By courtesy of S. Hendfield-Jones, MD, Institute of Dermatology, keratinocyte.
London, UK.
Fig. 13.72 Fig. 13.74

Juvenile colloid milium: this shows an apoptotic keratinocyte, the cytoplasm of Juvenile colloid milium: the papule consists of an intradermal deposit of eosinophilic
which is filled with fascicles of pale-staining filaments that contrast strikingly with material. There is no inflammatory response.
adjacent tonofilaments.
Histologically, the deposits are present in the superficial dermis where they
The initial change is one of filamentous transformation whereby the impinge on the overlying and often somewhat frayed epidermis (Figs 13.74–
relatively straight electron-dense keratin filaments are converted into short- 13.77). The colloid is composed of eosinophilic amorphous aggregates, often
ened, curved 8–10 nm filaments arranged in weaved or whorled fascicles (Fig. showing a fractured appearance. The overlying epithelium shows prominent
13.72).7 Occasionally, both types of filament may be identified simultane- cytoid bodies, while laterally, acanthosis associated with downward and
ously within the cytoplasm of basal keratinocytes. With progression, filamen- inward growth results in cuffing or even encirclement of the colloid islands by
tous transformation comes to affect the entire cell, and nuclear, cytoplasmic, an epidermal collarette.2 An admixture of fibroblasts and mast cells may be
and desmosomal remnants may be identified within the filamentous mass evident and pigmentary incontinence is sometimes present. Juvenile colloid
(Fig. 13.73). Residual desmosomes are sometimes present around the border milium is histochemically indistinguishable from amyloid: it is diastase-
of the colloid deposit. Finally, the apoptotic cell is extruded into the adjacent resistant, PAS positive, thioflavine-T positive and shows positive staining
dermis. In addition to the transformed filaments characteristic of all cytoid with Congo red with apple-green birefringence.
bodies, amyloid filaments have also been identified in juvenile colloid milium,
thereby prompting the authors to classify this entity along with other amy-
loid-K dermatoses.2 Positive labeling of the deposits for epidermal keratin
Adult colloid milium
gives support to this hypothesis.2,12
Juvenile colloid milium has also been shown by direct immunofluores- Clinical features
cence to be accompanied by immunoglobulin, complement, and fibrin This variant, which is much commoner than the childhood form, affects middle-
deposits.7 Whether this represents an autoimmune-mediated reaction as is aged patients and shows a predilection for males. Outdoor workers are most
seen in macular-lichenoid amyloidosis or a secondary non-specific reactive often affected and lesions seen on sun-exposed skin are often accompanied by
phenomenon has yet to be determined. the features of solar elastosis, giving rise to the synonym of papular elastosis.
Colloid milium 545
Fig. 13.77
Juvenile colloid milium: the amorphous material that characterizes this condition
is of epidermal derivation. Tonofilaments undergo filamentous degeneration
Fig. 13.75 (apoptosis). Note the keratin positivity of the colloid aggregates (pankeratin).
this high-power view
shows the faceted nature
of the deposit.
Fig. 13.78
Adult colloid milium: predominantly unilateral, streaked, orange plaque involving the
forehead and nose. By courtesy of the Institute of Dermatology, London, UK.
mineral oils.18 A single case has also been described in a patient with beta
thalassemia major.19 Rare cases of pigmented colloid milium have been doc-
umented as a consequence of exogenous ochronosis due to bleaching creams
and fertilizers.1,13
Fig. 13.76
the adjacent epidermis
shows massive apoptosis. In contrast to the keratinocyte changes seen in the juvenile variant, adult col-
loid milium represents an extreme degree of actinic damage centered upon the
upper dermal elastic fibers. Although earlier studies suggested that the colloid
Adult colloid milium presents as dome-shaped yellowish translucent might have represented abnormal collagen or a fibroblast secretory product,
apules measuring 0.1–0.5 cm in diameter and, in common with juvenile
p more recent studies suggest that it derives from actinic elastoid.14,20–22
colloid milium, they contain gelatinous material. Lesions are most often Ultrastructural studies have shown that there is direct continuity between
seen on the face, ears, neck, and the dorsum of the hands (Fig. 13.78) and actinic elastoid and the colloid deposits and that, within the electron-dense
may be skin colored to brown.2,13 Adult colloid milium affects fair-skinned colloid, remnants of both normal and elastotic fibers may sometimes be
patients and follows excessive sun exposure. This has been dramatically identified.21,23 Amyloid filaments are not present. Further support for this
illustrated in patients whose lesions are limited to sun-exposed areas of the hypothesis is given by the identification of serum amyloid P component within
body.14,15 Adult colloid milium has also been reported following the exces- the colloid deposits.21 Although this protein is characteristically present within
sive use of cosmetic ultraviolet A (UVA) sunbed exposure.16 A rare associa- amyloid, it is also a constant component of normal elastic tissue and has also
tion with multiple myeloma has been described.17 A further report described been identified in actinic elastoid.24,25 Adult colloid milium does not label with
a patient who developed lesions of adult colloid milia in areas exposed to antikeratin antibodies, and immunoglobulins and complement are absent.
The gene for lipoid proteinosis has been mapped to chromosome 1q21
and the disease is caused by mutations in the extracellular matrix protein 1
gene (ECM1) which lead to partial or complete loss of function of the pro-
tein.12 ECM1 is thought to play a critical role in dermal structure and orga-
nization by binding to dermal ground susbstance (molecules such as perlecan
and matrix metalloproteinases), in the formation and maintenance of the
basement membrane, and in stromal signaling.13 It has been called ‘biological
super-glue’.13,14 It is also overexpressed in cancers, influencing tumor growth
and metastasis.13 Over 40 different mutations in this gene have been reported
in association with lipoid proteinosis, and studies thus far have not demon-
strated a relationship between the specific type of mutation and clinical
phenotype.13,14 Interestingly, patients with lichen sclerosus have auto
antibodies to ECM1.15
The initial symptom, a hoarse cry, develops in infancy and results from
incomplete closure of the vocal cords, which are thickened and irregular due
to the hyaline deposits. Induration of the oral mucosa (including the inner
aspect of the lips, the gingivae, uvula, palate, and floor of the mouth) begins
in childhood and is progressive, so that adults have extensive yellow infiltra-
tion (Fig. 13.81).4,16 The lower lip often assumes a cobblestone appearance.
Fig. 13.79 The tongue also tends to be thick and immobile with sublingual frenulum
Adult colloid milium: deposits of eosinophilic material are present in the superficial
thickening and ankyloglossia. Recurrent ulcers on the tongue have been
dermis. There is adjacent solar elastosis.
described.5 Nail growth is frequently abnormal and the upper incisors, pre-
molars or molars can be hypoplastic or aplastic.6
Early inflammatory skin lesions (bullae, pustules, and crusts) are followed
by acneiform infiltrated scars on the face and limbs (Fig. 13.82).10
Papulonodular lesions develop on the face, fingers, and around the eyelashes,
where they produce the pathognomonic ‘string of beads’ appearance (monili-
form blepharosis) (Fig. 13.83). Thicker xanthoma-like plaques, which some-
times become verrucous, later develop on the areas of trauma including the
knees, elbows, feet, and hands.17 With chronicity in severely affected patients
the entire skin becomes yellow, waxy and thickened, particularly the flex-
ures.18 Similar lesions in the scalp may produce alopecia, which can be patchy
or diffuse.6,8
Intracranial disease sometimes occurs, associated with calcification, which
is thought to complicate deposition of hyaline material around cerebral blood
vessels and basal ganglia.4 Epilepsy is a not uncommon result.17,19,20 Other
neurological manifestations include memory loss, rage attacks, and mild
mental retardation.21
Involvement of the small bowel by the disease may lead to intestinal
bleeding.22
The disease is usually associated with normal life expectancy although
there might be some increase in the mortality rate during childhood due to
Fig. 13.80 respiratory insufficiency.2
Adult colloid milium: the typical faceted appearance.
Histologically, the eosinophilic amorphous, autofluorescent clefted depos-

its are typically separated from the epidermis by a grenz zone containing nor-
mal collagen (Figs 13.79, 13.80).21 Fibroblasts often occupy the fissures
between the fragmented deposits.21
Histochemically, adult colloid milium is diastase-resistant, PAS positive,
thioflavine-T positive and demonstrates apple-green birefringence with
Congo red.14 It is also Dylon positive.2 Colloid milium can be difficult to
distinguish from amyloidosis, and electron microscopy may be
necessary.26,27
Hyalinosis cutis et mucosae

Clinical features
Hyalinosis cutis et mucosae (Urbach-Wiethe disease, lipoid proteinosis), is a
very rare, autosomal recessive condition first described in 1929 in which hya-
line material is deposited in virtually any organ in the body, but particularly
the skin, the pharyngeal mucosa, and the larynx.1–7 It has been reported most
frequently in South Africa (descendants of German and Dutch immigrants) Fig. 13.81
and Sweden, and it has been suggested that up to 35% of documented cases Lipoid proteinosis: small pale papules are present on the mucosal aspect of the
have had South African lineage.8–11 lower lip. By courtesy of the Institute of Dermatology, London, UK.
Hyalinosis cutis et mucosae 547
Fig. 13.82
Lipoid proteinosis: marked thickening of the skin is present with conspicuous
scarring. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Fig. 13.84
Lipid proteinosis: the
blood vessel walls are
thickened by pale-staining,
eosinophilic homogeneous
material.
Fig. 13.83
Lipoid proteinosis: note the waxy nodules on the lower eyelid, producing the
typical ‘string of beads’ appearance. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 13.85
Pathogenesis and histological features Lipoid proteinosis: in this advanced example, there is considerable involvement of
The epidermis is acanthotic and occasionally papillomatous, with overlying eccrine sweat glands which, as a result, are atrophic.
hyperkeratosis. Homogeneous eosinophilic material is distributed in a very
characteristic pattern in the dermis.8 Initially, it is found around capillaries The etiology of bullous lesions in lipoid proteinosis is unclear. A recent
and concentrically around sweat coils (Figs 13.84, 13.85); later, more exten- report sheds light on a possible pathogenesis. It describes subcorneal and
sive deposits are seen, which tend to be vertically orientated within the der- intraepidermal acantholysis without dyskeratosis in a child with lipoid
mis. The hair follicles and arrector pili muscles are often surrounded by a proteinosis.27 Subepidermal clefting was also noted but thought to be artifac-
hyaline mantle.23 In advanced cases, the perineurium of nerves can also be tual. Direct immunofluorescence studies were negative.
affected.24 This material stains very strongly with PAS (diastase-resistant) and Despite considerable research, the precise pathogenesis of lipoid proteinosis
only very weakly with Congo red and thioflavine-T (Fig. 13.86). The name remains an enigma. Quantitative abnormalities of dermal collagen have been clearly
lipoid is used because the hyaline material usually has a lipid component.25 demonstrated, but little is known about the nature of the hyaline deposits other than
Ultrastructurally, the deposit is amorphous, electron dense, and may con- that they are probably composed of an admixture of glycoproteins, glycosaminogly-
tain ill-defined, anastomosing amyloid-like (5–10 nm) filaments and delicate cans, and lipids, as may be determined by s pecial staining techniques.8
collagen fibers (Figs 13.87, 13.88).23 Reduplication of basal lamina is evi- Numerous mechanisms have been hypothesized, but none has satisfactorily
dent around blood vessels, hair follicles, and sweat glands, and excess type IV unraveled the nature of the primary disturbance in this disease. The identifica-
collagen has been demonstrated immunohistochemically.8,17,18,26 The tion of lipid droplets within the hyaline deposits therefore led to the suggestion
fibroblasts contain abundant rough endoplasmic reticulum and numerous that lipoid proteinosis might represent a systemic lipoidosis.8 However, the
mitochondria. Intracytoplasmic inclusions, probably lysosomal in nature, lipid deposition is very variable and lesional chemical analyses have not dem-
have also been described. onstrated any consistent abnormalities. Fibroblast tissue culture experiments
Fig. 13.88
Lipoid proteinosis: high-power view of amorphous electron-dense material
containing occasional collagen fibers.
Fig. 13.86
Lipoid proteinosis: the
deposit is strongly periodic have not supported this concept.25 It probably denotes a secondary phenome-
acid–Schiff positive non. The ultrastructural finding of intracytoplasmic inclusions – including
(diastase-resistant). myelin figures and lysosomes accompanied by an increased fibroblast
hexuronic acid content – has raised the possibility of a lysosomal storage dis-
order.28 This has recently been given further support by the demonstration of
abnormal lysosomes in eccrine cells and histiocytes in two patients with this
disease.29 These lysosomes were found to contain amorphous granular mate-
rial, zebra bodies, and curved tubular profiles. The curved tubular profiles are
similar to those found in Farber's disease and it has been suggested that lipoid
proteinosis represents a disease with not only impaired production of collagen
but also with alterations in ceramide metabolism.
A number of recent publications have described a variety of changes in the
dermal collagen content.30 The reduplicated basement membrane laminae
noted ultrastructurally have been shown to be composed of laminin accom-
panied by collagen types III and IV.31 This feature, however, is of doubtful
significance as similar appearances have been described in a wide variety of
conditions including psoriasis, systemic lupus erythematosus, and diabetes
mellitus.8 Basement membrane replication most likely represents a non-spe-
cific secondary response to a range of stimuli.
Dry weight studies of lipoid proteinosis dermis have shown an apparent
decrease in collagen content although there appears to be a relative increase
A in collagen types III and V compared with collagen type I.32 Immunofluorescence
data, however, suggest that there are reduced absolute levels of both type I
and type III collagen.8 In vitro studies of fibroblast collagen synthesis as deter-
mined by radioactive hydroxyproline synthesis have revealed no significant
abnormality.17 Fibroblasts, however, have reduced replicative capacity. Recent
investigations have disclosed reduced fibroblast type I procollagen mRNA
and a diminished type I:III procollagen mRNA ratio.17 Type IV procollagen
mRNA levels have been shown to be raised.33 No DNA abnormalities or
chromosomal alternations have yet been identified in lipoid proteinosis.
It is likely that the collagen changes are not directly responsible for the
accumulation of the granular hyaline material so characteristic of this disorder.
It is, however, most probably of fibroblast derivation.34
Cutaneous macroglobulinosis
Clinical features
Cutaneous macroglobulinosis (IgM storage papules) is a rarely documented
B manifestation of Waldenström's macroglobulinemia.1–7 The latter is a chronic
lymphoproliferative condition that typically presents in the fifth and sixth decades
Fig. 13.87 and shows a slight predilection for males.5 It is characterized by proliferation of
(A, B) Lipoid proteinosis: transverse section through blood vessel showing lymphoplasmacytoid cells in the bone marrow, lymph node, and spleen and IgM
reduplication of the basement membrane. paraproteinemia.5 Patients present with weakness, fatigue, weight loss, anemia,
Porphyria 549
mucous membrane bleeding, retinal hemorrhages, lymphadenopathy, hepatos- Direct immunofluorescence shows that the deposits stain strongly for
plenomegaly, peripheral neuropathy, and the hyperviscosity syndrome.7,8 Skin IgM.2,5,7
involvement is very uncommon and includes tumors, plaques, and macroglobu- Ultrastructurally, the deposits are composed of amorphous or granular and
linosis cutis. Additional features that sometimes encountered include purpura, sometimes filamentous material which by immunoelectron microscopy consists
xanthomata, cryoglobulinemia, and Raynaud's phenomenon.7 of IgM.1–3,7 The periodicity of amyloid is absent in the filamentous
Clinically, macroglobulinosis presents as sometimes pruritic, skin-colored, ery- component.7
thematous or translucent papules measuring up to 1.0 cm in diameter distributed The plaques and tumor nodules are composed of lymphoplasmacytoid
predominantly on extensor sites including knees, elbows, buttocks, and the arms infiltrates.
and legs..7 Umbilication, erosion, and crusting and hyperkeratosis are commonly
seen.5,9,10 Cutaneous tumor deposits present as violaceous nodules and plaques.
Porphyria
The porphyrias constitute a heterogeneous group of conditions characterized
The papules are characterized by homogeneous eosinophilic material in the by the excessive production of porphyrins or their precursors resulting from
papillary and reticular dermis (Fig. 13.89).2 Hair follicles may be encased.2 defects in the activity of the enzymes regulating heme synthesis (Fig. 13.91).1–12
The deposits are PAS positive but are Congo red negative (Fig. 13.90). Porphyrin synthesis occurs mainly in the erythropoietic system and the liver.
A lymphoplasmacytoid infiltrate is variably present.7 The plasma cells may
contain intracytoplasmic IgM-rich vacuoles.4
Fig. 13.89
Macroglobulinosis
cutis: these are nodular
deposits of eosinophilic
material in the superficial
dermis. By courtesy of
A. Wang, MD, Brigham
and Women’s Hospital,
Boston, USA.
Fig. 13.90 Fig. 13.91

Macroglobulinosis cutis: the material is strongly periodic acid–Schiff positive. Biochemistry of porphyria. Reproduced with permission from Young, J.W., and
By courtesy of A. Wang, MD, Brigham and Women’s Hospital, Boston, USA. Conte, E.T. (1991) International Journal of Dermatology, 30, 399–406.
Deficiency of a specific enzyme results in an accumulation of heme precursors arrow. In the hepatic porphyrias the altered synthesis mainly occurs in the
m
due to stimulation of the rate-limiting enzyme aminolevulinic acid synthetase as liver (porphyria cutanea tarda, hepatoerythropoeitic porphyria, acute inter-
a consequence of diminished heme concentration.10,13 mittent porphyria, aminolevulinic acid (ALA) dehydratase deficiency, varie-
Genetic mutations account for the enzyme deficiencies seen in the various gate porphyria, and hereditary coproporphyria). Of the eight major types of
types of porphyria. These mutations have all been delineated at a molecular porphyria, six are associated with cutaneous disease (Table 13.4). The clini-
level, are very heterogeneous, and often result in enzyme deficiencies that may cal and biochemical findings are very different in these six types of porphyria,
remain silent throughout life.13 If a patient is homozygous for a specific muta- although the cutaneous histology is similar in all.20–23 Type II porphyria
tion, however, symptoms usually develop even in early life. cutanea tarda, hereditary coproporphyria, variegate porphyria, and erythr
Patients may present with acute porphyria (abdominal pain with neurologi- opoietic protoporphyria are all inherited as autosomal dominants with incom-
cal and/or psychiatric symptoms) often induced by drugs, fasting, alcohol or plete penetrance. Fewer than 20% of affected individuals display symptoms
sex hormones.14–17 The enzyme defect leads to the accumulation in the skin of a and patients often deny a family history.2
photosensitizing porphyrin, which absorbs light predominantly in the
400–410 nm range. The energy absorbed may then be released to adjacent
nucleic acids or proteins, either directly or indirectly by involving acceptor mol-
Congenital erythropoietic porphyria
ecules such as oxygen, and toxic changes causing damage to lysosomal and cel-
lular membranes result.16,17 There is also some evidence to suggest that activation Clinical features
of the complement cascade may be involved in the phototoxic reaction mecha- Congenital erythropoietic porphyria (Gunther's disease) is the most severe
nism.16,17 The cutaneous manifestations in acute attacks consist of prominent and mutilating of the erythropoietic porphyrias. It is inherited as an auto-
erythema in sun-exposed areas with a burning sensation. Subacute or chronic somal recessive and develops as a consequence of deficiency of the fourth
skin involvement consists of skin fragility, blister formation, and progressive enzyme of the heme pathway (uroporphyrinogen III synthase) resulting in
scarring. Exceptional cases of a photosensitive bullous eruption associated with excessive production of uroporphyrin I and coproporphyrin I, which give the
transient elevation of porphyrin levels have been described in neonates during urine a pink–burgundy color.1–3 Patients with the more severe form of the dis-
phototherapy for treatment of hyperbilirubinemia due to hemolytic ease may present with fetal hydrops.4 The diapers of affected children usually
disease.18,19 show a characteristic pink stain. Uroporphyrin I accumulates in the bone
Porphyria is primarily classified into erythropoietic and hepatic types marrow, peripheral blood, and other organs. It has been demonstrated that
depending upon which tissue is predominantly affected. The erythropoietic there is a clear correlation between the degree of porphyrin excess and disease
porphyrias (congenital erythropoietic porphyria and erythropoietic protopor- severity.5 There is increased production of uroporphyrins and coproporphyrins
phyria) are characterized by altered heme synthesis mainly in the bone in the urine and coproporphyrins in the feces.
Table 13.4
Classification of porphyria
Site of metabolic
Condition Mode of inheritance Enzyme defect expression Laboratory abnormality
Non-acute porphyrias producing cutaneous lesions
Congenital erythropoietic Autosomal recessive URO-S Erythroid cells Elevated uroporphyrin
porphyria Coproporphyrin in urine and feces
Porphyria cutanea tarda Hepatocytes Urinary uroporphyrin:coproporphyrin = 3:1
inherited Autosomal dominant URO-D Elevated urinary uroporphyrin
sporadic Acquired/sporadic URO-D Urinary and stool isocoporphyrins
toxic Acquired
Erythropoietic protoporphyria Autosomal dominant Ferrochetalase Erythroid cells and Normal urine
hepatocyte Elevated plasma, RBC and stool
protoporphyrin
Elevated fecal and RBC coproporphyrin
Hepatoerythropoietic porphyria Autosomal recessive URO-D (severe) Erythroid cells and Increased urine and stool URO
hepatocyte Elevated stool coproporphyrin and
isocoproporphyrin
Elevated RBC protoporphyrin
Acute porphyrias (porphyrias producing abdominal, neurological and psychiatric symptoms)
Acute intermittnt porphyria Autosomal dominant Porphobilinogen Hepatocyte Stool and blood usually normal
deaminase Elevated urinary ALA and PBG
ALA dehydratase deficiency Autosomal recessive ALA dehydratase ? ALA alone elevated
(porphobilinogen
synthase)
Porphyrias producing abdominal, neurological, psychiatric and cutaneous manifestations
Variegate porphyria Autosomal dominant Protoporphyrinogen Hepatocyte Urine normal between attacks
oxidase Increased stool protoporphyrins and
coproporphyrin
Increased urinary ALA and PBG during
attacks
Hereditary coproporphyria Autosomal dominant Coproporphyrinogen Hepatocyte Increased stool and urine coproporphyrins
oxidase
ALA, aminolevulinic acid; PBG, porphobilinogen; RBC, red blood cell; URO, uroporphyrinogen.
Reproduced with permission from Young, J.W., Conte, E.T. (1991) International Journal of Dermatology, 30, 399–406.
Porphyria 551
Affected patients develop intense photosensitivity to sunlight as well as to

fluorescent light, typically in infancy (Fig. 13.92). Symptoms include painful
and pruritic erythema and swelling which occurs within minutes of sun expo-
sure. Vesicles and bullae are supervened by a mutilating scarring process on
the face and hands, where autoamputation may occur (Figs 13.93, 13.94). A
rare case of metastatic squamous cell carcinoma has been reported in an
amputation stump.6 Sclerodermoid change is sometimes seen.7 Coarse hair
may be found on the face, and lanugo hair develops on the limbs. Pigmentary
changes are sometimes evident. In addition, patients develop cicatricial alope-
cia of the scalp, nail changes, conjunctivitis, ectropion, keratoconjunctivitis,
symblepharon, blepharitis, or brown staining of the teeth (erythrodontia).8,9
The teeth characteristically fluoresce intense orange–red with Wood's light
(400 nm). The sclera also demonstrates pink fluorescence under Wood's
light.10
Fig. 13.94
Congenital erythropoietic
porphyria (Gunther’s
disease): adult patient
showing very severe
photodamage. By
Hemolytic anemia and splenomegaly occur in a large proportion of the

patients and hypersplenism is sometimes a feature. Patients with congenital
erythropoietic porphyria have an increased risk of bone fragility with resultant
fractures and developmental defects.2 Acro-osteolysis, soft tissue calcifica-
tions, and widening of the diploic space have also been documented.11 Early
death may result, often in the third decade. Rare cases are associated with the
Fig. 13.92 nephrotic syndrome, probably secondary to renal siderosis.12 A delayed
Congenital erythropoietic porphyria (Gunther’s disease): this variant is associated late-onset variant has rarely been described.13–15 Some of these patients present
with severe photosensitivity. There is marked erythema and edema of the backs of with thrombocytopenia and others with myelodysplasia.14–17
the hands and fingers. Scarring frequently supervenes. By courtesy of G. Murphy, The URO-synthase gene has been mapped to chromosome 10q25.3-
MD, Beaumont Hospital, Dublin, Eire. q26.3,15 The molecular defects in this disease are very heterogeneous and up
to 38 mutations in the URO-synthase gene have already been described.18–23
These include single base substitutions, insertions and deletions, and splic-
ing defects. By far the most common mutation is C73R, which has been
found in up to 40% of patients with the disease. Two other relatively com-
mon mutations include L4F and T228M, seen in 8% and 7% of patients,
respectively.19 Prenatal diagnosis of the disease is possible not only by
measurement of uroporphyrin I levels in amniotic fluid but also by DNA
mutation analysis.24
Erythropoietic protoporphyria
Clinical features
Although this condition was not recognized until 1961, it is now known to
be the second commonest type of porphyria. It results from increased pro-
Fig. 13.93 duction of protoporphyrin due to diminished ferrochelatase (heme synthase)
Congenital erythropoietic activity.1–3 Ferrochelatase is the enzyme responsible for the combination
porphyria (Gunther’s between protoporphyrin IX and iron to form heme. Urinary porphyrins are
disease): in this severely normal because protoporphyrins are insoluble in water. Protoporphyrin is
affected patient, there is elevated in plasma, erythrocytes, and occasionally in the feces.1
marked hyperpigmented Coproporphyrins may be found in erythrocytes and feces. The mode of
scarring on the cheeks, inheritance is predominantly autosomal dominant with incomplete pene-
nose, and around the
trance although an autosomal recessive inheritance has also rarely been
mouth. The brownish
discoloration of the teeth
reported.4,5 The gene for ferrochelatase has been mapped to the long arm of
is characteristic. By chromosome 18 (18q21.3).6
courtesy of G. Murphy, The variable clinical manifestations of this disease are probably the
MD, Beaumont Hospital, result of heterogeneity of the ferrochelatase gene defects.7 Acute photosen-
Dublin, Eire. sitivity usually presents in early childhood.8 A painful burning erythema
with edema occurs immediately after exposure to sunlight.9 Petechiae can patients and rarely to cirrhosis.6,12–14 Patients who develop liver failure have a
occur, particularly with prolonged exposure. Vesicles are uncommon, but a different form of the disease with an autosomal recessive form of transmis-
scaly, erythematous reaction may be seen, leading to circular or linear sion.15 Neurological manifestations are not common. Anemia is rare and if
depressed scars on the face (particularly on the bridge of the nose and present is very mild.
around the mouth) and over the knuckles (Figs 13.95–13.99).1 Purpura Recently, a late-onset variant has been described, which is more commonly
and urticaria are sometimes seen. There may also be a waxlike thickening associated with hematological malignancy, where the disease occurs second-
of the skin, particularly of the dorsum of the hands and, more rarely, the ary to an acquired somatic mutation in the malignant clone within the bone
face (Fig. 13.100).1 Bullae and milia have been documented exceptionally.3 marrow.16–19 Exacerbation of the disease by blood transfusion and by iron
A further case presented with pseudoainhum.10 An association with lupus ingestion has been described.20,21
erythematosus is very rare.11 Hypertrichosis and hyperpigmentation are
not typically seen.2
In the majority of cases the disease is limited to the skin, but some affected
patients develop protoporphyrin-rich gallstones, and 5–10% of patients
develop liver disease, which may progress to liver failure in fewer than 5% of
Fig. 13.97
Erythropoietic
protoporphyria: there
are characteristic,
depressed, small linear
scars on the bridge and
Fig. 13.95 sides of this patient’s
Erythropoietic nose. By courtesy of the
protoporphyria: crusted Institute of Dermatology,
lesions are present London, UK.
on the cheeks, nose,
and around the mouth.
By courtesy of G. Murphy,
MD, Beaumont Hospital,
Dublin, Eire.
Fig. 13.98
Erythropoietic
protoporphyria: there
is very severe actinic
damage.
Fig. 13.96 By courtesy of the
Erythropoietic protoporphyria: there is marked scarring. Note the depressed linear Institute of Dermatology,
lesions. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire. London, UK.
Porphyria 553
with jaundice, severe chronic hemolytic anemia starting in the neonatal period,
hepatosplenomegaly, and photosensitivity. Neuropsychiatric symptoms or
abdominal pain are not seen. These patients usually have a specific mutation
(K404E) on one or both alleles of the coproporphyrinogen gene.11
Porphyria cutanea tarda

Clinical features
This is the commonest type of porphyria and usually manifests in middle
age.1–3 It shows a marked male predominance.4 The highest incidence is found
in the South African Bantu.4 Cases are also often seen in Europe and North
America.
There are two main forms of porphyria cutanea tarda: familial and spo-
radic.1 Both variants have in common a reduced activity of uroporphyrinogen
decarboxylase (URO-D), which catalyzes the decarboxylation of uroporphy-
rinogen to coproporphyrinogen. In the familial variant there is decreased
URO-D activity in erythrocytes and most other tissues while in the sporadic
form there is decreased URO-D activity restricted to the liver.5,6 In rare familial
Fig. 13.99
cases, normal URO-D activity has been reported in erythrocytes.7
Erythropoietic protoporphyria: note the characteristic scaly scars over the knuckles.
The rare familial form exhibits an autosomal dominant inheritance. The
onset tends to be earlier than that of the sporadic form and the exceptional
cases occurring in childhood are usually familial. The disease is related to
many different mutations in the URO-D gene.8,9 There is no clear correlation
between disease severity and the type of mutation.10 Porphyria cutanea tarda
may be precipitated by many exogenous factors including alcohol abuse, iron
overload, childbirth, and sun exposure.11 Pregnancy may exacerbate the
symptoms of the disease during the first trimester.12 Multiple factors often
contribute to precipitate the disease in a given patient.13 Rare cases of familial
porphyria cutanea tarda present with constrictive pericarditis.14
The second much more common form is sporadic or acquired. Up to 80%
of patients with porphyria cutanea tarda have the sporadic form of the dis-
ease. It has been demonstrated that sporadic porphyria cutanea tarda is a
multifactorial disorder involving a combination of genetic and environmen-
tal factors. Recent studies have demonstrated that the hemochromatosis
gene mutations C282Y and H63D represent a susceptibility factor in Western
European and Australian patients affected by this form of the disease.15–19
These mutations probably induce the disease through iron overload. It has
also been suggested that the IVS4+198 T allele in the human transferrin
receptor-1 may play an independent role in the development of the disease.15
However, this has not been substantiated in other studies.18 Coinheritance of
mutations in the uroporphyrinogen decarboxylase and in the hemochroma-
Fig. 13.100
tosis genes appears to accelerate the onset of porphyria cutanea tarda.20
Erythropoietic protoporphyria: there is characteristic waxy thickening of the skin of
the hands. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.
Sporadic cases mainly occur in patients exposed to a variety of hepatotoxic
chemicals, such as ethanol, estrogens, griseofulvin, vitamin B12, sulfon-
amides, tamoxifen, pravastatin, barbiturates, hydantoins, and chlorinated
hydrocarbons: for example, an epidemic form occurred in Turkey due to
Hereditary coproporphyria exposure to the fungicide hexachlorobenzene.21–25 Rare associations include
diabetes mellitus, Wilson's disease, myelofibrosis, the CREST syndrome,
Clinical features and hepatocellular carcinoma.26–29
This very rare autosomal dominant form of porphyria develops as a result of Increased hepatic iron stores are a major predisposing factor.6,30 The mech-
a deficiency of coproporphyrinogen oxidase.1,2 This enzyme catalyzes the anism by which this happens is not well understood. Iron catalyzes the forma-
sixth step in the heme biosynthetic pathway. It has been mapped to the long tion of reactive oxygen species and this may enhance uroporphyrin formation
arm of chromosome 3 (3q11.2).3 A number of different mutations have been by increasing the rate at which uroporphyrinogen is oxidized to uroporphy-
documented.4,5 Heterozygous patients often do not manifest symptoms of the rin, leading to the manifestations of the disease. A second possible proposed
disease.6 In those who develop symptoms, these usually appear after puberty. mechanism considers the indirect inhibition of uroporphyrinogen decarboxy-
Affected patients develop intermittent attacks of abdominal pain in associa- lase by iron. Whatever the mechanism, the iron overload has important
tion with neurological and psychiatric manifestations. About 30% of cases therapeutic implications as venesection can induce a remission.
develop photosensitivity, usually at the time of the acute attacks. The cutane- Hepatitis C virus infection is often associated with porphyria cutanea
ous changes are similar to those described for porphyria cutanea tarda. The tarda.31–33 A frequent association is also the acquired immunodeficiency syn-
disease may be precipitated by pregnancy, the contraceptive pill, fasting, drome (AIDS).34–39 AIDS patients with porphyria cutanea tarda are often hep-
infections, and the anabolic steroid methandrostenolone.3,7–9 Diagnosis is atitis C virus-positive.40 Patients who have had both acquired and familial
confirmed by the presence of increased excretion of coproporphyrinogen III variants have developed the typical features of increased skin fragility, blister-
in urine and feces. Porphobilinogen and aminolevulinic acid are increased ing, hyperpigmentation, and hypertrichosis, but scarring and milia have
during the episodic attacks. rarely been evident.41 Often, the development of porphyria has preceded the
Harderoporphyria is regarded as a variant form of hereditary copropor- diagnosis of HIV infection.41 In many instances this has been related to
phyria in which hematological alterations predominate.2,10 Patients present excessive alcohol consumption and/or infectious hepatitis, particularly
epatitis C.38,42 The association has been reported too often to be merely
h cheeks and temples, the eyebrows, ears, and arms (Fig. 13.105).4 The
fortuitous and liver damage seems to be the common denominator. The causal sclerodermatous features, which are more common in females, are found on
agent (be it hepatitis C virus or HIV) seems to have a direct effect upon hepa- both light-exposed and unexposed skin. Sites that are particularly affected
tocyte porphyrin metabolism. It has been demonstrated that elevated serum include the face, neck, scalp, chest, and backs of hands, and often there is
porphyrin levels occur in early-stage HIV infection and hepatitis C infec- hyper- or hypopigmentation or both.4,49 Hyperpigmentation, if present, may
tion.43 Porphyria cutanea tarda has also been described in association with be diffuse, reticulate or spotty. Preauricular calcification is a common
nonalcoholic liver disease, chronic hemodialysis, noninsulin dependent diabe- complication. The dermal fibrosis appears to be related particularly to high
tes mellitus and lupus erythematosus.1,44,45 An autoantibody study in a large uroporphyrin levels.49 Uroporphyrin has been shown to stimulate fibroblast
series of patients with lupus erythematosus suggests that the association is collagen synthesis independent of ultraviolet light.50
fortuitous.46 The association with hematological malignancies including leu- Uncommon cutaneous manifestations of porphyria cutanea tarda include
kemia and lymphoma is usually related to the treatment, particularly repeated alopecia affecting the frontoparietal, temporal, and occipital regions of the
blood transfusions.47,48 scalp, and centrofacial papular lymphangiectasis.51,52 Hair darkening has also
Typically, blisters occur on light-exposed skin and are traumatic or actini- been reported.53 Very rare cases have been documented presenting with
cally induced (Figs 13.101–13.103).4 Cutaneous fragility is usually marked. plaques or simulating solar urticaria.54,55
The blisters are slow to heal and leave superficial atrophic scars with milia.
Although they are most often seen on the backs of the hands, they may also
be found on the palms, face, scalp, forearms, trunk, and under the finger
nails.4 Hypertrichosis and premature aging with chronic actinic damage are
usual and sclerodermatous changes may be marked (Fig. 13.104). The hyper-
trichosis is characterized by long dark lanugo hair developing about the
Fig. 13.103
Porphyria cutanea tarda: note the scarring and milia. By courtesy of the Institute of
Fig. 13.101
Porphyria cutanea tarda: in addition to a blood-filled vesicle there are numerous
milia. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.
Fig. 13.104
Porphyria cutanea
tarda: there is marked
facial scarring with
sclerodermiform features.
Fig. 13.102 By courtesy of G. Murphy,
Porphyria cutanea tarda: there are numerous ruptured blisters. Milia are also MD, Beaumont Hospital,
evident. By courtesy of the Institute of Dermatology, London, UK. Dublin, Eire.
Porphyria 555
Fig. 13.106
Fig. 13.105 Variegate porphyria:
Porphyria cutanea numerous ruptured
tarda: hypertrichosis as vesicles are present on
seen in this patient is the back of the hand
a very typical feature. and fingers. By courtesy
By courtesy of the of G. Murphy, MD,
Institute of Dermatology, Beaumont Hospital,
London, UK. Dublin, Eire.
Acute attacks are not a feature of this variant. Biochemical evidence of

liver involvement is common, but clinical manifestations are unusual.1 Urinary
porphyrin levels are increased and result in pink–red fluorescence with a
Wood's lamp.56
The diagnosis is confirmed by the presence of uroporphyrin and hepta
carboxylic porphyrins in urine and plasma and by the presence of
isocoproporphyrin in feces.
Hepatoerythropoietic porphyria
Clinical features
Hepatoerythropoietic porphyria is very rare and, in fact, represents the
homozygous form of familial porphyria cutanea tarda.1 Both diseases share
some of the mutations that have been described.2 This form of porphyria is
also heterogeneous and different mutations in the URO-D gene may occur.3,4
The activity of uroporphyrinogen decarboxylase is much lower than in
porphyria cutanea tarda. As a consequence, disease manifestations are
typically severe. Recently, mild variants have been reported in association
with certain genetic mutations.5,6 Extreme immediate photosensitivity occurs Fig. 13.107
in infancy.7–9 Erythema, edema, and vesicles lead to severe scarring, with Variegate porphyria: there are ruptured blisters with scarring and milia. By courtesy
hypertrichosis and sclerodermatous changes in exposed areas.10 Ocular fea- of the Institute of Dermatology, London, UK.
tures include photophobia, conjunctivitis, and scleromalacia perforans.11
Hepatitis, cirrhosis, and normochromic anemia may also occur.
chromosome 1q22-23.5,6 The genotype is not a significant determinant of the
clinical manifestations.7–9 Usually, there is approximately a 50% reduction in
Variegate porphyria the activity of the enzyme.9
Acute attacks may be precipitated by a wide range of drugs that induce
Clinical features hepatic microsomal activity including barbiturates, alcohol, oral contracep-
This familial type of porphyria manifests the cutaneous features of porphyria tives, pregnancy, anticonvulsants, and sulfonamides.10–13 Acute variegate por-
cutanea tarda and the acute abdominal and neurological attacks of acute phyria has also presented during an episode of viral hepatitis.10 The cutaneous
intermittent porphyria, both of which usually become apparent in the second manifestations are sometimes mild or absent during the acute attack and the
or third decade (Figs 13.106–13.109).1,2 It is particularly common in South condition may therefore be misdiagnosed as acute intermittent porphyria.2
Africa where it can be traced to the descendants of a single Dutch family.2,3 It
is an autosomal dominantly inherited condition and more severely affected Histological features of the porphyrias
homozygotes have been recognized (Figs 13.110, 13.111). Variegate por- Direct immunofluorescence reveals immunoglobulin (particularly IgG and
phyria is associated with diminished activity of protoporphyrinogen oxidase, to a lesser extent IgM), fibrinogen, and C3 outlining characteristic donut-
the penultimate enzyme in the heme biosynthetic pathway.4 Several different shaped blood vessels in the papillary dermis (Fig. 13.112). Although this is
mutations have been demonstrated in the protoporphyrin oxidase gene on particularly evident in erythropoietic protoporphyria, it is also a feature of
Fig. 13.110
Fig. 13.108 Homozygous variegate
Variegate porphyria: note the blistering over the toes and dorsum of the foot. porphyria: there is
By courtesy of the Institute of Dermatology, London, UK. marked scarring of the
dorsal surface of the
forearms, hands, and
fingers. By courtesy of the
London, UK.
Fig. 13.109
Variegate porphyria: an intact blister is present on the left little finger. Elsewhere,
there is marked scarring and milia are present. By courtesy of the Institute of
the other ‘cutaneous’ variants.1,2 Immunoreactants are also frequently pres-

ent at the dermoepidermal junction and have been identified within the Fig. 13.111
Homozygous variegate porphyria: note the perioral erosions and scarring. By courtesy
basement membrane region of eccrine sweat glands and ducts.1–4 This find-
ing is believed to be due to the non-specific binding of serum components
rather than an immunologically mediated reaction.3 In addition, both type
IV collagen and laminin are present in increased amounts, thereby contrib-
uting to the vessel wall thickening.5 Cytoid bodies are also commonly evi- lamellated appearance. These appearances are particularly conspicuous in
dent.3 Recently, direct immunofluorescence studies have demonstrated erythropoietic protoporphyria.1,7 Alcian blue-positive mucin is sometimes
granular and homogenous deposition of the membrane attack complex evident around the blood vessels and to a lesser extent at the dermoepidermal
C5b-9 in vessel walls of the superficial and mid dermis in patients with por- junction in both porphyria cutanea tarda and erythropoietic protoporphyria.1
phyria cutanea tarda. It is proposed that UV light activated uroporphyrins Lipid droplets are sometimes also demonstrable. A false-positive Congo red
in turn activate complement, possibly playing a pathological role.6 Indirect stain for amyloid may be evident in the lower dermis.1
immunofluorescence is invariably negative for basement membrane zone Electron microscopic observations include considerable basement mem-
autoantibodies. brane reduplication around the dermal vasculature and to a lesser extent at
The histological changes for all types of porphyria are very similar. The the dermoepidermal junction (Fig. 13.115).1,7 This is consistent with the
characteristic feature is the presence of a PAS-positive, diastase-resistant, hya- effects of repetitive endothelial cell injury and regeneration with subsequent
line material around the blood vessels of affected skin (Figs 13.113, 13.114). new basement membrane formation. In addition, finely fibrillar material is
In mild disease the deposits are delicate and are usually limited to the papil- typically present both around the vessels and at the epidermal basement mem-
lary dermal capillaries, but in more severe cases the deposits are widespread, brane region. Irregular electron-dense amorphous deposits may also be
occur more deeply in the dermis, and give the vessel walls a characteristic evident.1
Porphyria 557
There may be subepidermal blisters, characteristically associated with slight The plane of cleavage appears to be variable.9 Some blisters arise beneath the
mononuclear inflammatory cell infiltration (Figs 13.116, 13.117). Neutrophil lamina densa in the superficial dermis similar to epidermolysis bullosa acquisita.
polymorphs showing leukocytoclasis have been described in acute lesions of In others, they develop within the reduplicated basement membrane constitu-
erythropoietic protoporphyria and red cell extravasation is sometimes evident.8 ents. Most often, however, as shown by antigen mapping experiments, blister-
Festooning of the dermal papillae is often, though not invariably, present. ing commences in the lamina lucida.9,10 Type IV collagen and laminin are
therefore usually present along the floor of the blister while bullous pemphig-
oid antigen is evident in the roof. Linear segmented structures composed of
type IV collagen and laminin have been identified in the roof of blisters from
patients with porphyria cutanea tarda.11 These so-called caterpillar bodies may
also be seen in specimens from patients with erythropoietic protoporphyria and
drug-induced pseudoporphyria (Fig. 13.117b).12 They are PAS positive and
appear as globules arranged in a linear fashion in the epidermis overlying the
subepidermal blisters. Ultrastructural studies suggest that these bodies represent
a combination of degenerating keratinocytes, colloid bodies, and basement
membrane fragments formed by repeated blistering and re-epithelialization.13
A recent study of caterpillar bodies demonstrated their presence in 43% of
Fig. 13.112
Porphyria cutanea tarda: the superficial blood vessels show striking IgG circumferential
deposition.
Fig. 13.114
Erythropoietic
protoporphyria: the
appearances are much
more dramatic in this
periodic acid–Schiff-
stained section.
B
Fig. 13.115
Fig. 13.113 Porphyria cutanea tarda: there is striking basement membrane reduplication
(A, B) Porphyria cutanea tarda: the superficial vessels are thickened and appear hyalinized. surrounding this small dermal vessel.
orphyria cutanea tarda specimens.14 ‘Caterpillar body-like clusters’ have also

p Rarely, a lichenoid tissue reaction has been documented in porphyria
been identified in patients with porphyria cutanea tarda, erythropoietic proto- cutanea tarda.15
porphyria, bullous pemphigoid, and junctional and dystrophic epidermolysis The histological features of the blisters seen in variegate porphyria are
bullosa. These clusters were histologically identical to classical caterpillar bod- identical to those described for porphyria cutanea tarda.16
ies but did not stain for type IV collagen or PAS stains.14 A secondary sclerodermatous change is frequently present in more
chronic lesions, characterized by thickened collagen bundles and reduced
numbers of cutaneous adnexae (Fig. 13.118).3,7,17 Diastase-resistant,
PAS-positive material may be identified throughout the involved dermis.1
This is particularly marked in porphyria cutanea tarda. Its distinction from
the dermal changes of scleroderma may be very difficult, but it has been
said that the texture of the collagen bundles is somewhat looser in
porphyria.1 Basement membrane thickening due to diastase-resistant, PAS-
positive material is usually present, particularly in porphyria cutanea
tarda.1,7 Solar elastosis is often evident in the latter condition, but this is
probably largely a consequence of the age of the patient and is unlikely to
be a fundamental process (Fig. 13.119). It is not a feature of erythropoietic
protoporphyria.1,7
In the alopecia associated with porphyria cutanea tarda, the initial changes
are those of swelling and homogenization of the perifollicular connective tissue
Fig. 13.116
Porphyria cutanea tarda: a bland subepidermal blister is present.
Fig. 13.118
Porphyria cutanea tarda: there is intense scarring of the entire dermis. The fat
entrapment is reminiscent of scleroderma.
Fig. 13.117 Fig. 13.119

Porphyria cutanea tarda: (A) the blister is cell free; (B) the superficial vessels are Porphyria cutanea tarda: there is colloid milium-like solar elastosis deep to this
thickened (periodic acid–Schiff). Note the caterpillar bodies in the overlying epidermis. blister.
Pseudoporphyria 559
sheath.18 Later, the features of sclerodermatous transformation of the reticular

dermis supervene. Centrofacial papular lymphangiectasis is characterized by Pseudoporphyria
the presence of dilated lymphatics in the superficial dermis.19
The hepatic changes of porphyria cutanea tarda are variable and Clinical features
include needle-shaped uroporphyrin crystals, hepatitis, liver cell degenera- Pseudoporphyria (drug-induced pseudoporphyria, drug-induced pseudopor-
tion and regeneration, fatty change, hemosiderosis, and scarring, some- phyria cutanea tarda, pseudoporphyria cutanea tarda, bullous dermatosis in
times amounting to cirrhosis (Fig. 13.120).18,20,21 There is an increased end-stage renal failure, bullous dermatosis of hemodialysis) refers to a photo-
risk of hepatocellular carcinoma.21 Hepatic changes of erythropoietic pro- distributed blistering dermatosis resembling porphyria cutanea tarda but in
toporphyria include birefringent, dark brown, protoporphyrin crystal the absence of any serum, urine or stool porphyrin abnormality (Figs 13.122–
deposition in the hepatocytes and Kupffer cells, hepatocyte necrosis, por- 13.125).1 It is now recognized as having many causes including drugs, exces-
tal and periportal fibrosis, cholestasis and, less commonly, cirrhosis (Fig. sive UVA (including the use of sunbeds), and sunlight exposure and may
13.121).22 develop in patients undergoing hemodialysis for chronic renal failure.1–20
Pseudoporphyria occurs in up to 6% of patients receiving hemodialysis.21
Small tense blisters develop on the backs of the hands and fingers, and
Differential diagnosis occasionally involve the face, upper chest, and legs.1,2 Milia, skin fragility,
The major differential diagnosis histologically is between porphyria, pseudo-
porphyria, epidermolysis bullosa acquisita and congenita, and bullous amy-
loidosis. All produce cell-poor or cell-free subepidermal blisters. Their
distinction is readily made in the majority of cases with clinical information,
immunofluorescence studies, and Congo red staining.
Fig. 13.122
Pseudoporphyria: there
is extensive purpura with
freckling and conspicuous
excoriations. The patient
had used a sunbed for a
number of years.
Fig. 13.120 By courtesy of G.M.
Porphyria cutanea tarda: in addition to fatty change and mild chronic inflammation, Murphy, MD, Beaumont
brown uroporphyrin crystals are evident. Hospital, Dublin, Eire.
Fig. 13.121 Fig. 13.123

Erythropoietic protoporphyria: the Kupffer cells contain abundant brown pigment. Pseudoporphyria: small tense grouped vesicles are present on the arm. By courtesy
By courtesy of D.R. Davies, MD, St Thomas’ Hospital, London, UK. of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.
photosensitivity, and scarring are often present. Hypertrichosis, hyperpig- including various antibiotics (e.g. nalidixic acid, tetracyclines, and cipro
mentation, sclerodermoid changes, and dystrophic calcification as seen in floxacin), antifungals (e.g. voriconazole) and diuretics (e.g. furosemide
porphyria cutanea tarda are not features of pseudoporphyria.1 In children (frusemide), torsemide) have also been incriminated (for details see references
affected with this condition (usually receiving naproxen for juvenile arthritis), 1 and 2).13–18,23–25 Recent case reports also implicate the tyrosine kinase inhibi-
facial scarring reminiscent of erythropoietic protoporphyria has been tor imatinib, ciclosporin, and oral contraceptive pills.27 The use of UVA sun-
documented.7,22 In general, hepatic abnormalities appear to be absent.1 tanning beds is also a well-recognized cause of pseudoporphyria.12,27 Young
females are almost exclusively affected and PUVA therapy has also rarely been
Pathogenesis and histological features incriminated.1 A rare case of narrow-band UVB-induced pseudoporphyria has
Pseudoporphyria is a UVA-related phototoxic dermatosis.1 It may develop fol- been reported in a patient being treated for psoriasis. 20
lowing both hemodialysis and peritoneal dialysis and also in patients with The blisters are subepidermal and rather bland, containing perhaps a little
chronic renal failure in the absence of dialysis. Suggested risk factors in such fibrin and, occasionally, red blood cells (Fig. 13.126).7,11,27,28 The floor of the
patients include iron overload, aluminum intoxication, PVC-induced photo- blister is typically lined by well-preserved dermal papillae (festooning). There
sensitivity, drugs, and ethanol.1,2 The condition has also been documented is usually no significant inflammatory component although occasionally, a
following use of non-steroidal anti-inflammatory medications including light perivascular lymphocytic infiltrate may be seen in the superficial dermis.
naproxen and cyclooxygenase inhibitors.7–10 A wide variety of other drugs Thickening of the superficial vessels (highlighted by a PAS stain) and dermal
sclerosis with elastosis may be apparent.
Direct immunofluorescence reveals Ig (usually IgG, IgM, and sometimes
IgA) with C3 around the superficial vasculature in a donut distribution and
as a fine granular deposit at the epidermal basement membrane region (Fig.
13.127).2,7,22,23,26–29 Indirect immunofluorescence is invariably negative.2
Fig. 13.124
Pseudoporphyria: note the hemorrhagic blister overlying the knuckle. By courtesy of
G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.
Fig. 13.126
Pseudoporphyria: (A) there
is a subepidermal blister;
(B) the superficial dermal
vessels are thickened
with a hyaline deposit.
(B) By courtesy of G.M.
A Murphy, MD, Beaumont
Hospital, Dublin, Eire.
Fig. 13.125
Pseudoporphyria: there
are multiple erosions and
milia. By courtesy of the
Institute of Dermatology, B
London, UK.
Pseudoporphyria 561
Fig. 13.127
Pseudoporphyria: the
vessel wall thickening is in
part due to excess type IV
collagen, as shown in this
field. By courtesy of G.M.
Murphy, MD, Beaumont
Hospital, Dublin, Eire.
On electron microscopic examination, the plane of cleavage is variable: in

some it has been shown to be within the lamina lucida, whereas in others it
has been deep to the lamina densa (Fig. 13.128).7,30,31 As in porphyria cutanea
tarda, basement membrane reduplication is typically present both at the der-
moepidermal junction and also around the superficial vasculature (Fig.
13.129).7
Differential diagnosis B
The invariably negative indirect immunofluorescence and absence of
porphyrin abnormalities distinguish this disease from autoimmune bullous Fig. 13.129
dermatoses and porphyria cutanea tarda.32,33 (A, B) Pseudoporphyria: note the striking basement membrane duplication.
A B
Fig. 13.128
(A, B) Pseudoporphyria: in this example, the blister is located in the superficial papillary dermis deep to the lamina densa (arrowed).
Gout
Clinical features
Gout represents a group of disorders of purine metabolism in which ele-
vated levels of uric acid occur.1–4 The majority of affected patients have
reduced excretion of purines which may be caused by diuretic therapy or
renal disease. Hyperuricemia may also complicate diabetic ketoacidosis
and starvation, and can develop in patients with sarcoidosis and psoria-
sis.5,6 Some have increased purine synthesis and this type of disturbance
can occur dramatically in the myeloproliferative diseases, particularly fol-
lowing therapy with cytotoxic drugs. Less commonly, gout represents a
primary inherited disorder of purine metabolism. A number of enzymatic
defects are recognized including hypoxanthine guanine phosphoribosyl-
transferase activity (X-linked recessive), abnormal phosphoribosylpyro-
phosphate synthetase variants (X-linked dominant) and
glucose-6-phosphatase deficiency.4 These defects represent a small propor-
tion of patients with gout. More recent genome-wide association studies
have rapidly expanded the knowledge of other genetic defects responsible
Fig. 13.130
for the disease.7–9 Many of the implicated genes are believed to function as
Gout: massive deposit on the dorsal aspect of the hand.
urate transporters in the renal tubules.8,9
Males are affected more often than females and presentation is usually in
the fourth to sixth decades. However, the incidence in females is rising, par-
ticularly in those on diuretics and those with altered renal function.10 The The diagnosis of gout rests primarily on the identification of uric acid
prevalence of the disease is higher in black patients.11 c rystals within joint fluid or tophi rather than on serum uric acid levels, which
Gout produces recurrent, acute, exceedingly painful monoarticular can be unreliable. Acute attacks of gout can be associated with normal uric
arthritis, classically of the great toe, but also of the large joints of the legs. acid levels.12
Many patients present initially with acute inflammation of the first metatar-
sophalangeal joint (podagra).12 The affected joint is characteristically
exceedingly tender, hot, and erythematous, and cellulitis may therefore Histological features
enter the differential diagnosis. Precipitating factors include trauma, exces-
The demonstration of uric acid crystals in tophi requires alcohol fixation
sive alcohol consumption, dietary excess (particularly red meat consump-
and anhidrous processing because monosodium urate is water soluble (Fig.
tion), lead exposure, hypertension, renal insufficiency, surgery, and
13.131).36 In formalin-fixed sections, uric acid crystals appear as amorphous
infections.4,12–14 Alcohol and obesity are associated with increased nucle-
material in the dermis or subcutaneous tissues, surrounded by a marked
otide catabolism and decreased urate excretion.15–17 Not surprisingly, more
granulomatous response in which many giant cells are usually evident (Figs
recent studies indicate a close relationship with the metabolic syndrome,
13.132, 13.133). Calcification may be a late complication. In secondarily
and as a consequence patients with gout also have an increased risk of dia-
infected lesions, a neutrophil polymorph infiltrate is sometimes present.37 In
betes, myocardial infarction, and premature death.8,18 Certain medications,
alcohol-fixed sections, the deposits are seen to be composed of needle-shaped
including diuretics (loop and thiazide), low-dose aspirin, and ciclosporin
brown crystals, which lie in bundles and show negative birefringence with
increase the risk of gout.14,19 With chronicity, a disabling and often crippling
polarized light and a first-order red compensator filter (Figs 13.134,
arthritis may develop, particularly affecting the hands and feet.3 Subsequently,
13.135).38
uric acid crystal deposition in skin and soft tissues produces gouty tophi;
these nodules are seen most commonly on the external ear, but also over the
elbows and on the digits (Fig. 13.130). When large, they often discharge a
chalky material. Rare clinical presentations include bullous lesions, a fun-
gating mass, and sparing of hemiplegic limbs by the tophi.20–22 Nowadays,
only a minority of patients present with tophi because of improvement in
the diagnosis and treatment of the disease.23 Tophi are rarely the first mani-
festation of the disease.24,25 They have exceptionally been described in the
mitral valve, breast, nose, cervical spine, sacroiliac joint, larynx, and eyes.26–32
Bone involvement gives rise to characteristic lytic lesions in the distal sub-
chondral region of the digits.4 Fracture due to bone erosion has been
reported.33
Renal disease, which is an important complication, presents as urate
nephropathy and/or uric acid nephrolithiasis.18,34,35 In secondary types asso-
ciated with increased cell turnover, including myeloproliferative disease and
multiple myeloma, acute precipitation of uric acid crystals sometimes occurs
in the collecting ducts of the kidney during chemotherapy. Uric acid neph-
ropathy may also develop in patients with the inherited variants. Patients
present with acute renal failure. More commonly, in primary gout, renal
stones are a feature, and chronic urate nephropathy (due to deposition of
monosodium urate monohydrate salt crystals in the interstitial tissues of the
kidney), presenting as mild proteinuria and hypertension, occasionally
develops.4 Uric acid stones develop in about 40% of patients with gout sec- Fig. 13.131
ondary to myeloproliferative diseases and in 10–25% of patients with the Gout: characteristic needle-shaped crystals. By courtesy of G.T. McKee, MD,
primary variants.4 Massachusetts General Hospital, Boston, USA.
Gout 563
A A
B B
Fig. 13.132 Fig. 13.134

Gout: (A) circumscribed deposits of uric acid are scattered within the dermis, note (A, B) Gout: characteristic needle-shaped uric acid crystals are seen in alcohol-fixed
the accompanying fibrosis; (B) formalin fixation has destroyed the uric acid crystals and anhydrous processed material.
to leave amorphous eosinophilic material.
Fig. 13.135
Fig. 13.133 Gout: the crystals display striking birefringence when viewed with polarized
Gout: multinucleate giant cells are present. light.
Ochronosis Exogenous ochronosis

The term ‘ochronosis’ was first used by Virchow in 1866 to describe a Clinical features
clinical condition in which blue–black cutaneous pigmentation in the Deposition in the skin of an identical pigment to that seen in alkaptonuria
skin was associated with the microscopic deposition of an ochre-colored may occur as a result of the application of phenol (carbolic acid) to leg
pigment. There are two main types: alkaptonuria and exogenous ulcers, therapy with resorcinol and picric acid, the oral and intramuscular
ochronosis. administration of antimalarials such as chloroquine, and the application to
dark skin of bleaching creams containing hydroquinone, most often in
black women.23–32 Antimalarials result in slate-gray pigmentation affecting
Alkaptonuria the knees, face, palate, and subungual regions.33 In hydroquinone-induced
ochronosis, lesions occur particularly over bony prominences such as the
forehead, temples, nose, and lower jaws and also on the sides of the neck
Clinical features (Fig. 13.136).34 Time to onset of lesions is approximately 6 months. The
This is an autosomal recessively inherited condition (with an approximate first stage is characterized by erythema and mild hyperpigmentation.24
incidence of 1:106) in which deficiency of homogentisate 1,2-dioxygenase Subsequently, the hyperpigmentation intensifies and patients develop wide-
(HGD) in the liver and kidneys (necessary for the catabolism of phenyla- spread ‘caviar-like’ black papules; cutaneous atrophy and colloid milia
lanine and tyrosine) leads to the accumulation of homogentisic acid may also occur.34 In longstanding disease, nodules develop.24,35–37
(2,5-hydroquinone acetic acid) in cartilage, tendon, skin, and fibrous tis- Hydroquinone-induced ochronosis is a major problem in the black popula-
sue.1–4 The condition is particularly seen in patients of Eastern European tion of South Africa. In one series the prevalence among users of skin light-
origin, mainly those from Slovakia where the incidence is as high as eners was almost 70%.28 The reason for the high incidence of ochronosis
1:19 000.5 Clinical features relate particularly to joint and cardiovascular in this population is not entirely clear but is thought to be due in part to
involvement, renal and prostatic stones, and ocular and cutaneous lesions. high concentrations of hydroquinone used in their products and the syner-
Alkaptonuria, or blackening of the urine after standing or alkalinization gistic effect of multiple compounds used in combination with hydroqui-
due to oxidation of homogentisic acid, usually becomes obvious in child- none such as mercury and resorcinol, which can also cause ochronosis.24
hood. Most patients present with either dark urine or early-onset arthritis. Exogenous ochronosis due to hydroquinone is thought to be photoacti-
The blue–black discoloration of the tissues (known as ochronosis) is due vated. Exogenous ochronosis tends to chronicity. In addition to causing
in part to the Tyndall effect. ochronosis, hydroquinones containing bleaching creams have been shown
The cutaneous changes develop later, at about 30–40 years of age. They to be carcinogenic in rodents. As a result, in 2006, the US Food and Drug
are seen particularly on sun-exposed skin and areas with maximum numbers Administration proposed a ban on all over-the-counter bleaching creams
of sweat glands.1–4 Deposition of polymerized oxidase pigment in the ear car- containing hydroquinone.29
tilage produces painful thickening and blue–black speckled discoloration.
Involvement of the eardrum and ossicles may result in tinnitus and deafness.4 Pathogenesis and histological features
Subsequently, discoloration of the sclera, conjunctiva, tendons, and skin of
In alkaptonuria, as a result of the deficiency of homogentisate 1,2-dioxy-
the face, hands, and flexures occurs.6 A rare case of vaginal hyperpigmenta-
genase, homogentisic acid is oxidized and polymerized by polyphenol
tion has been reported.7 The skin pigmentation may be more prominent on
oxidase to form benzoquinone acetic acid. This results in a black pigment
the palms and soles.8 Finally, a characteristic arthritis, which is often severe,
that binds irreversibly to collagen. Polyphenol oxidase is particularly com-
develops in almost all patients.9 Low back pain is followed by involvement of
mon in cartilage and skin and this reflects in their preferential involvement.
the large joints of the limbs. Spinal involvement leads to disc herniation,
spondylosis, and osteophytosis with resultant limitation of movement and
loss of height.1,10 Musculoskeletal disease caused by alkaptonuria can be
severe and result in significant disability.12 Despite widespread morbidity,
alkaptonuria is not associated with significant mortality, and life expectancy
is typically normal.1
Osteoarticular involvement – which is particularly evident in the
knees, shoulders, and hips, and in advanced cases the vertebral column –
is characterized by pigmentation of the articular cartilage, synovium,
and capsule associated with fibrillation, fragmentation, calcification,
and erosion. 11,12 Osteoarthritis may also be evident and chronic
n on-specific synovitis is commonly present. Cardiovascular involvement
occurs in up to 50% of patients and mainly consists of pigmentation and
calcification of the aortic valve, which may lead to stenosis. 13–15
Cardiovascular pigmentation, which is especially seen on the endocar-
dium and valves (aortic and mitral), also affects the intima and media of
arteries. Surprisingly, even with heavy pigment deposition and smooth
muscle cell degeneration, aneurysm formation is not a feature of vascular
involvement.16
In up to 60% of patients the kidneys typically show very marked pigmenta- Fig. 13.136
tion, especially involving the pyramids and calculi.17 Ochronotic prostatic stones Exogenous ochronosis:
hyperpigmented plaque
are a nearly invariable feature, but bladder calculi are much less frequent.4,16
with numerous colloid
Asymptomatic ocular involvement is seen in up to 70% of patients.18
milia in a Bantu female.
Pigmentation particularly affects the sclera and to a lesser extent the conjunc- The lesions developed
tiva and cornea.6,16 The lesions are typically noninflammatory. as a consequence
Ochronotic pigmentation is frequently seen in the hyaline cartilage of the of the application of
larynx, trachea, and bronchi.16,19 Involvement of endocrine organs, central hydroquinone bleaching
nervous system, and teeth is rare.20–22 cream.
Pellagra 565
The pigment formed has not been characterized but there are some simi-
larities to melanin.38 It appears that the pigment deposition occurs both in
previously damaged collagen and in normal collagen. The gene responsi-
ble for alkaptonuria has been localized to chromosome 3q.23-21.39–41 The
human homogentisate 1,2-dioxygenase gene has been cloned and it has
been shown that patients with alkaptonuria carry two copies of a loss-of-
function homogentisate 1,2-dioxygenase allele.42 Over 91 different genetic
mutations have been identified thus far in the HGD gene.41 A study of
patients with alkaptonuria has demonstrated that they have a significantly
higher prevalence of HLA-DR7 than those without the disease.43
The exact pathogenesis of exogenous ochronosis is not known. Proposed
mechanisms include:
• the inhibition in the skin of homogentisate 1,2-dioxygenase by
hydroquinone with formation of pigment, 44
• increased tyrosinase activity induced by hydroquinone.23
Ochronosis presents as yellow–brown, sharply defined, irregularly shaped
and frequently fragmented fibers in the superficial dermis (Fig. 13.137).1,26
The ochronotic pigment is autofluorescent, appears black with methylene
blue, but does not stain with van Gieson, Perl's stains or the Masson-Fontana
reaction.1 Pigment granules are often present in the epithelium and basement
membrane of sweat glands, in endothelial cells, and within dermal
macrophages.16,19
In ochronosis due to hydroquinones the skin may, in addition, show Fig. 13.138
Exogenous ochronosis:
melanophages in the upper dermis associated with depigmentation of the
early lesion showing
epidermal melanocytes.35 markedly swollen collagen
In early lesions the collagen fibers appear basophilic and swollen before fibers.
developing the characteristic yellow ochronotic morphology (Fig. 13.138).
With chronicity, large amorphous eosinophilic granules may develop, resem-
bling colloid milium.35 Solar elastosis and foreign body granulomata (some- Hartnup disease
times indistinguishable from sarcoidosis) are less common features.26,27,37,45
An actinic granuloma-like variant has been described.36 Transepidermal and Clinical features
transfollicular elimination of ochronotic fibers has occasionally been
Hartnup disease is an autosomal recessive disorder characterized by defective
documented.37,46
gastrointestinal absorption and renal reabsorption of monoamine and mono-
Antimalarial pigmentation is due to melanin and hemosiderin deposition
carboxylic amino acids due to a defect in the neutral brush border system.1
in addition to the classical ochronotic fibers.1
One of the effects is tryptophan deficiency.2 The disease typically presents in
Electron microscopic studies have shown that initially electron-dense
childhood. In addition to a pellagra eruption (see below), patients also have a
ochronotic pigment is deposited around swollen collagen fibrils that charac-
characteristic aminoaciduria and cerebellar ataxia.3,4 An uncommon cutane-
teristically lose their banding pattern.35 These fibrils subsequently degenerate
ous manifestation is an acrodermatitis-like eruption involving the perioral
until the whole collagen fiber is replaced by amorphous ochronotic pigment.
region, perineum and acral skin.5 The disease may, however, sometimes be so
Rupture of the fibrils also occurs, so that the pigment comes to lie scattered
mild as to remain asymptomatic.6 Additional symptoms include diarrhea and
free in the dermis. Phagocytosis of the latter by macrophages and giant cells
central nervous system dysfunction ranging from mild apathy to psychosis
may be seen.16,26 The colloid milium-like deposits in hydroquinone-associated
and frank dementia.7 An exceptional case of a patient with identical symp-
ochronosis consist of electron-dense granular material lacking a significant
toms and signs of Hartnup disease in the absence of a recognized metabolic
fibrillar component.35
abnormality or aminoaciduria has been described.8 The disease has been
mapped to chromosome 5p15 and the defective gene is SLC6A19, a sodium
dependent neutral amino acid transporter.9–11
The cutaneous histology is identical to that of pellagra (see below).
Pellagra
Clinical features
Pellagra develops as a consequence of deficiency of nicotinic acid (niacin,
vitamin B3) or its precursor tryptophan.1–3 The cause may be dietary. It has
traditionally been associated with high consumption of corn.3 In developed
countries it is most frequently observed in alcoholics, in those living in condi-
tions of socioeconomic deprivation, and in patients with anorexia nervosa or
malabsorption due to extensive gastrointestinal disease (e.g. partial gastrec-
Fig. 13.137 tomy, gastroenterostomy, and Crohn's disease).1,4 A severe case of cytomega-
Ochronosis: typical lovirus colitis in an immunocompetent patient has also been associated with
swollen, irregular, golden- pellagra.5 It is sometimes also a feature of the carcinoid syndrome because the
brown fibers are seen tumor cells consume available tryptophan to produce serotonin.5,6 Pellagra
(bottom left). occasionally develops after therapy with a number of drugs including
isoniazid, 6-mercaptopurine, and 5-fluorouracil.6–10 Finally, it can occur in Histological features

Hartnup disease and in association with defects in the metabolism of trypto-
The appearances in pellagra are usually non-specific. There is hyperkeratosis,
phan.11 Pellagra is particularly prominent in parts of Africa and Asia where
parakeratosis, and acanthosis associated with increased melanin pigmenta-
nutritional deficiencies are prevalent.1 A rare case has been described in asso-
tion and, in early lesions, keratinocyte vacuolation in the upper reaches of the
ciation with the intake of alternative medicines.12 A further report describes
epidermis.7,8 Telangiectasia and a perivascular chronic inflammatory cell infil-
an association with amyloidosis secondary to multiple myeloma.13
trate in the upper dermis may also be evident. Older lesions sometimes show
The classic triad of pellagra is ‘dermatitis, diarrhea, and dementia’. The
epidermal psoriasiform hyperplasia.14 In some instances the histology can
skin eruption of pellagra is photosensitive in nature. An initial painful sun-
resemble that of necrolytic migratory erythema and acrodermatitis
burn-like erythema subsides to leave a dusky brownish discoloration with a
enteropathica.
dry scaly appearance (Figs 13.139, 13.140). Blisters may sometimes be
evident. The eruption is typically sharply demarcated, symmetrical, and Differential diagnosis
occurs on the backs of the hands (most commonly), the forearms, the knees,
central chest, neck, and face.7 The thickened skin around the photoexposed The diagnosis is very much dependent upon clinicopathological correlation,
skin of the neck typically resembles a necklace (Casal's necklace). Other particularly in those cases that resemble necrolytic migratory erythema and
features sometimes present include cheilosis, glossitis, angular stomatitis, and acrodermatitis enteropathica.
oral or perianal sores.3,7
Gastrointestinal disease in pellagra manifests as nausea, vomiting, abdom-
inal pain, gastritis, and diarrhea. Neurological involvement evolves, with
Scurvy
headache, depression, and ataxia initially and more severe symptoms of Clinical features
disorientation, delirium, and coma and eventually death.3
Scurvy, due to vitamin C deficiency, results from a diet inadequate in fresh
fruit and vegetables and is nowadays most often encountered following inap-
propriate dieting, food fads, and in alcoholics and socially isolated individu-
als.1 Scurvy is rare in children but does occur in those with developmental and
psychiatric disorders. It may also be secondary to drinking boiled or evapo-
rated milk which is deficient in vitamin C.2
Cutaneous manifestations include dry skin, follicular hyperkeratoses par-
ticularly affecting the forearms, legs and abdomen, perifollicular hemorrhages
especially affecting the legs, petechiae and subungual splinter hemorrhages,
leg edema, alopecia, erythematous, swollen and bleeding gums with tooth
loss, and clinical evidence of poor wound healing.1–4 Painful subperiosteal
hemorrhage, ‘Barlow's disease’, is characteristically seen in infants.2 Less spe-
cific manifestations which may cause a delay in diagnosis include fatigue,
arthralgia, and myalgias.3

Vitamin C is necessary for hydroxylation of proline and lysine residues dur-
ing the conversion of procollagen into collagen fibers. As a result of impaired
collagen synthesis, basement membrane synthesis is defective, with conse-
quent loss of blood vessel wall integrity. This, combined with impaired der-
mal connective tissue constituents, results in a bleeding tendency.
Fig. 13.139 The cutaneous features include follicular dilatation and keratin plugging,
Pellagra: scaling and hyperpigmentation are present on the dorsal aspect of the perifollicular hemorrhages with chronic inflammation, and hemosiderin
knuckles and fingers. By courtesy of the Institute of Dermatology, London, UK.
deposition.4–7 The alopecia is characterized by hair shaft fracture and
corkscrew hairs within a dilated and plugged follicle (Fig. 13.141).1,4,8
Calcinosis cutis
Calcinosis cutis may occur when connective tissue is abnormal (dystro-
phic) or where calcium or phosphate levels in the blood are high
(metastatic); alternatively, there may be no obvious underlying cause (idio-
pathic) (Table 13.5).1–3
Dystrophic calcinosis cutis

Clinical features
In this, the most common variant of calcinosis, the changes are limited to the
dermis and subcutaneous tissues and there is no involvement of internal
organs. This form of calcinosis always occurs in tissue that has been previ-
ously damaged either by external agents or as the result of a disease. Under
this variant, iatrogenic calcinosis cutis induced by local application of
chemicals or medications is also included. In the localized form of dystrophic
calcinosis cutis, the underlying anomaly may be inflammatory or traumatic in
Fig. 13.140 nature, for example acne scars, burns, fat necrosis or subcutaneous and
Pellagra: close-up view of hyperpigmentation and scaling. By courtesy of the Institute intramuscular injections.4,5 Calcification and necrosis have been reported
of Dermatology, London, UK. following electroencephalography and electromyography.6,7 Calcification is a
Calcinosis cutis 567
Fig. 13.141
Scurvy: the hair follicle
is dilated and there is a
typical corkscrew hair cut
in multiple planes. Note Fig. 13.142
the surrounding chronic Dystrophic calcinosis cutis: calcification has developed in this ruptured cyst.
inflammation and red cell
extravasation. By courtesy
of S. Tahan, MD, Beth
Israel and Deaconess
Medical Center, Boston,
USA.
Table 13.5
Classification of calcinosis cutis
Type Distribution Clinical features

Dystrophyic Localized Acne scars; fat cell necrosis;
Widespread epidermoid cysts; pilomatrixoma;
infantile calcinosis of the heel
Dermatomyositis; systemic lupus
erythematosus; Ehlers-Danlos
syndrome; pseudoxanthoma
elasticum
Metastatic Hypercalcemic Hyperparathyroidism; sarcoidosis;
vitamin D excess; milk alkali
syndrome; destructive bone disease
Normocalcemic Chronic renal failure; Fig. 13.143
pseudohypoparathyroidism Iatrogenic calcinosis cutis: this widespread dermal calcification followed calcium
Idiopathic Generalized Calcinosis universalis gluconate infusion.
Localized Subepidermal calcified nodule;
localized idiopathic dermal
calcinosis; tumoral; scrotal
nodules which can ulcerate. They usually develop within a few weeks of expo-
sure.18 Deep soft tissue calcification has been described in association with
pentazocine and pitressin.19,20 Similar reactions following calcium-containing
characteristic feature of pancreatic disease-associated panniculitis and in heparin in patients with renal insufficiency have also been reported.21,22
older lesions of subcutaneous fat necrosis of the newborn. Auricular calcifica- Widespread dystrophic calcification occurs most commonly as a sequel to
tion (also known as ‘petrified ear’) may occur as a result of chondritis, trauma connective tissue disease (Figs 13.144, 13.145). Localized dystrophic calcifi-
or frostbite.1,8,9 Less commonly, it is associated with hypercalcemia associated cation with bone formation has also been described in mixed connective tis-
with systemic disorders and endocrinopathies.8,9 A distinct example of dys- sue disease.23 Dermatomyositis, especially in children, may be complicated by
trophic calcification is infantile calcinosis cutis of the heel, in which calcific extensive deposits of calcium in the skin and subcutaneous tissues, as well as
dermal nodules develop approximately 1 year after birth in infants who have in muscles and tendons. Scleroderma, especially the CREST variant, tends to
had multiple heel punctures for venesection.10,11 show localized deposition of calcium, particularly on the digits and over bony
Localized dystrophic calcinosis may also complicate epithelial cysts or prominences. Fingertip lesions are a common presentation in patients with
neoplasms (Fig. 13.142).12 It is particularly seen within the keratin of trichil- Raynaud's phenomenon (with or without underlying connective tissue dis-
emmal cysts. Calcification may occur in many adnexal tumors, for example ease) and have also been reported in a patient with Sjögren's syndrome who
pilomatrixoma and trichoepithelioma. It is much more common in basal cell did not have Raynaud's.24,25 Systemic lupus erythematosus is infrequently
carcinoma than in squamous cell carcinoma.13,14 Subungual epidermoid associated with calcinosis.26,27 It is usually an incidental radiological observa-
inclusions are rare tumors of the nail bed in which calcification may occur.15 tion, most commonly seen in the buttocks and extremities and unassociated
Calcinosis cutis has also been documented following the intravenous with panniculitis. Mostly it develops in patients with severe acute disease
administration of calcium chloride, phosphate, and gluconate (iatrogenic cal- including cardiac, renal or central nervous system (CNS) manifestations.2 It
cinosis cutis) (Fig. 13.143).16–18 Lesions consist of multiple, erythematous also appears to correlate with high doses of corticosteroids and myositis.28,29
Fig. 13.144 Fig. 13.146

Dystrophic calcinosis cutis: this large deposit is associated with focal ulceration Metastatic calcinosis cutis: there are gross deposits, many ulcerated. By courtesy
and transepidermal elimination. By courtesy of the Institute of Dermatology, of R.A. Marsden, MD, St George’s Hospital, London, UK.
London, UK.
Metastatic calcinosis cutis

Clinical features
Metastatic calcification occurs as a result of hypercalcemia or hyperphos-
phatemia as may be seen in chronic renal failure, hyperparathyroidism, and
sarcoidosis.38–41 Calcium deposits occur in the skin, subcutaneous tissues,
muscle, tendon, and internal organs. In the skin, the clinical appearances are
of hard nodules and plaques, which may ulcerate to liberate chalky material
and ultimately leave a scar (Fig. 13.146). This may be particularly frequently
seen over large joints, the iliac crest or in the flexures. Fingertip lesions are
usually very painful. A case report describes a patient with vulvar cystic nod-
ules and hyperphosphatemia.42
Albright's hereditary osteodystrophy is a genetic disorder associated with
end-organ resistance to parathyroid hormone. Patients present in infancy or
childhood with obesity, short stature, mild mental retardation, shortened
fourth and fifth metacarpals, and cutaneous calcification.43,44 The skin lesions
are typically multiple erythematous to purpuric papules, plaques, and nod-
ules on the trunk and extremities.
Vascular calcification with thrombosis may lead to livedo reticularis, ulcer-
Fig. 13.145 ation, and gangrene, particularly affecting the hands, fingers, toes, and lower
Dystrophic calcinosis cutis: multiple digital deposits are present. By courtesy of the legs (so-called clinical calciphylaxis).41,45,46 A frequent complication is sepsis
Institute of Dermatology, London, UK. and this often results in death. Patients usually have chronic renal failure in
association with hyperphosphatemia and hyperparathyroidism.47–49 Other
conditions associated with calciphylaxis include hypervitaminosis D and A,
hypercalcemia, primary or secondary hyperparathyroidism, AIDS, and pro-
Calcification complicating discoid lupus erythematosus and subacute lupus tein C deficiency.50,51 The exact mechanism of calciphylaxis is not clear but it
erythematosus is limited to a few case reports.30,31 Lupus panniculitis and seems to be related to an imbalance in calcium and/or phosphorus metabo-
other types of panniculitis (including pancreatic fat necrosis) may also be lism.52 Rarely, the condition occurs in patients with normal levels of calcium
associated with calcification.32 Patients with porphyria cutanea tarda rarely and phosphorus.52
develop calcinosis cutis. Lesions are most common on the scalp, neck, preau-
ricular area, and hands, and are more likely to develop in patients with scle-
rodermoid disease.33 Calcium is also deposited in inherited connective tissue
Idiopathic calcinosis cutis
disorders, especially Werner's syndrome, pseudoxanthoma elasticum (PXE),
and Ehlers- Danlos syndrome, in which small calcific nodules typically Clinical features
develop within atrophic scars over bony prominences. Alternatively, dystro- There are six main clinical types of calcinosis in which there is no known pre-
phic calcification in PXE may occur as large, painful, pruritic nodules in areas disposing condition:
involved by the underlying disease.34 • In calcinosis universalis, there is progressive deposition of calcium in the
Calcification has recently been described in patients with nephrogenic sys- skin and subcutaneous tissue, producing discharging hard nodules and
temic fibrosis, associated with the cutaneous lesions as well as in fascia and plaques very similar clinically to those seen in metastatic calcification.
muscle.35,36 The etiology of calcification in this disease is debated. Some Some cases may represent dermatomyositis in which the acute phase was
believe it occurs secondarily as part of a dystrophic process while others con- not diagnosed.
tend that calcification is intrinsic to the pathological process, particularly as • In contrast, idiopathic calcinosis may occur as a solitary nodule on the
it is also seen in vessels, in patterns resembling calciphylaxis.37 extremities and face, particularly the eyelids (subepidermal calcified
Calcinosis cutis 569
Fig. 13.147
Tumoral calcinosis: bilateral nodules over the elbows, with perforation on the
patient’s left. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Fig. 13.149
Tumoral calcinosis: subcutaneous deposits are present overlying the thigh and
lateral border of the knee. By courtesy of R.A. Marsden, MD, St George’s Hospital,
London, UK.
• Finally, milia-like idiopathic calcinosis cutis is a rare condition seen in

children (usually under the age of 21 years).61,62 Lesions are multiple, skin
colored to whitish papules with a generalized distribution. Perforation
may occur. Two-thirds of cases have been associated with Down's
syndrome and up to one-third of patients have coexisting syringomata.
Lesions resolve spontaneously without scarring.

Calcium stains blue with hematoxylin and eosin. In calcinosis cutis a rather
homogeneous deep blue material is seen, either as small superficial deposits
or as deeper globular ones (Fig. 13.150). Owing to the concomitant presence
of phosphate and carbonate, the deposit stains black with the Von Kossa
stain (Fig. 13.151).
The presence of calcium in the skin variably excites a foreign body reac-
tion, so giant cells are sometimes seen at the edge of the deposit. On other
occasions a chronic inflammatory cell infiltrate is present. Transepidermal
Fig. 13.148 elimination of calcified debris is sometimes a feature.4
Tumoral calcinosis: these small deposits are undergoing transepidermal elimination. Dystrophic calcification due to extravasation of intravenous solutions
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. containing calcium is characterized by dermal calcium surrounding degener-
ated collagen bundles.18 Lesions caused by calcium-containing heparin also
demonstrate calcium in fat lobules, surrounding adipocytes, in septae as well
nodule, cutaneous calculus).53,54 It usually presents in early childhood and as within the media of small vessels in the subcutaneous fat and dermis.22
is more common in males; the majority of the nodules are hyperkeratotic There may be fibrosis of vessel walls; however, thrombosis is not a usual
and tender on palpation. Rarely, it may be present at birth and feature.20,22
occasionally multiple lesions are present.55 In calciphylaxis, there is prominent calcification of walls of dermal and
• Localized idiopathic dermal calcinosis may also occur as a solitary subcutaneous small blood vessels (Fig. 13.152).52 Often, the findings also
nodule on the limbs.56,57 The fingers and elbows are particularly affected.1 include some degree of intimal proliferation and thrombosis. These changes
An equivalent lesion, designated oral mucosal calcified nodule, which result in prominent ischemic necrosis. Calcification of the subcutaneous fat
affects the gingiva and tongue, has recently been documented.58 accompanied by lipophagic necrosis may also be seen.
• In tumoral calcinosis, large deposits of calcium are present in the skin The pathogenesis of calciphylaxis is not completely understood. Recent
and subcutaneous tissues, typically over bony prominences (hip, elbow, studies point to osteopontin as a possible factor.63 Osteopontin is a phospho-
and scapula) (Figs 13.147, 13.148). It is rare in Europe and North protein adhesion molecule with a high affinity for calcium. It is normally
America, but is not uncommon in South, Central and East Africa and expressed by various cell types, including osteoblasts, osteocytes, fibroblasts,
Papua New Guinea, where it is known as hip stone. It shows a female macrophages, and smooth muscle cells. It plays an important role in bone
preponderance (2:1) and affects younger age groups. These deep deposits remodeling. Previous studies have suggested a role for osteopontin in calcifi-
may be visualized radiologically (Fig. 13.149). cation of heart valves and pilomatrixoma.64,65 A recent study examined its
• Scrotal calcinosis may occur spontaneously. Patients present in childhood presence in calciphylaxis and demonstrated expression in the media and, less
or early adulthood with multiple, asymptomatic, flesh-colored or yellow often, the intima of vessel walls and surrounding adipocytes in the subcutane-
nodules of varying sizes, which often release granular chalky material.59 A ous fat in areas involved by calcification.63 The authors speculate that calci-
similar finding on the penis has also been reported in young men with no phylaxis may be caused by osteogenic differentiation of vascular smooth
prior history of trauma and without a known underlying adnexal lesion.60 muscle cells.
Fig. 13.150
Calcinosis cutis: (A) small deposits of intensely basophilic
A B material are present in the superficial dermis; (B) these
calcium deposits are associated with scarring.
Fig. 13.151 Fig. 13.152

Calcinosis cutis: the calcified deposit stains positively with the Von Kossa reaction. Calciphylaxis: note the subendothelial calcification and thrombosis.
Calcification deposits in nephrogenic systemic fibrosis occur in the dermis, eosinophilic debris undergoing calcification. In advanced lesions, densely calci-
associated with CD34-positive spindled cells and in the media of small arteries fied material is seen embedded in hyalinized connective tissue. The occasional
in the deep dermis and subcutaneous fat, similar to that seen in finding of necrobiosis and vasculitis may have pathogenetic significance.
calciphylaxis.37 The pathogenesis of the scrotal variant is most probably calcification of
A report of an exceptional case of metastatic calcification showed calcifi- the contents of pre-existent dermal cysts, mostly epidermoid, but occasionally
cation only of sweat ducts.66 pilar.62,68–72 Some authors have failed to detect an epithelial component;43
There may be histological evidence of the underlying disease process. however, this may be a reflection of the age of the lesion. A recent study of 20
In localized dystrophic calcinosis, for example, there is sometimes evidence of cases identified residual epidermal cysts in 14.71 In many examples, typical
a preceding epidermoid cyst. In widespread dystrophic calcinosis cutis epidermoid lining epithelium surrounds the calcified deposit and sometimes
secondary to connective tissue disease, there is occasionally evidence of residual keratinous contents are visible. A foreign body giant cell reaction is
preceding collagen degeneration. not uncommon.
In a subepidermal calcified nodule, there is sometimes pseudoepithelioma- The etiology of milia-like calcinosis cutis is unclear. Theories include
tous hyperplasia, associated with transepidermal elimination of calcium. increased calcium content of excreted sweat and calcification of a pre-existing
In tumoral calcinosis the histological features depend upon the stage of evo- cyst.61 Histologically, there is a focus of calcium in the papillary dermis sur-
lution of the lesion (Figs 13.153–13.155).67 In early examples, multiple cystic rounded by a lymphocytic infiltrate and giant cells. Perforation may be
spaces lined by epithelioid and giant cells are seen. The cyst lumina contain present.61,62 Cyst epithelium is not present.
The mucinoses 571
The mucinoses
The mucinoses are a group of conditions in which accumulation of acid gly-
cosaminoglycans (mucin), particularly hyaluronic acid and to a lesser extent
chondroitin (-4 and -6) sulfate and heparin, occurs either diffusely or focally
in the dermis (Table 13.6).1–6 Mucinosis also may occur as a secondary phe-
nomenon in dermatoses such as lupus erythematosus, scleroderma, dermato-
myositis, Degos' disease, granuloma annulare, and chronic graft-versus-host
disease.5,7 In this chapter, however, only primary cutaneous mucinoses are
discussed.
The glycosaminoglycans, which are secreted by fibroblasts, are constitu-
ents of normal cell membranes and connective tissue. This substance is usu-
ally secreted in only small amounts by fibroblasts. It is not clear why mucin
production is increased in pathological states. Although the cause is probably
multifactorial, it has been suggested that cytokines and/or immunoglobulins
and unidentified factors in the serum of affected patients can induce synthesis
of glycosaminoglycans.5,8–10 Cytokines that play an important role in this pro-
cess include tumor necrosis factor, interleukin-1, and transforming growth
Fig. 13.153 factor beta (TGF-β).5,11,12 Actively secreting fibroblasts have a characteristic
Tumoral calcinosis: this low-power view shows a dense hyalinized stroma with stellate shape and contain intracytoplasmic secretory vesicles; their presence
numerous cystic cavities containing necrotic and calcified debris. in sections should therefore prompt a careful search for mucin deposition
(Figs 13.156–13.158).
Table 13.6
Classification of the dermal mucinoses
Diffuse
lichen myxedematosus – generalized form (scleromyxedema)
scleredema
reticular erythematous mucinosis
generalized myxedema
pretibial myxedema
Focal
lichen myxedematosus – discrete papular form
acral persistent papular mucinosis
papular and nodular mucinosis associated with lupus erythematosus
self-healing juvenile cutaneous mucinosis
cutaneous mucinosis of infancy
cutaneous focal mucinosis
myxoid cyst
Follicular
follicular mucinosis
Fig. 13.154
Tumoral calcinosis: early lesions characteristically show a histiocytic and giant cell
palisade around eosinophilic, degenerate connective tissue.
Fig. 13.155 Fig. 13.156

Tumoral calcinosis: in older lesions, calcified deposits lie within lacunae. Myxoma: Note abundant stromal mucin.
Hyaluronic acid stains with colloidal iron (blue–green), Alcian blue at pH

2.5 (blue) (but not at pH 0.4), and mucicarmine (red) but it is negative for
PAS. It also stains metachromatically with toluidine blue, methylene blue,
and thionine.13 Sulfated acid mucins stain with Alcian blue at pH 0.5 and
aldehyde-fuschin.2 Hyaluronic acid absorbs enormous amounts of water,
which accounts for the induration and thickening common to this group of
conditions.14
Routine fixation and processing results in an anhydrous state so that
mucin presents as basophilic strands and granules in hematoxylin and eosin
stained sections.3 In normal skin it is found particularly around appendages
and the vasculature (Fig. 13.159). In the cutaneous mucinoses the deposits
are hyaluronidase sensitive because most of the mucin present is hyaluronic
acid. The excessive mucin disrupts the collagen fibers, giving them a frayed
appearance. In general, with the exception of scleromyxedema, there is con-
siderable histological overlap within this group of conditions. Diagnosis
depends considerably upon clinical features and the results of biochemical
investigations.14
There are five major mucinoses:
• generalized myxedema,
Fig. 13.157
Mucinosis: this electron micrograph from a patient with acral persistent papular
• pretibial myxedema,
mucinosis shows collagen bundles widely separated by a faintly electron-dense
• lichen myxedematosus,
granular deposit. • reticular erythematous mucinosis,
• scleredema.
Follicular mucinosis is considered in Chapter 29.
Generalized myxedema
Clinical features
Generalized myxedema occurs as a consequence of severe hypothyroidism.
Patients with myxedema may appear pale yellow due to the combined effects
of edema, anemia, and carotenemia.1,2 The last, which is due to defective con-
version of betacarotene to vitamin A in the liver, is seen particularly on the
palms, soles, and in the nasolabial folds.3 Rarely, the color change is general-
ized.4 The skin is cool, dry, coarse, waxy, and puffy, especially around the eyes
and cheeks, and the hands and feet may show nonpitting edema (Fig.
13.160).3,5–7 The face is often expressionless. Eccrine and sebaceous gland
secretions are reduced and this may result in xerosis, an ichthyotic appear-
ance or asteatotic eczema.4 Hyperkeratosis over bony prominences resem-
bling avitaminosis A is also sometimes evident.8 Alopecia is a common finding
and the outer third of the eyebrows is typically affected. There is usually thin-
ning of the beard and sexual hair in addition to loss of the scalp hair.
Myxedema is associated with a greatly increased percentage of hair follicles
A in the telogen phase.9 The rate of hair growth is also diminished. Residual
Fig. 13.158
Mucinosis: (A) actively secreting fibroblasts contain abundant rough endoplasmic Fig. 13.159
reticulum; (B) numerous intracytoplasmic vesicles containing amorphous material Eccrine sweat gland: this section of normal skin from the sole of the foot shows
are commonly present. abundant dermal mucin when stained with Ehrlich’s hematoxylin.
The mucinoses 573
Fig. 13.161
Fig. 13.160 (A, B) Generalized
Generalized myxedema: myxedema: this
note the waxy infiltrated patient has widespread
plaques on the eyelid. xanthomata.
By courtesy of R.A. By courtesy of the
Marsden, MD, St George’s A Institute of Dermatology,
Hospital, London, UK. London, UK.
hair is dry, coarse, and brittle.3 The nails often become thin, brittle, and stri-
ated.1 Additional cutaneous manifestations have included pruritic papular
lesions, purpura and ecchymoses, impaired healing, generalized follicular
mucinosis, and multiple focal cutaneous mucinoses.1,5,9–11 Oropharyngeal and
laryngeal involvement is common and many patients are hoarse. Patients
with myxedema have an increased risk of developing hyperlipidemia with
resultant eruptive and tuberous xanthomata (Fig. 13.161).
The epidermis may show mild hyperkeratosis with occasional follicular
plugging.3 Most frequently, the dermal changes are subtle and nondiagnos-
tic. However, in cases of greater severity, there is slight swelling and separa-
tion of the collagen bundles with edema, and special stains show that small
quantities of mucin are present within the dermis and occasionally in the
subcutaneous fat.12 Fibroblastic proliferation is not a feature of generalized
myxedema.13 B
Localized (pretibial) myxedema

be involved.9 Small lesions are usually asymptomatic or mildly p ruritic; the
Clinical features larger plaques are often painful.10 Infrequently, localized myxedema occurs
Localized (pretibial) myxedema is most often associated with hyperthyroid- on other sites such as the arms, shoulders, abdomen, neck, face, and even
ism.1 It occurs in 3–5% of cases.2 It is one of three processes classically seen the ears (Fig. 13.164).11 Nodular lesions rarely occur on the hands.12
in autoimmune thyroid (Graves') disease, the other two being exophthal- Deposition on the forearm has been described as ‘preradial myxedema’.12
mos and thyroid acropachy (clubbing of the digits associated with Occurrence at atypical sites is most likely related to trauma.13 For example,
subperiosteal new bone formation). Pretibial myxedema, also known as it has been described localized to scar tissue.14–16 The latter includes the site
‘Graves’ or thyroid dermopathy', is usually a late manifestation of Graves' of a smallpox vaccination scar.17 Presentation at the site of a thigh donor
disease and follows the development of Graves' ophthalmopathy.3 It has graft site has also been reported.18
only been reported exceptionally preceding the diagnosis of Graves' disease Rare patients with pretibial myxedema have no evidence of thyroid dis-
and in the absence of ophthalmopathy.4 In 10% of cases of Graves' disease, ease. Biopsies from these patients tend to show changes associated with sta-
patients are not clinically hyperthyroid.5 They may be hypothyroid or euthy- sis and this feature is useful in the histological differential diagnosis.19 One
roid.5 Pink or yellow waxy plaques, nodules, and sometimes ‘tumors’ such variant has been described in morbidly obese patients with
develop, most frequently first on the anterolateral aspects of the lower legs lymphedema.20,21 Lesions occur as papules, vesicles, and nodules on the
(Fig. 13.162). Lesions are classically nonpitting. In some patients there is pretibial surfaces.
induration with prominence of the follicles, giving rise to a peau d'orange Pretibial myxedema is sometimes self-limiting, involution occurring after a
appearance, and secondary hypertrichosis is occasionally marked. Localized number of years. Complete remission occurs in up to 26% of cases but this
hyperhidrosis at the site of the myxedema may also rarely occur.6 The dis- depends on the severity of the disease.5,22
ease may progress to involve much of the lower leg, which rarely becomes An exceptional form of pretibial mucin deposition that may be confused
grossly elephantiasiform (Fig. 13.163).2,7–9 The feet and toes sometimes can with pretibial myxedema associated with Graves' disease has been documented
Fig. 13.162
Pretibial myxedema: Fig. 13.163
(A) erythematous, Pretibial myxedema: in
somewhat translucent this extreme example,
plaques are present over the features resemble
the shin; (B) close-up view. elephantiasis. By courtesy
By courtesy of R.A. of R.A. Marsden, MD,
A Marsden, MD, St George’s St George’s Hospital,
Hospital, London, UK. London, UK.
Localization to the legs most typically is thought to be due to dependency

and mechanical factors.3 Additionally, tobacco is a known risk factor for the
development of pretibial myxedema and Graves' ophthalmopathy; however,
the precise mechanism for this is presently unknown.3
The epidermis is often hyperkeratotic, with follicular plugging; in
gross cases it may be papillomatous and acanthotic. The reticular dermis
shows separation of collagen bundles by large quantities of mucin (Figs
13.165, 13.166).1 Fragmentation of collagen fibers can be seen.3 Stellate
fibroblasts are evident, but there is usually no increase in their number
except perhaps in the more elephantiasiform examples. Lesions seen in
the setting of lymphedema and obesity are also characterized by small
vessel angiogenesis, vessel wall thickening, edema, and hemosiderin
deposition.20,21
Immunofluorescent studies are usually negative, although granular depos-
B its of IgM have been identified within the superficial papillary dermis.10
Electron microscopic studies show amorphous granular material both
within fibroblast endoplasmic reticulum, coating the surface of the fibroblast,
and in the interstitium surrounding the widely separated collagen and elastic
fibers.8 Tubuloreticular structures have been identified in the cytoplasm of
in association with Sjögren's syndrome under the name acral ichthyosiform
endothelial cells in one case and in the dermis of another.10,14
mucinosis.23 In the cases described, the patients had normal thyroid function
tests and the mucin deposition was predominantly in the papillary dermis.
Lichen myxedematosus/scleromyxedema
The etiology is uncertain; the presence of pretibial myxedema is usually asso- Clinical features
ciated with detection of long-acting thyroid stimulator (LATS) in the serum, As originally classified, there were four variants of this rare disease of adults.1
but LATS is not believed to be causal.24 It was suggested in 1978 that a fibro- These were:
blast stimulating factor associated with mucigenic properties isolated from • generalized lichenoid papular eruption (Figs 13.167, 13.168).
the serum of patients with pretibial myxedema might play a role in the patho- • discrete papular variant presenting as much smaller numbers of flesh-colored
genesis of the disease.25 More recent studies have shown that fibroblasts in papules on the trunk and extremities (Fig. 13.169),
pretibial skin and in the orbit of affected patients contain sequences identical • localized and generalized lichenoid plaques mimicking lichen planus,
to those of the thyroid stimulating hormone receptor.26,27 It has also been pro- • urticarial or nodular lesions, which often evolved into the generalized
posed that the fibroblasts might contain a cross-reacting protein rather than papular form.2,3
the true receptor, which binds with the autoantibodies against thyroid stimu- With the subsequent delineation of new entities, the validity of this classi-
lating factor receptor.28,29 Based on these observations, it has been proposed fication was called into question.4 Lichen myxedematosus is now divided into
that autoantibodies against thyroid-stimulating hormone receptor react with three forms:5–8
fibroblasts containing these sequences, resulting in production of cytokines • a localized form, which includes several variants: discrete papular lesions
and induction of increased glycosaminoglycan secretion.28,29 occurring at any site, acral persistent papular mucinosis (see below),
The mucinoses 575
Fig. 13.164
(A, B) Localized
myxedema: these pictures
came from same patient
shown in Figure 13.162.
Following a road traffic
accident, the patient
developed additional
mucinous deposits on
her arm close to the site Fig. 13.165
of a fracture. By courtesy Pretibial myxedema: there
of P.G. Goodwin, MD, is loss of collagen fibers
A The Royal Bournemouth associated with mucin
Hospital, UK. deposition.
self-healing papular mucinosis (see below), papular mucinosis of infancy

(see below) and nodular mucinosis,
• a generalized form (scleromyxedema) characterized by lichenoid papules, Fig. 13.166
indurated and thickened skin and a monoclonal gammopathy; by
Pretibial myxedema: the
definition, thyroid function is invariably normal. mucin (hyaluronic acid)
• an atypical or intermediate form where patients may have generalized stains positively with
lesions without systemic symptoms/gammopathy, localized lesions with Alcian blue.
systemic symptoms/gammopathy or other manifestations that do not
strictly fulfill criteria for either the localized or generalized variants.
The generalized form of lichen myxedematosus (scleromyxedema) occurs and a mask-like facies may result (Fig. 13.170).4 Gross involvement of the
equally in males and females and is seen most often in the fourth and fifth glabellar skin sometimes causes a leonine appearance.12 A rare patient with
decades.3 It often presents on the hands and wrists, but soon becomes gener- leonine facies and tumor-like nodules mimicking lymphoma has been
alized although lesions are particularly seen on the hands, elbows, neck, face, reported.13 The lack of acral calcification and absence of Raynaud's phenom-
and upper trunk.9,10 Prominent linear papules may be evident on the fore- enon help to distinguish this condition from scleroderma. The mucous mem-
head, neck, axillae, and behind the ears.11 The papules are small, 2–3 mm in branes are not usually affected.3 The lesions are variably pruritic.
diameter, white or erythematous, and often have a waxy consistency. They There are occasional reports of systemic symptoms. Esophageal aperistal-
tend to coalesce to form infiltrated plaques and, when associated with sis, peripheral neuropathy, proximal myopathy, and cardiac and cerebrovas-
hardening and thickening of the underlying skin (scleromyxedema), result in cular diseases have all been described.4,14 There has been little postmortem
tethering and limitation of movement, so that sclerodactyly, microstomia, confirmation of visceral involvement and therefore it is likely that many of
Fig. 13.169
Lichen myxedematosus:
Fig. 13.167 this is an example of the
Lichen myxedematosus: discrete papular form
erythematous papules are showing small numbers
widely distributed over the of papules on the anterior
forearms. A more diffuse wrist. By courtesy of R.A.
plaque is present over the Marsden, MD, St George’s
dorsum of the left hand. Hospital, London, UK.
inflammatory myopathy not dermatomyositis has been described in associa-

tion with scleromyxedema.30 It has been suggested that the development of
myopathy is associated with a poor prognosis.30
Scleromyxedema is usually (but not invariably) associated with a parapro-
teinemia; most often this is IgG with lambda light chains.15,31–34 Occasionally
it has been of the IgM or IgA class.3 An occasional association with multiple
myeloma has also been noted but occurs in less than 10% of patients.5,9

The pathogenesis of lichen myxedematosus is unknown. There is no evidence
to suggest that the paraprotein is responsible for the fibroblastic prolifera-
tion. However, serum from scleromyxedema patients has been shown to con-
tain a nonparaprotein-associated fibroblast growth factor. This requires
further characterization.8,35 There is some evidence to suggest that the para-
protein may, however, have mucinogenic properties.36,37 Fibroblasts grown in
tissue culture produce greater quantities of hyaluronic acid and sulfated gly-
cosaminoglycans than normal controls.38 Collagen synthesis, as determined
by H3-hydroxyproline estimations, is diminished.
Fig. 13.168 Immunofluorescent studies have revealed immunoglobulin (IgG and to a
Lichen myxedematosus: numerous papules are present in the antecubital fossa. lesser extent IgM) in the reticular dermis or just below the epidermis in 35%
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. of cases.12 Indirect immunofluorescence is invariably negative.
The epidermis may be normal, acanthotic or atrophic, and sometimes
hyperkeratosis with parakeratosis is evident. In early lesions stellate
these associations are no more than coincidental. Neurological manifestations fibroblasts are seen between disorganized collagen fibers in the reticular
have, however, been reported most often and are probably of significance. dermis (Figs 13.171, 13.172).3,7 The papillary dermis is not affected.
They have included acute psychoses, encephalopathy and coma, epileptiform Increased numbers of mast cells are sometimes present.29 Focal deposits of
seizures, aphasia, memory loss, depression, and motor dysfunction.9,14–16 mucin are readily identifiable (Fig. 13.173).2 A slight perivascular chronic
Dermatoneuro syndrome describes a rare manifestation of central nervous inflammatory cell infiltrate is often seen in the superficial dermis.
system disease where patients develop high fever, flulike symptoms followed In the more severe scleromyxedema variant, fibroblasts are numerous and
by seizures, and coma.17,18 Carpal tunnel syndrome has also been reported there is consequent fibrosis and thickening of the dermis (Figs 13.174–
fairly frequently.19–21 Pulmonary involvement is not uncommon and consists 13.176).4 Mucin deposits may be less evident or even absent.12 Decreased
of restrictive or obstructive disease and pulmonary hypertension.22 Renal dis- elastic fibers have occasionally been reported.3 A chronic inflammatory cell
ease similar to that seen in scleroderma is rare.23 There is usually no infiltrate is frequently present surrounding the superficial vasculature.
relationship between lichen myxedematosus and neoplasia. An exceptional Recently, a less common granulomatous variant of scleromyxedema has
case of lichen myxedematosus and hepatocellular carcinoma has been been described in which there is an interstitial histiocytic infiltrate with giant
reported.24 Rare cases associated with HIV infection have also been cells, similar to granuloma annulare or interstitial granulomatous dermati-
documented.25,26 Further associations include chronic hepatitis C and tis.39,40 Although there is increased mucin, prominent stellate fibroblasts and
dermatomyositis.27–29 The latter finding is interesting because in the past dense bundles of collagen are not a feature.
The mucinoses 577
Fig. 13.170
(A, B) Scleromyxedema: this
severely affected patient
shows sclerosis and linear
papules on the forehead. Note
the pinched, mask-like facies.
By courtesy of R.A. Marsden,
A B MD, St George’s Hospital,
London, UK.
Ultrastructural studies show active fibroblasts characterized by abundant r ectal mucosa and in muscle in one patient with scleromyxedema. Whether
rough endoplasmic reticulum and Golgi apparatus, increased numbers of this represents true primary involvement or a secondary unrelated phenom-
mitochondria, and cytoplasmic inclusions accompanied by collagen enon is uncertain. In a particularly unusual case the features of systemic scle-
deposition.41 rosis were found in the kidney.9 In the absence of any autopsy evidence of
Systemic involvement has only rarely been documented. Mucin deposi- further sclerodermatous lesions, it may be that the renal vascular and glom-
tion has been described in the adventitia of visceral blood vessels and in the erular changes reflected unrecognized scleromyxedematous pathology.
renal papillae in single case reports.9,41 It has also been described within Demyelination and focal gliosis have also been reported.12,42 Nevertheless,
A B
Fig. 13.171 Fig. 13.172

Lichen myxedematosus: increased mucin is evident (A, B) Lichen myxedematosus: the collagen fibers are widely separated by mucin deposits. Fibroblasts are
in the superficial dermis. increased in number.
Fig. 13.173 Fig. 13.175

Lichen myxedematosus: staining with colloidal iron emphasizes the mucin deposits. Scleromyxedema: delicate strands of mucin separate the collagen fibers.
Fig. 13.176
Scleromyxedema: Alcian blue.
Fig. 13.174
Scleromyxedema: the Acral persistent papular mucinosis
dermis is markedly
thickened. There is fibrosis Clinical features
and increased numbers of
fibroblasts are evident. This rare condition, which predominantly affects females, is characterized by
the development of persistent multiple discrete and often symmetrical smooth-
surfaced small papules (2–7 mm) on the dorsal aspects of the hands and
autopsy studies have usually shown no evidence of widespread mucinosis wrists, sometimes extending on to the forearms (Fig. 13.177).1–4 The condi-
and it is likely that in the great majority of cases the pathological changes are tion is generally regarded as a localized variant of lichen myxedematosus.5–11
limited to the skin. The papules are ivory or flesh-colored and translucent, and on puncture char-
acteristically contain clear viscous fluid.2 Lesions do not occur on the face or
Differential diagnosis trunk and there is no thickening or induration of the skin.12 Pruritus is excep-
It may be impossible to distinguish scleromyxedema from nephrogenic tional.13 Occurrence in two sisters has been reported, raising the possibility of
systemic fibrosis based solely on histopathological features.43 Both conditions a familial form of the disease.14 Acral persistent papular mucinosis is not usu-
demonstrate an intradermal proliferation of spindled cells associated with ally known to be associated with any systemic abnormalities such as thyroid
increased mucin. The spindled cells stain for CD34, factor 13a, and procol- disease or paraproteinemia.15,16 An exceptional case associated with IgA
lagen I in both disorders. Although correlation with clinical parameters is monoclonal gammopathy has been reported.17
critical for ultimate distinction between the two disorders, a recent study sug-
gests that the depth of the infiltrate may be a helpful differentiating feature.44 Histological features
In scleromyxedema the infiltrate is confined to the mid to deep dermis, The papules show extensive mucin deposition in the upper reticular dermis
whereas in nephrogenic systemic fibrosis the process begins in the dermis but separated by a grenz zone from the overlying epidermis (Figs 13.178,
also extends into the septa of the subcutaneous fat. 13.179).10,12,18 Increased numbers of spindled or stellate-shaped fibroblasts
The mucinoses 579
Fig. 13.177
Acral persistent papular Fig. 13.179
mucinosis: discrete papule Acral persistent papular mucinosis: close-up view showing mucin deposits.
on the dorsal surface of
a forefinger. This patient
had similar lesions on the
The eruption consists of densely grouped, firm, 1–2 mm papules on the
arms. By courtesy of R.A.
elbows and smaller numbers of more dispersed lesions about the forearms
Hospital, London, UK. and dorsa of the hands.1 Congenital linear papules on the backs of two fingers
have been reported in one infant and another was born with clustered papules
on the lower back.2,3 More recently, a patient with multiple congenital pap-
ules on the fingers and toes has been described.6 Owing to the paucity of
cases, the natural history and prognosis of this condition are unknown.
Excessive mucin (hyaluronic acid) is present in the papillary dermis under an
acanthotic epidermis. Sectioning artifact may make the deposits appear to
have an intraepidermal location. Biopsies from late lesions show features
identical to those of lichen myxedematosus with fibrosis and proliferation of
dermal fibroblasts.4 A perivascular chronic inflammatory cell infiltrate is
evident in the superficial dermis.
Self-healing juvenile cutaneous mucinosis

Clinical features
This is an extremely rare condition, only a handful of cases having been docu-
mented.1–17 It most commonly presents in children, with a rapid onset of
asymptomatic erythematous papules and plaques, which show a predilection
for the face, neck, scalp, abdomen, and extremities, accompanied by deep nod-
Fig. 13.178 ules on the face and periarticular regions.1 The plaques have a characteristic
Acral persistent papular mucinosis: note the presence of a discrete superficial
appearance as linear groups of papules, giving the skin a corrugated appear-
papule with a well-developed collarette.
ance.3 The deep nodules can mimic fasciitis.11 The eruption resolves within a
period of weeks to months. Mild arthritis involving the elbows, knees, and
interphalangeal joints has been documented as has possible polychondritis.1,3
may occasionally be evident.19 Fibrosis, however, as seen in lichen myxedema-
These latter manifestations may be persistent.1 In one patient bilateral carpal
tosus, is not a feature of this condition. Direct immunofluorescence has revealed
tunnel syndrome was present. Non-specific features of fatigue, weight loss,
granular IgM at the dermoepidermal junction and linear IgG around the eccrine
and myalgia may also be evident. The age of those who are typically affected
glands in one case.2 Ultrastructural studies reveal active fibroblasts with promi-
ranges from infancy to teenagers. Exceptionally, the disease presents in
nent dilated rough endoplasmic reticulum. The collagen bundles are widely
adults.14–17 There is no evidence of thyroid dysfunction or paraproteinemia.
separated and focal deposits of electron-dense amorphous material are evi-
dent.5 Conspicuous lamellated electron-dense lysosomes have been described in
one case.19 This probably represents a non-specific secondary change.
The etiology is unknown although it has been suggested that the fibroblast
activity may have been stimulated by a preceding viral infection.3
Cutaneous mucinosis of infancy Histologically, the epidermis is normal or may show mild hyperkeratosis.
Mucin deposition is seen in the papillary and upper reticular dermis separat-
Clinical features ing and splitting the collagen bundles. In one case the mucin was PAS positive
This variant of papular mucinosis is very rare.1–3 It has recently been sug- and identified as a sialomucin, whereas in others it was found to consist of
gested that the condition might represent a pediatric localized form of lichen hyaluronic acid.1,3,9,10,12,14,16 Fibroblasts are slightly increased in number and a
myxedematosus.4,5 Familial cases have been documented.4 mild chronic inflammatory cell infiltrate surrounds the superficial vasculature.
Deeper nodules demonstrate similar involvement of the septa and lobules of

the subcutaneous fat which can also extend into the fascia. Epithelioid,
ganglion-like histiocytes can be seen and may cause confusion with prolifera-
tive or nodular fasciitis.11,12
Reticular erythematous mucinosis

This condition is described in Chapter 8.
Scleredema
Clinical features
Scleredema (Buschke) is a rare primary mucinosis that presents with nonpit-
ting indurated edema and associated dermal hardening in the absence of any
significant clinical abnormality of the overlying skin.1,2 Three distinct subtypes
are recognized:2–5
• Most commonly seen is an acute variant predominantly affecting children
and characterized by a rapid onset arising a few weeks after an infection,
most often of the upper respiratory tract. Streptococcal infections are
Fig. 13.180
particularly implicated, but cases have followed a variety of viral illnesses
Scleredema: a diffuse, firm thickening of the tissues is present over the neck
including measles, mumps, influenza, cytomegalovirus infection, and and shoulders. By courtesy of G. Murphy, MD, Institute of Dermatology,
chickenpox.6–8 Scleredema has also occurred in the setting of chronic London, UK.
scabies and secondary streptococcal infection.9 Although many of these
cases resolve spontaneously within a period of months and years, a
significant number are persistent and exacerbations are not uncommon.10
Females are affected more often than males and the disease is more
common in the winter months.11 Sometimes there is a prodromal illness
of malaise, myalgia, generalized myasthenia, and arthralgia.10 Some
patients develop a variety of cutaneous manifestations including transient
erythema, urticarial or annular eruptions and dermographism before the
onset of the more typical features.4 Scleredema in children may
exceptionally present overlapping features with eosinophilic fasciitis.12
• Secondly, scleredema may have an insidious onset unaccompanied by any
previous acute illness.2
• Lastly, scleredema sometimes develops in association with late-onset
diabetes mellitus. Patients, more often males, are often obese and there
are usually other manifestations of diabetes including nephropathy,
hypertension, coronary and peripheral vascular insufficiency, retinopathy
and peripheral neuropathy.2,13,14 The diabetes commonly precedes the
development of scleredema, which is usually widespread and associated
with a chronic course.1,15,16 This variant of scleredema does not tend to
resolve spontaneously or with treatment.
Scleredema is occasionally associated with a paraproteinemia (usually IgG,
but sometimes IgA) and rarely multiple myeloma.17–19 There is no evidence
that the paraprotein results in the skin lesions; hence it is probably a second- A
ary phenomenon. Evolution to systemic amyloidosis has been reported in one
patient.20
It should be noted that despite the original nomenclature of scleredema
adultorum, many of the patients are in fact children.10,11,21 Only very rarely
are childhood cases associated with diabetes.21 An exceptional case of con-
genital scleredema has been reported.22
Rare cases have had associated primary and secondary hyperparathyroid-
ism, rheumatoid arthritis, Sjögren's syndrome, and sarcoidosis.23–26 Scleredema
has also been described in HIV infection, in association with a nuchal fibroma,
following exposure to organic solvent, in the setting of a malignant insuli-
noma and carcinoid, with acanthosis nigricans, with generalized hyperpig-
mentation, and as an adverse consequence of infliximab.13,18,27–32 The
cutaneous manifestations are similar for all three subtypes, differences being
merely a matter of degree.
Patients present with symmetrical nonpitting edema and dermal hardening,
which particularly affects the posterior and lateral aspects of the neck
(Fig. 13.180).2 The face, anterior neck, upper trunk, and upper limbs are also
frequently affected.1 Rarely, the disease may spread to the lower abdomen and B
legs. Confinement of the changes to the thighs has been described.33 The palms
and soles are rarely affected and genital involvement is uncommon.10 Lesional Fig. 13.181
skin is shiny and feels hard, and wrinkling is impossible due to involvement of (A, B) Scleredema: there is marked thickening and induration of the skin of the
the papillary dermis (Fig. 13.181). In severely affected patients reduced mobility upper back. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.
The mucinoses 581
is often a problem. The face may be expressionless, the lines of cleavage lost,
and smiling and mouth opening may be difficult.1 The overlying skin may
demonstrate erythema, hyperpigmentation and/or a peau d' orange appearance.
An unusual case with hyperkeratosis has been described.8
In some patients systemic disease may be evident, including pericardial,
pleural, and peritoneal effusions, dysarthria and dysphagia due to tongue and
pharyngeal lesions, hepatosplenomegaly, cardiac and skeletal muscle mani-
festations, parotid gland involvement and ocular changes presenting as indu-
ration of the eyelids and conjunctivae.10,11,34 Periorbital edema can be the sole
presentation.35 In cases with systemic involvement, mucin deposition has been
demonstrated in the bone marrow, liver, nerve, salivary gland, and heart.36,37
Cardiac and pulmonary disease may exceptionally lead to death.38

The pathogenesis of scleredema is unknown. The serum from one patient
with scleredema and a paraprotein markedly stimulated collagen production
in normal skin fibroblast cultures, suggesting that a circulating factor(s) prob-
ably related to the paraprotein might induce the dermal fibrosis.39 The
involved skin shows increased synthesis of type I collagen, which appears to
Fig. 13.183
be responsible, at least in part, for the dermal fibrosis.40,41 The fibroblasts in Scleredema: the collagen fibers appear swollen. There is excess mucin.
involved skin from individuals with scleredema show increased protein pro-
duction, collagen synthesis, and glucosamine incorporation. This correlation
is associated with increased levels of type I and type III collagen.42 Biochemical
analysis of involved skin in scleredema has confirmed an increase in gly-
cosaminoglycans, the main component being hyaluronic acid.43
The histological features are often subtle and the diagnosis is difficult. The
epidermis may be slightly thinned or appear normal. The reticular dermis is
greatly thickened, often at the expense of the subcutaneous fat, and the eccrine
glands therefore become abnormally situated within the upper third or mid
dermis (Figs 13.182, 13.183).1 The collagen fibers are broadened and,
particularly in the earlier stages, are abnormally separated by clear spaces
(dermal fenestration).2 The latter may contain small quantities of mucin, but
often special stains (Alcian blue, colloidal iron) and multiple biopsies are
necessary for their demonstration (Fig. 13.184).16,44 Up to one-third of cases
may not demonstrate mucin even with the aid of special stains.45 Fibroblasts
are present in normal numbers. A mild chronic inflammatory cell infiltrate is
sometimes evident in the superficial dermis and mast cells may be increased in
number (Fig. 13.185).1 Direct immunofluorescence studies are negative.2,17
Fig. 13.184
Scleredema: the abundant mucin is highlighted by Alcian blue/chromotrophe 2R
staining.
Scleredema may be distinguished clinically from scleroderma by the absence
of Raynaud's phenomenon, acral sclerosis with calcification, pigmentary
changes, and telangiectasia.2 Histologically, the appendages are atrophic and
compressed or absent in scleroderma and there is diffuse dermal sclerosis
rather than the fenestrated appearance seen in scleredema.
Papular and nodular cutaneous mucinosis

of systemic lupus erythematosus
Clinical features
Mucin deposition as a specific clinical manifestation of lupus erythematosus
has been recorded only rarely in the literature yet is said to occur in up to
1.5% of dermatological patients with this disease.1–3 The condition presents as
asymptomatic, flesh-colored, occasionally umbilicated papules and nodules
Fig. 13.182 on the neck, trunk, and upper limbs.4–12 Presentation with massive cutaneous
Scleredema: early lesion mucinosis has also rarely been reported.13 The papules may rarely be hyperpig-
showing collagen bundle mented.14 Lesions are best appreciated using tangential light, which gives the
separation. skin a lumpy appearance.5 Mucin deposition occurs most often in patients
Fig. 13.186
Myxoid cyst: the translucency is typical. By courtesy of R.A. Marsden, MD, St George’s
Fig. 13.185
Scleredema: superficial
dermal lymphohistiocytic
infiltrate.
with the systemic variant, usually with diffuse antinuclear factor and anti-
DNA antibodies, and is particularly associated with joint and kidney
lesions.4,11,15 There are, however, occasional reports of its occurrence in patients
with discoid and subacute cutaneous lupus erythematosus 4,7–9 An inconstant
relationship to sunlight has been recorded.4,16 Exceptionally, systemic sclerosis
may present with similar papular and nodular mucinous lesions.17
The epidermis shows no significant features; in particular, the changes of
lupus erythematosus are usually absent. However, an interface change has
been described in a single case.18 The mucin is present in the papillary and
upper reticular dermis associated with a slight perivascular chronic inflam-
matory cell infiltrate.4,19 Fragmentation of collagen bundles has been noted in
one case in association with mucin accumulation.11
Direct immunofluorescence may show linear or granular immunoglobulin Fig. 13.187
Myxoid cyst: localization
(IgG, IgM) deposits and complement at the dermoepidermal junction.
over the distal
interphalangeal joint is
Myxoid cyst characteristic. By courtesy
of the Institute of
Clinical features Dermatology, London, UK.
Cutaneous myxoid cyst, sometimes inappropriately referred to as synovial

cyst, presents as a soft or fluctuant cystic nodule on the dorsal aspect of the
and acanthosis may be seen at the edges. Early lesions are sometimes
distal interphalangeal, the metacarpophalangeal and, less frequently, the meta-
indistinguishable from cutaneous focal mucinosis. There is no evidence of any
tarsophalangeal joints (Figs 13.186, 13.187).1,2 An exceptional case occur-
connection with an underlying joint.
ring on the lateral aspect of the knee has been described.3 Occasionally, lesions
are multiple.4 Cutaneous myxoid cysts may present at any age and are more
common in females. The surface is usually smooth, although verrucous vari- Cutaneous focal mucinosis
ants are occasionally encountered. The cyst contains yellow, clear viscous
fluid. Lesions are often painful or tender. Myxoid cyst involving the proximal Clinical features
nail fold can be associated with longitudinal grooving of the nail.5 Although Cutaneous focal mucinosis presents as an asymptomatic, usually solitary,
the precise cause is not well elucidated, underlying osteoarthrosis is sometimes dermal papule or nodule most commonly on the face, neck, trunk or extremi-
evident, and repetitive trauma is proposed to be one possible mechanism.1,4 ties of adults.1–5 It is not seen in relation to the joints of the hands, feet or
wrists. The lesion is usually dome-shaped, white or flesh-colored and
Histological features sometimes has an erythematous halo.2 Occasional verrucous variants have
The cyst is devoid of any lining and consists of a large pool of mucin con- been documented.1 There is usually no evidence of an associated thyroid
taining spindled/stellate fibroblasts with prominent cytoplasmic processes abnormality. Exceptional cases, however, are associated with reticular
(Fig. 13.188). The overlying epidermis is often atrophic and hyperkeratotic, erythematous mucinosis or scleromyxedema.6 Multiple lesions are rare.7
Acanthosis nigricans 583
Patients present with papules, nodules and/or plaquelike lesions, usually with
a linear or dermatomal distribution.4 Large pedunculated lesions are rare.6
A familial case has been described in two young brothers.7
Histologically, the mucin is located in the superficial dermis where it replaces
the collagen and elastic fibers.5 Some cases are associated with epidermal
hyperplasia and these may represent a combined epidermal and mucinous
nevus.3,8 A recent immunohistochemical evaluation demonstrated that the
stromal cells are CD34 positive, with rare cells staining for factor 13A.9
These lesions must be distinguished from the mucinous eccrine nevus, which
comprises abundant mucin surrounding eccrine glands and ducts.10
Neuropathia mucinosa cutanea

A There is only one case report of this condition, which presented in a young
male with hyperesthesia and livedoid lesions on the lower limbs. A biopsy of
these lesions revealed hypertrophic nerves surrounded by mucin.1
Self-healing infantile familial cutaneous

mucinosis
This very rare entity has been reported only once, in two brothers. Multiple
lesions developed during the first few months of life and in one patient
regressed spontaneously over a few years.1
Localized mucinosis secondary to venous

insufficiency
A recent case report describes two elderly patients with violaceous plaques
and coalescing papules on the lower extremities.1 The lesions were painful
and occurred in the setting of venous stasis. There was no history of thyroid
disease, connective tissue disease or antecedent treatment with ultraviolet
light. The histological features consisted of large amounts of mucin deposi-
B
tion in the papillary and reticular dermis with characteristic extension around
the eccrine glands. There was a slight increase in the number of blood vessels
Fig. 13.188
which demonstrated thickened walls. However, an inflammatory infiltrate
(A, B) Myxoid cyst: excessive mucin deposition has resulted in this fluid-filled cyst.
The overlying epithelium may appear attenuated or verrucous and occasionally the was not present. The pathogenesis of this condition is unknown.
cyst is, in part, intraepidermal in location.
Secondary cutaneous mucinoses
The lesion is usually located in the mid and upper dermis, often separated from the Clinical features
epidermis by a grenz zone of dermal sparing.2 It consists of a localized, but usually Mucinous lesions on the skin have been described as part of a reactive process
poorly delineated, focus of mucin deposition containing increased numbers of associated with various triggers. A patient recently developed multiple ery-
spindled cells and stellate fibroblasts with elongated cytoplasmic processes.2 thematous to skin-colored papules following infection with varicella-zoster
Sometimes these contain conspicuous intracytoplasmic vacuoles.3 Collagen fibers virus.1 The lesions occurred in the same dermatome affected by postherpetic
are usually diminished in number.4 A mild perivascular chronic inflammatory cell neuralgia and resolved as the pain improved. Mucinosis complicated by cuta-
infiltrate is often present in the adjacent dermis. There may be an increase in the neous necrosis can occur following injection with interferon. Recombinant
number of small-caliber blood vessels. The overlying epidermis is typically interferon-beta-1b and interferon alfacon-1 have been implicated in the setting
uninvolved; however, immature follicular germlike induction can occur.8 of treatment for multiple sclerosis and hepatitis C, respectively.2,3 Erythematous
Ultrastructurally, the fibroblasts contain prominent rough endoplasmic ulcerative plaques develop at injection sites. Additionally, mucinosis papules
reticulum and membrane-bound intracytoplasmic vesicles containing abun- and plaques have been described in the vicinity of a recently replaced joint.4
dant granular electron-dense material.3
Differential diagnosis These mucinous disorders are characterized by intradermal mucin without a
Cutaneous focal mucinosis must be distinguished from superficial angiomyx- significant increase in dermal fibroblasts. 1–4 Ulcerative lesions associated
oma, a benign myxoid cutaneous and subcutaneous lesion with a tendency with interferon injections can also demonstrate intravascular thrombi.3
for local recurrence, associated with Carney complex.
Acanthosis nigricans
Mucinous nevus
Clinical features
Clinical features Acanthosis nigricans develops under a variety of circumstances.1–3 In addition
Mucinous nevus (nevus mucinosis) is a rare lesion that may be congenital or to the well-recognized tumor-associated variant, acanthosis nigricans may
acquired.1–5 The most common site affected is either the trunk or lower limbs. present with benign familial forms, endocrinopathy and drug-related variants,
and the condition can be seen in association with a range of congenital condi-
tions including lipoatrophy, leprechaunism and the type A and type B syn-
dromes described below. Genetic conditions associated with acanthosis
nigricans include:
• Alstrom syndrome (retinopathy, progressive sensorineural hearing loss,
truncal obesity),
• Crouzon syndrome (facial palsy, sensorineural hearing loss with skeletal
and mental retardation),
• Seip-Lawrence syndrome (congenital lipodystrophic diabetes),
• Costello syndrome (postnatal growth deficiency, coarse facies, redundant
skin of the neck, palms, soles, and fingers, dark skin, and papillomas),
• Bannayan-Riley-Ruvalcaba syndrome (subcutaneous lipomas, vascular
malformations, lentigines of the penis and vulva, warty lesions,
macrocephaly, mental retardation, intestinal polyposis, skeletal
abnormalities, vascular malformations of the central nervous system, and
thyroid tumors),4–8
• Lelis syndrome (ectodermal dysplasia with hyptrichosis, hypohidrosis,
hypodontia, palmar-plantar hyperkeratosis, perioral furrows).9
Acanthosis nigricans has been described in association with a missense
mutation of the fibroblast growth factor receptor.4 This disease is also associ-
ated with severe neurological impairment and severe achondroplasia.10 Fig. 13.190
Additional rare associations include Wilson's disease (hepatolenticular degen- Acanthosis nigricans:
eration) and primary biliary cirrhosis.11,12 In the latter case, the acanthosis there is velvety thickening
of the axillary skin.
nigricans resolved after liver transplantation. In an exceptional family with
By courtesy of the
several members affected by acanthosis nigricans, absence of the eyebrows Institute of Dermatology,
and eyelashes and sparse hair elsewhere has been reported.13 London, UK.
Development of acanthosis nigricans may also antedate or present con-
comitantly with a variety of connective tissue diseases including systemic
lupus erythematosus, systemic sclerosis, and dermatomyositis.14–16
The condition is characterized by the presence of symmetrical brown vel-
vety or verrucous plaques with a predilection for intertriginous sites such as
the back of the neck, groin, and axillae (Figs 13.189, 13.190). In more
extreme forms the changes may be generalized.17 Involvement of the eyelids
also rarely occurs.18 In addition, there is sometimes brown thickening of the
skin over the dorsum of the fingers or, rarely, the palms of the hands (tripe
palms) (Fig. 13.191). The latter is a distinctive appearance due to broadened
epidermal ridges and deep sulci giving the skin a velvety rugose texture.19
Tripe palms are usually associated with internal malignancy and often (but
not invariably) accompany acanthosis nigricans. However, the lesion may
Fig. 13.191
Acanthosis nigricans: tripe palms. The palmar skin is thickened and the creases are
accentuated. By courtesy of the Institute of Dermatology, London, UK.
also represent a benign reversible phenomenon unassociated with neoplasia.

Less frequently, there are similar changes on mucosal surfaces such as the
mouth (particularly the tongue and upper lip) or genitalia (Fig. 13.192).20,21
The latter changes are more common in cases related to malignancy.
Oral lesions have been reported in 25–50% of all cases of acanthosis nig-
ricans and in at least 35% of patients with associated malignancy.20,22,23 The
tongue lesions consist of hypertrophied filiform papillae producing a deeply
fissured papillomatous surface and the lips develop papillary and verrucous
lesions.20 The palate and buccal mucosa may also be involved.23 Oral lesions
are usually nonpigmented. Involvement of the esophagus is rare and is almost
Fig. 13.189 invariably associated with malignancy, particularly in the gastrointestinal
Acanthosis nigricans:
tract.24
thickening of the skin of
the groin. By courtesy
A drug-induced variant has been documented, and glucocorticoids, nico-
of R.A. Marsden, MD, tinic acid, oral contraceptives, and diethylstilbestrol have been implicated.25
St George’s Hospital, Acanthosis nigricans has also been reported in association with somatotrophin
London, UK. therapy.26
Acanthosis nigricans 585
• In type A, the patients are young (particularly black) women with

acanthosis nigricans, primary amenorrhea with hypertestosteronemia,
virilization, increased somatic growth, hyperglycemia and hyperinsulinemia,
with insulin resistance due to a congenital defect of insulin receptors.
• In type B, the patients are older and have features suggesting other
autoimmune diseases, including raised erythrocyte sedimentation rate (ESR),
proteinuria, and hypocomplementemia with antinuclear and anti-DNA
antibodies. Antibodies directed against the insulin receptor may be detected.
• A third type, type C, has recently been proposed, in which acanthosis
nigricans and insulin resistance are associated with a postinsulin receptor
defect.
Studies have found that the presence of acanthosis nigricans in African-
Americans and Native Americans is a cutaneous marker of hyperinsulinemia
and insulin resistance.44,45
Obesity-associated acanthosis nigricans, previously called pseudoacantho-
sis nigricans, develops in the flexures of obese patients. This is the most com-
mon type of acanthosis nigricans in children and adults and is associated with
insulin resistance.46
Transient acanthosis nigricans-like lesions have been described at the sites
Fig. 13.192
Acanthosis nigricans: the skin of the groins and vulva is thickened and hyperpigmented.
of healing lesions of pemphigus vulgaris and pemphigus foliaceous.47,48
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Acanthosis nigricans-like lesions have been described after local applica-
tion of fusidic acid.49

Rarely, the disease presents as an autosomal dominant nevoid lesion, The pathogenesis is uncertain, although in the diabetes-associated patients
which may present at birth, in childhood or at puberty.27,28 The condition has hyperinsulinemia is likely to be of importance.41 In malignancy-related acan-
also been reported in association with Cohen's syndrome (truncal obesity, thosis nigricans, peptide or hormonal secretion appears to be of significance
hypotonia, mental retardation, microcephaly, and ocular abnormalities).29 in at least a proportion of cases.32 It has been demonstrated that some malig-
So-called benign familial acanthosis nigricans occurs more commonly in nant tumors secrete transforming growth factor alpha (TGF-α) in large quan-
females. This autosomal dominantly inherited condition usually presents in tities and this stimulates proliferation of keratinocytes.50
early childhood with lesions that particularly affect the face, dorsal surfaces The histopathological findings are subtle, comprising delicate, elongate
of the fingers, and the flexures.30 There are usually no associated endocrinop- papillomatosis, hyperkeratosis and slight acanthosis, sometimes alternating
athies or congenital abnormalities. with foci of atrophy (Fig. 13.193). The occasional presence of keratin-filled
Acanthosis nigricans presents in up to 51% of patients with Down's syn- cysts may result in a seborrheic keratosis-like appearance.20 Despite the clini-
drome and is probably due to insulin resistance.31 It has also been described cally obvious brown appearance of the lesions, there is normally little increase
in up to 5% of patients with severe atopic dermatitis but the pathogenesis in in the amount of melanin present. A non-specific perivascular chronic inflam-
this setting is unknown.31 matory cell infiltrate is sometimes evident in the superficial dermis.
It may occur as a sign of occult malignancy and obesity. The sex incidence Distinguishing this type of benign acanthosis from others such as epidermal
is equal. Malignant acanthosis nigricans is often severe, widely disseminated, nevi may be difficult.
and has a rapid course. Lesions may also be pruritic and are more difficult to Oral lesions show hyperkeratosis and patchy parakeratosis associated
treat. Tumors that are particularly associated include gastric adenocarci- with marked acanthosis and epithelial papillary hyperplasia.20
noma, and, less often, malignancies of the extrahepatic biliary tree, breast, Tripe palms are characterized by hyperkeratosis, acanthosis, and papillary
pancreas, bladder, and colon.24,32,33 Ovarian and uterine tumors, bronchial dermal hypertrophy.19
squamous and adenocarcinoma, and lymphoma have also been implicated.34 Florid cutaneous papillomatosis is also characterized by hyperkeratosis,
Acanthosis nigricans as an indicator of insulin resistance has been reported papillomatosis, and acanthosis.36
in HIV-positive patients receiving treatment with protease inhibitors.35
The malignant form sometimes develops in association with other cutane-
ous markers of internal malignancy including palmoplantar hyperkeratosis,
eruptive seborrheic keratoses (Leser-Trélat sign), and florid cutaneous papil-
lomatosis.36 The last condition presents as numerous viral wartlike itchy pap-
illomata, which show a predilection for the trunk and extremities and
invariably accompany an internal malignancy, most often gastric adenocarci-
noma. The course of malignant acanthosis nigricans usually parallels that of
the underlying neoplasm, which is generally aggressive and associated with a
high mortality. Lesions may sometimes abate following surgical removal of
the tumor, only to return with its recurrence.
Acanthosis nigricans is also associated with a wide range of endocrine dis-
eases, including Cushing's disease, acromegaly, gigantism, Addison's disease,
polycystic ovary syndrome, diabetes mellitus, acromegaly, and thyroid disor-
ders. The association between hyperandrogenism (HA), insulin resistance
(IR), and acanthosis nigricans (AN) is known as HAIR-AN syndrome. There
appears to be an association between acanthosis nigricans, obesity, hyperten-
sion, ischemic heart disease, and type 2 diabetes, the inheritance of which is
autosomal dominant.37 Acanthosis nigricans may also occur in nonobese
patients in association with diabetes mellitus and insulin resistance due to
diminished receptor binding.38–43 Patients with this sporadic syndrome are Fig. 13.193
divided into two groups: Acanthosis nigricans: there is hyperkeratosis, papillomatosis, and slight acanthosis.
of zinc in breast milk secondary to a defect in zinc uptake from maternal

Acrodermatitis enteropathica serum into the breast.28 In premature infants, the problem is aggravated by
the low gastrointestinal absorption of zinc and low body stores of zinc that
Clinical features were transferred from mother to fetus in the last 10 weeks of pregnancy.28
Acrodermatitis enteropathica is a rare autosomal recessive inherited disorder Many other conditions with acquired zinc deficiency have been associated
of zinc malabsorption, which predominantly affects infants and responds with signs and symptoms of acrodermatitis enteropathica including Crohn's
dramatically to dietary zinc supplements.1–4 It presents with diarrhea, stoma- disease, alcoholic cirrhosis, alcoholic pancreatitis, intestinal bypass opera-
titis, irritability, and failure to thrive, accompanied by erythematous scaly tion, chemotherapy for hematological malignancies, anorexia nervosa, lym-
and crusted lesions with vesicles, pustules, and erosions, predominantly phoma, biotin deficiency, dialysis, cystic fibrosis, Hartnup disease, essential
affecting the extremities, perineal, and periorificial region (Figs 13.194, fatty acid deficiency, citrullinemia, deficiency of ornithine transcarbamylase,
13.195). Frankly bullous lesions have been described. 5 Nonscarring alopecia and following total intravenous hyperalimentation.9,29–49 A similar picture has
may also be present. Additional features include nail dystrophy, prolonged also been described in a number of aminoacidopathies and organic acidemias.
wound healing, impetiginization, short stature, psychiatric symptoms, and The latter include methylmalonic acidemia, propionic acidemia, glutaric aci-
photophobia.1–7 Corneal lesions and decreased visual acuity have also excep- duria type I, and nonketotic hyperglycinemia.50–56 The changes are due not
tionally been reported.8,9 Patients are also prone to developing infections, par- only to zinc deficiency, but also to a deficiency in branched chain amino acids
ticularly by bacteria and fungi, illustrating the importance of normal zinc including isoleucine. This is induced by the low protein diet that these patients
levels in maintaining the integrity of the immune system.10–13 The disease can receive. Acrodermatitis enteropathica has also been described in relation to
persist into adulthood or rarely be diagnosed for the first time in adult life.14–16 HIV infection.57
An acquired variant may complicate artificially fed or, rarely, breast-fed
infants either full term or premature.17–28 This is due to the low concentration Pathogenesis and histological features
The manifestations of acrodermatitis enteropathica result from insufficient
absorption of zinc by the intestine. The mechanism of the disease involves a
defect in a zinc transporting protein. Initial studies of genes that encode for
proteins important in the transport of zinc including SLC30A4 and ZNT4
did not show association with the disease.58–60 More recently, the gene for
acrodermatitis enteropathica has been identified on chromosome 8q24.3.61
This gene, designated SLC39A4, encodes a histidine-rich transmembrane
protein known as hZIP4 which is involved in zinc uptake.62–69 The mutation
in acrodermatitis enteropathica also affects zinc metabolism in fibroblasts
and reduces the activity of 5′-nucleotidase.70,71 Over 30 different mutations in
this gene have been described thus far in association with acrodermatitis
enteropathica.67 The vast majority of patients carry a homozygous or com-
pound heterozygous mutation in SLC39A4. However, there are some without
such an identifiable genetic mutation, indicating that other genetic factors
may possibly play a causative role in the disease.67
The mechanism of infections in acrodermatitis enteropathica is related to
alterations in the immune system due to zinc deficiency.12,13 Zinc is critical to
the development and function of lymphoyctes, neutrophils, macrophages, NK
cells, and cytokine production. It also functions as an antioxidant and prevents
cellular damage by free radicals.13 Lymphopenia and thymic atrophy are
Fig. 13.194 frequent findings in acrodermatitis enteropathica and are due to the loss of
Acrodermatitis enteropathica: extensive crusted erosions in a characteristic B- and T-cell precursors in the bone marrow. The zinc deficiency induces apop-
distribution. By courtesy of Z.S. Tannous, MD, Harvard Medical School, Boston, USA. tosis mediated by glucocorticoids with resultant decrease in lymphopoiesis.
The histopathology varies according to the stage of evolution.72 Very early
lesions show subtle changes consisting of focal parakeratosis alternating with
orthokeratosis. As lesions advance, the parakeratosis becomes more promi-
nent and confluent and the stratum granulosum is decreased or absent. The
keratinocytes in the upper layers of the epidermis display marked cytoplasmic
pallor (Figs 13.196, 13.197). In addition there is focal spongiosis.
Dyskeratotic cells are rarely seen.
In late stages there is cytoplasmic vacuolation and necrosis which may
result in intraepidermal vesicles or occasionally progress to blister forma-
tion.73,74 Subcorneal pustules may be seen and usually indicate secondary
infection. An atypical case of bullous acrodermatitis enteropathica with a
lichenoid infiltrate has been reported.75
Histologically, acrodermatitis enteropathica is indistinguishable from necro-
lytic migratory erythema and pellagra. Very similar histological features are
also seen in necrolytic acral erythema, a condition that occurs on the dorsum
of the feet and legs of patients with hepatitis C infection.76–79 Lesions are ery-
thematous and psoriasiform plaques and decreased serum and lesional zinc
Fig. 13.195 levels have been associated with this condition.78,79 Prominent pallor of
Acrodermatitis enteropathica: in this infant, there is very extensive involvement keratinocytes in the upper layers of the epidermis is also seen in deficiency of
with widespread erosion. By courtesy of Z.S. Tannous, MD, Harvard Medical the M subunit of lactate dehydrogenase.80,81 The cutaneous manifestation of the
School, Boston, USA. latter condition has been described as annually recurring acroerythema.82
Necrolytic migratory erythema 587
anemia, nausea, diarrhea, abdominal pain, neurological symptoms (ataxia

and fecal and urinary incontinence), thromboembolic pathology (deep
vein thrombosis and pulmonary thromboembolism), and weight loss in
addition to the cutaneous manifestations.10 About 57% of patients pres-
ent with the typical visceral, cutaneous, and laboratory abnormalities.11
Exceptional cases of glucagonoma arise from the duodenum, kidney, and
lung.12–14
Necrolytic migratory erythema, so-called because of its superficial resem-
blance to toxic epidermal necrolysis and the waxing and waning nature of the
eruption, is seen most frequently on the central face, particularly around the
mouth, on the perineum and other intertriginous sites, the thighs, buttocks,
and distal limbs (Fig. 13.198).3 Patients most often present in their sixth
decade (median 52 years) with intense erythema, which progresses to flaccid
bullae that rupture readily and develop crusting.11,15 Pressure, friction, and
trauma have occasionally been noted to precipitate the eruption.8 Central
healing with active borders gives rise to annular and serpiginous lesions.
Lesions are often painful and pruritic.
Postinflammatory hyperpigmentation follows resolution. Individual
lesions usually last 1–2 weeks and, characteristically, lesions in varying stages
Fig. 13.196 of evolution are evident at any one time.8,15
Acrodermatitis Additional features may include stomatitis, angular cheilitis, blepharitis,
enteropathica: low- conjunctivitis, hair loss, and nail changes.9–11 Laboratory investigations com-
power view showing monly reveal an abnormal glucose tolerance test, normochromic normocytic
hyperkeratosis and
anemia, hypoproteinemia, hypoalbuminemia, and hypoaminoacidemia.9,16
marked epidermal
eosinophilia on the right
Low amino acid levels were detected in 96% of patients in one reported
side. series.17 However, in larger series, the percentage of patients with low amino
acid levels has been lower, ranging between 41% and 78%.10,11
Glucagonoma syndrome may constitute part of the multiple endocrine
neoplasia syndrome.18
Rarely, necrolytic migratory erythema has been described in the absence
of a glucagonoma, so-called ‘pseudo-glucagonoma syndrome’.19–25 Abnormal
liver function tests have usually been present and it has been suggested that
this may have resulted in impaired glucagon catabolism with resultant
hyperglucagonemia or raised levels of one of the glucagon immunofrac-
tions.20 Patients have had associated gastrointestinal malabsorption disor-
ders such as celiac disease, ulcerative colitis, Crohn's disease, short bowel
syndrome, liver diseases including cirrhosis and hepatitis, as well as chronic
pancreatitis, cystic fibrosis, and other malignancies.23,26–30 A study of 24
patients with nonglucagonoma-associated necrolytic migratory erythema
found increased glucagon in 52% of patients and low zinc levels in 37% of
patients.23
Despite its relatively indolent growth characteristics, a large majority of
tumors have metastasized by the time of diagnosis.
Fig. 13.197
Acrodermatitis
enteropathica:
keratinocyte necrosis is
seen in this high-power
view.
Necrolytic migratory erythema

Clinical features
Necrolytic migratory erythema is a distinctive dermatosis that is classi-
cally seen in patients with the glucagonoma syndrome.1–9 The latter, due to Fig. 13.198
a slowly progressive malignant tumor of the pancreatic islets, consists of Necrolytic migratory erythema: note the intense erythema in a characteristic
hyperglucagonemia, diabetes mellitus, glossitis, normochromic normocytic distribution. By courtesy of the Institute of Dermatology, London, UK.

The precise etiology of necrolytic migratory erythema is unknown. Although
it is certainly related to hyperglucagonemia, this is not necessarily causal.
Therefore, although the signs and symptoms rapidly abate following surgery
or the use of glucagon secretion inhibitors such as somatostatin,
hyperglucagonemia does not readily explain the intermittent nature of the erup-
tion.20 The topical or intradermal application of glucagon does not produce the
dermatoses.8 Similarly, there are alternative causes of hyperglucagonemia
including burns and acute trauma, diabetes mellitus, septicemia, cirrhosis,
renal failure, Cushing's syndrome, and primary hyperglucagonemia, in which
necrolytic migratory erythema is not a feature.16
Hypoaminoacidemia is an extremely common manifestation and it may
have pathogenetic significance for the cutaneous lesions. It has been proposed
that the diminished amino acid availability may result in epidermal protein
depletion and eventual necrosis.15 Certainly, treatment with intravenous
amino acids has been shown to control the eruption, but this, of course, may
have been coincidental, considering the characteristic fluctuating course of
the dermatoses.20 Fatty acid and zinc deficiency and abnormal arachidonic
acid distribution have also been proposed as pathogenetic mechanisms.9,31 It Fig. 13.200
has been suggested that diminished tryptophan levels may be the cause of the Necrolytic migratory erythema: close-up view of Figure 13.199.
dermatoses.9 A further hypothesis points to hepatic dysfunction as having a
role in the pathogenesis of the disease.20,21,23,25,32 This is mainly based on the
fact that patients with necrolytic migratory erythema and absence of gluca-
gonoma often have liver dysfunction. The model of ‘multifactorial malnutri-
tion’ has been suggested as an explanation for the several disorders associated
with this disease.25 It is proposed that deficiencies in zinc, amino acids, fatty
acids, and protein result in a metabolic alteration which affects a final com-
mon pathway that manifests clinically with epidermal inflammation and
necrosis in areas of trauma. The precise pathways involved remain
unknown.
Histological examination reveals parakeratosis accompanied by vacuola-
tion and pallor of the mid and upper keratinocytes (Figs 13.199–13.201).33
Dyskeratosis has been described as a clue to early diagnosis.34 This is accom-
panied by necrosis and separation of the upper layers of the epidermis, giving
rise to intraepidermal clefting or vesiculation.33 A neutrophil polymorph infil-
trate may be evident, particularly in well-established lesions.35 Subcorneal
pustulation has also been described.16 This may develop in a background of
epidermal necrosis or, less often, represents an isolated phenomenon.35
Suprabasal acantholysis has exceptionally been described.36 The dermis shows
a lymphohistiocytic chronic inflammatory cell infiltrate surrounding dilated
blood vessels. In lesions associated with pustulation, neutrophils may also be
Fig. 13.201
Necrolytic migratory erythema: high-power view showing marked overlying
parakeratosis.
present. Older lesions may show parakeratosis, marked acanthosis, and pap-
illary dermal angiogenesis, and psoriasis may therefore enter the differential
diagnosis.7,33,35 Pustular folliculitis in association with more typical features
has also been described.35
Immunofluorescence studies are invariably negative.13,15,31,35,37
An ultrastructural study revealed widening of the intercellular space with
reduced numbers of desmosomes in the absence of acantholysis.38 Cytoplasmic
vacuolation with lysed organelles and dyskeratotic cells was also present.
These changes are largely degenerative and non-specific.
Necrolytic migratory erythema shows considerable clinicopathological
overlap with acrodermatitis enteropathica, and niacin and zinc deficiencies,
suggesting a possible shared pathogenesis.9 Pellagra can also show similar
histological features. The histology of necrolytic acral erythema is that of
necrolytic migratory erythema. This condition is, however, associated with
Fig. 13.199 hepatitis C infection and clinically tends to be restricted to the dorsum of
Necrolytic migratory erythema: low-power view showing extensive vacuolation with the feet, with less common involvement of the lower legs and dorsal
vesiculation. hands.39
Bullosis diabeticorum 589
If subcorneal pustules are evident, impetigo, dermatophyte infection,

ustular psoriasis, subcorneal pustular dermatosis, and pemphigus foliaceus
p
enter the differential diagnosis. Multiple biopsies are sometimes necessary
before the correct diagnosis can be established.
Bullosis diabeticorum
Clinical features
There are numerous cutaneous manifestations of diabetes mellitus. These
include vascular complications such as peripheral gangrene, especially
affecting the foot, and infective lesions including candidiasis and dermato-
phytosis. Other dermatological features include necrobiosis lipoidica
diabeticorum, disseminated granuloma annulare, acanthosis nigricans,
eruptive xanthomata, scleredema, diabetic dermopathy (shin spots), waxy
skin, and bullous lesions.1–4
Bullosis diabeticorum (bullous eruption of diabetes mellitus) is rare, affect-
ing approximately 0.16% of diabetics, and affects men more commonly
(male:female ratio 2:1).5 It usually presents as spontaneous blisters, typically
without underlying inflammation, affecting the periphery. Lesions, which are Fig. 13.202
Bullous eruption of diabetes: this example from the fingertip shows a subepidermal
sometimes mildly painful or associated with a burning sensation, are found
vesicle.
most often on the feet and lower legs although the hands may also be
affected.6–10 Blisters range in size from a few millimeters to a few centimeters
and can evolve rapidly and become hemorrhagic.4 The lesions, which are
often recurrent, commonly heal in a few weeks and are not associated with
scarring. Rarely, secondary ulceration and infection can occur. 5 Osteomyelitis
has been reported recently.11

The cause of blistering in diabetic patients is unknown, but theories implicat-
ing a vascular or neurological mechanism have been favored in the literature.
The occasional finding of epidermal infarction overlying the blister cavity
favors the former in at least some patients.6 The discovery that diabetic patients
have a diminished threshold for suction-induced blisters may have pathoge-
netic significance.12 Others have suggested an abnormality of calcium and
magnesium metabolism as a consequence of diabetic nephropathy.13 Despite
lesions being predominantly acral in distribution, trauma does not seem to be
generally implicated. In all likelihood, the cause is probably multifactorial.
The reported histopathological features have been variable and include
subcorneal, suprabasal, and subepidermal vesiculation, sometimes associated
with spongiosis (Figs 13.202, 13.203).13–15 Some of the discrepancies may be
due at least in part to variable ages of the lesions, biopsies with re-epithelial-
ization resulting in an apparent intraepidermal location. Electron microscopic Fig. 13.203
Bullous eruption of
studies in two cases have shown that the plane of separation is through the
diabetes: in this field,
lamina lucida in the subepidermal lesions.6,13 Absence of hemidesmosomes the epidermis shows the
and anchoring filaments has also been described.13 changes of infarction.
Immunofluorescence studies are almost invariably negative, although one Note the intense
report described IgM and C3 around the superficial vasculature in uninvolved cytoplasmic eosinophilia
skin.16 and absence of nuclei.
Chapter
14 Cutaneous adverse reactions

to drugs
Nooshin Brinster
See
for references and
additional material
Adverse drug reactions – Vasculitic drug reactions 604 Penicillamine 617

introduction 590 Gold 618
Purpuric drug reactions 605 Silver 619
Type A drug reactions 591 Mercury 619
Granulomatous drug reactions 605
Type B drug reactions 591 Bismuth 620
Drug-induced erythema nodosum 606 Voriconazole 620
Type C drug reactions 591 Lithium 620
Drug-induced alopecia 606
Barbiturates and coma blisters 621
Adverse drug reactions – clinical Drug-induced lupus erythematosus 607
Chemotherapeutic agents 621
manifestations 592 Bullous drug reactions 607 Chemotherapy-induced acral erythema 623
Exanthematous reactions 592 Drug-induced linear IgA disease 607
Drug-induced bullous pemphigoid 608 Chemotherapy-associated eccrine gland
Urticarial reactions, angioedema and Drug-induced epidermolysis bullosa acquisita 609 reactions 623
anaphylaxis 594 Drug-induced pemphigus 609 Neutrophil eccrine hidradenitis 623
Drug-induced pseudoporphyria 609 Eccrine squamous syringometaplasia 624
Serum sickness/serum sickness-like drug
reactions 594 Psoriasiform drug reactions 609 Adverse reactions to cytokine therapy 625
Phototoxic and photoallergic reactions 595 Pityriasiform drug reactions 610 Cutaneous reaction of lymphocyte
recovery 626
Anticonvulsant hypersensitivity Pustular drug reactions 611
syndrome 597 Dental amalgam tattoos 626
Ichthyosiform drug reactions 612
Lichenoid and interface drug reactions 598 Tumor necrosis factor-a inhibitors 626
Drug-induced pseudolymphoma 612
Fixed drug eruptions 599 Esthetic microimplants 627
Specific drug reactions 614
Erythema multiforme 601 Arsenic 614 Alpha-melanocyte stimulating hormone
Iododerma 615 analogues (melanotan I and II) 629
Stevens-Johnson syndrome and toxic
epidermal necrolysis 601 Bromoderma 615 EMLA cream 630
Warfarin 616
Drug-induced hyperpigmentation 601 Heparin 617
Adverse drug reactions – Introduction

Adverse drug reactions are unintended and undesired effects of drugs used for diagnostic difficulties are worsened by the multitude of drugs prescribed. The
prevention, diagnosis or treatment of disease.1,2 In light of the ever-increasing problem is further compounded by the multiplicity of different eruptions that
number of medications available, it should come as no surprise that such any one particular drug may induce. Contrariwise, a given clinical appearance
reactions are extremely common. The incidence statistics vary considerably may be caused by a large number of unrelated drugs.10
depending upon the method by which the data are derived and the nature of The prevalence of agents responsible for adverse drug reactions reflects
the population under study.3 Estimates, however, range from 2% to 7% of the prescribing tendencies for any given population as much as the relative
hospital inpatients.4–8 Although most reactions are mild, they are sometimes risks ascribed to any particular drug.11 It should come as no surprise, there-
severe and a source of considerable morbidity and occasional mortality.6,7 fore, that – in a hospital environment – antibiotics, nonsteroidal antiinflam-
The diagnosis of an adverse drug reaction is frequently problematical, the matory agents (NSAIDs) and psychotropic drugs are commonly reported as
clinical appearances often being similar, if not identical, to a number of pri- being the most frequently incriminated.8 In a large hospital survey, penicil-
mary dermatoses and infectious conditions (particularly viral exanthems) and, lin and sulfonamides accounted for over 80% of all adverse drug reactions.8
in the context of transplantation patients, graft-versus-host disease (GVHD). Experience in general practice has been much less often documented. In a
The histological diagnosis can also be extremely difficult, as drug reactions can survey from the Netherlands, sulfonamide-trimethoprim combinations, flu-
demonstrate several inflammatory histological patterns that mimic other der- oroquinolones, and penicillin were the most common antibacterials caus-
matoses (i.e. spongiotic, psoriasiform, lichenoid, pityriasiform).9 The problem ing drug-related eruptions.3 In the series of approximately 150 000 patients,
is exacerbated in the immunologically compromised patient. Frequently, the 1% developed a reaction.
Type C drug reactions 591
Adverse drug reactions are mostly nonimmunologically mediated. They Idiosyncratic drug reactions
develop either as a result of an unwanted but known property of the drug
Idiosyncratic reactions (drug intolerance) develop as a result of genetic or
(and hence are entirely predictable) or as a consequence of drug intolerance/
metabolic influences. They may represent the effects of abnormal or altered
idiosyncrasy (and are completely unpredictable).5,12–15 The former are by far
hepatic drug metabolism. For example, a lupus erythematosus-like condition
the more common, accounting for approximately 80% of all adverse drug
is a rare complication of hydralazine therapy in the average population but
reactions. Less often, adverse drug reactions represent a manifestation of an
the risk is greatly increased in patients who metabolize the drug slowly.3,7
immunological phenomenon, so-called allergic drug reactions.5,15 Although
Drug-induced lupus erythematosus may also be caused by procainamide,
in theory the above subdivisions are sharply defined, in many patients the
chlorpromazine, isoniazid, methyldopa, penicillamine, minocycline, quini-
underlying pathogenetic mechanisms are far from clear.13
dine, and sulfasalazine.36–38 Cefaclor-induced serum sickness-like eruptions
Adverse drug reactions are particularly encountered in certain population
and the antiepileptic hypersensitivity syndrome are also believed to result
groups, for example the elderly, females, patients with Sjögren's syndrome,
from reactive intermediate metabolic products.39,40
and those suffering from the effects of immune deficiency including patients
receiving immunosuppressive therapy and those suffering from the acquired
immunodeficiency syndrome (AIDS).5 Exacerbation of a pre-existing condition
Adverse drug reactions can be divided into three categories: type A, type This is a not uncommon problem; for example, lithium, beta-blockers, anti-
B, and type C.1,12,16 malarial drugs, NSAIDs, and tetracycline may precipitate, aggravate or induce
a psoriatic eruption.4,41–45
Type A drug reactions Pseudoallergic drug reactions

Type A reactions, which are predictable and are related to the pharmacologi- Pseudoallergic reactions result from the nonimmunologically mediated
cal actions or metabolism of the drug, include:1 release of effector substances such as histamine from tissue-bound mast cells
• side effects, or circulating basophils with resultant urticarial reactions, angioneurotic
• drug toxicity, edema, and anaphylaxis.1,4 The complement system can also be activated
• drug interactions. by similar nonimmune mechanisms, and there is evidence that perturbation
of arachidonic acid metabolism may be involved in some cases.1,3,17 Drugs
Side effects which have been incriminated in such pseudoallergic reactions include radio-
contrast media, NSAIDs, acetyl salicylic acid, opium derivatives, codeine,
Side effects, which occur with almost all drugs, represent unwanted phar-
curare, d-tubocurare, polymyxin B, and angiotensin-converting enzyme
macological actions. For example, methotrexate, cyclophosphamide and
(ACE) inhibitors.46–50
nitrosourea commonly result in anagen alopecia by inducing Bax protein-
mediated apoptosis.17–21 Gold may be associated with cutaneous pigmenta-
tion (chrysiasis) and penicillamine can be associated with the development of
skin laxity and fragility.22–25 Type C drug reactions
Type C reactions are rare, immunologically mediated, and develop as a conse-
Drug toxicity
quence of previous exposure to the drug with resultant allergy.1 The majority
Drug toxicity develops as a consequence of the gradual accumulation of of drugs are of low molecular weight (less than 1000 Daltons) and therefore
a drug or its metabolite (e.g., minocycline or amiodarone deposition with on their own are incapable of eliciting an immune response. By functioning
resultant abnormal pigmentation).15,26–29 Delayed toxicity may take months as haptens and forming conjugates with carrier plasma proteins or cell mem-
to many years before expression (e.g., arsenical keratoses).30–33 brane constituents they develop immunogenic potential.1,2,17 The ability of
the majority of drugs to cause an immune response is therefore dependent
Drug interactions on whether it is able to bind to circulating or tissue protein.51 A number of
Drug interactions develop when one drug alters the pharmacological effi- drugs are likely to induce allergic reactions, including antibiotics, anticon-
cacy of another that is given concurrently.12,13,34,35 The effect may enhance or vulsants, chemotherapeutic agents, heparin, insulin, protamine, and biolog-
diminish the effect of the drug with resultant toxicity or loss of therapeutic ical response modifiers such as interferons and growth factors.1 A variety
value.13,14 Drug interactions are thought to arise when one drug affects clear- of mechanisms may be involved in cutaneous drug-induced hypersensitivity
ance of the other as a consequence of several mechanisms including:3,4 reactions including:12
• alteration in the rate of absorption resulting in diminished drug levels, • IgE mediated type 1 reactions,
• alteration in the renal excretion resulting in inappropriately high drug • immune complex-associated type 3 reactions,
levels, • type 4 delayed hypersensitivity reactions.
• plasma protein or tissue drug binding site competition resulting in
displacement and inappropriately high drug levels,
IgE-mediated type 1 cutaneous reactions
• alterations in hepatic cytochrome P-450-mediated drug metabolism.
The last is believed to be of particular importance and includes increased In type 1 reactions, the release of histamine and other chemical mediators
enzyme synthesis with excessive drug degradation and diminished circulating from tissue-fixed mast cells results in increased vascular permeability with
or tissue levels and inhibition of drug breakdown with increased circulating development of edema in the dermis or deeper tissues.5,17 Immediate reac-
and tissue levels.34,36 tions which develop within an hour or less of drug exposure present as
Drug interactions are of particular importance in the elderly, the immuno- urticaria, angioedema or anaphylaxis whereas accelerated reactions which
suppressed, and in those patients receiving multiple medications.3,4 develop from 1 to 72 hours following the administration of the drug are usu-
ally urticarial.17 Urticaria following treatment with penicillin is a typical type
1 reaction. Certain other antibiotics, antisera, and gammaglobulin are also
Type B drug reactions common offenders.12
The most common cause of anaphylaxis is penicillin.52 Other causes
Type B reactions are uncommon and unpredictable. They do not have an include foods, stings, anesthetics, muscle relaxants, latex, contrast material,
allergic pathogenesis and include: 1 antibiotics, and allergenic extracts.52–54 In addition to histamine, anaphylaxis
• idiosyncratic drug reactions, is mediated through a number of substances including prostaglandin D2,
• exacerbation of a pre-existing condition, leukotriene C4, interleukin (IL)-4 and IL-13, and tumor necrosis factor alpha
• pseudoallergic drug reactions. (TNF-α).51
592 Cutaneous adverse reactions to drugs
Immune complex-associated type 3 reactions reactions are of importance in many other adverse allergic drug reac-
tions including exanthematous/morbilliform, bullous, and interface vari-
Type 3 reactions are expressed as urticaria, the Arthus reaction, serum sick-
ants.55–58 Although most delayed hypersensitivity reactions are immune
ness, and leukocytoclastic (allergic) vasculitis.12 The disease manifests a week
responses to the hapten-carrier complex, recent studies indicate that some
or more after exposure to the drug, by which time sufficient circulating anti-
drugs may be capable of directly activating the immune system, inde-
body has been generated to result in immune complexes of an appropriate
pendent of a covalent drug–peptide complex.59 Certain medications may
size to avoid phagocytosis. Their deposition in the tissues or within blood ves-
directly bind T-cell receptors and MHC molecules and trigger the release
sel walls is accompanied by complement fixation and resultant acute inflam-
of cytokines which recruit specific leukocytes. The delayed hypersensitiv-
matory reaction.
ity reactions may be subclassified based on the cell type recruited: mono-
Delayed hypersensitivity type 4 reactions cytes (type 4a), eosinophils (type 4b), T cells (type 4c), and neutrophils
(type IVd). The resultant clinical phenotype may be determined by which
Delayed hypersensitivity reactions are T-lymphocyte mediated and exem- cells are involved.59
plified in acute allergic contact dermatitis.12,17 Cytotoxic T-cell-mediated
Adverse drug reactions – clinical manifestations

Although the range of drugs that may result in adverse drug reactions is
extensive, the variety of clinical responses encountered is fairly limited. Many
drugs may cause more than one clinical response and any given reaction pat-
tern may result from a wide range of drugs. There are, however, a number of
clinicopathological responses that are fairly unique to a particular drug and
these are dealt with individually, later in this chapter.1–8
Adverse drug reactions may therefore present with a considerable number
of clinical manifestations as outlined in Box 14.1.1,2
Exanthematous reactions
Clinical features
Exanthematous (morbilliform, maculopapular) reactions are the most fre-
quently encountered adverse drug reaction, accounting for 51% to 95% of
skin reactions, and mimic a variety of infective conditions including scarlet
fever, measles, and rubella (Figs 14.1, 14.2).1–5 Patients present with ery-
thematous macules and papules that may become confluent or gyrate/ polycy-
clic. Pruritus, low-grade fever, and eosinophilia are sometimes present.2 The Fig. 14.1
eruption is often symmetrical and usually presents on the trunk and extremi- Exanthematous
ties or sites of pressure and trauma.1 The palms and soles are sometimes drug reaction: typical
affected but the mucous membranes are not usually involved. erythematous
maculopapular eruption
on the lower extremities
due to ampicillin. By
Box 14.1
Clinical manifestations of adverse drug reactions
• Exanthematous reactions
• Urticaria, angioedema and anaphylaxis
• Serum sickness
• Phototoxic/photoallergic eruptions
• Hypersensitivity syndrome
• Lichenoid drug reactions
• Fixed drug eruptions
• Stevens-Johnson syndrome/toxic epidermal necrolysis
• Pigmentary abnormalities
• Vasculitis
• Purpura
• Granulomatous drug reactions
• Erythema nodosum
• Drug-induced alopecia
• Lupus erythematosus-like drug reactions
• Bullous drug reactions
• Psoriasiform drug reactions
• Pityriasis rosea-like eruptions
• Pustular drug reactions
• Ichthyosiform drug reactions
• Pseudolymphomatous drug reactions Fig. 14.2
• Eczematous drug reactions Exanthematous drug reaction: more extensive lesions on the abdomen associated
with amoxicillin therapy. By courtesy of the Institute of Dermatology, London, UK.
Exanthematous reactions 593
Exanthematous eruptions typically develop within 1–2 weeks of starting

the drug.1 Occasionally, the eruption is delayed and may even present after
the treatment has ceased.1,6 In more seriously affected patients the eruption
can progress to erythroderma (exfoliative dermatitis) in which the erythema
becomes generalized and is often accompanied by scaling.7 Resolution of
exanthematous drug reactions is characterized by exfoliation and sometimes
is followed by postinflammatory hyper- or hypopigmentation.1 Penicillin, sul-
fonamides, ampicillin, amoxicillin, phenylbutazone, isoniazid, barbiturates,
phenytoin, carbamazepine, benzodiazepines, gold, and trimethoprim are
especially incriminated.1,8–10 Patients who suffer from infectious mononucleo-
sis are at risk of developing an exanthematous reaction following therapy
with ampicillin or amoxicillin.11

The pathogenesis of exanthematous drug reactions is not fully understood,
although a cytotoxic T-cell-mediated reaction is likely in most cases (see
Immunohistochemistry).
The histological features are often subtle. Although the epidermis may
appear normal, focal parakeratosis is commonly present. The characteris- Fig. 14.4
tic changes include lymphocytic exocytosis with mild spongiosis, typically Exanthematous drug
reaction: in this example
accompanied by basal cell liquefactive degeneration and a few dyskeratotic
due to carbamazepine
keratinocytes (Figs 14.3–14.7).12,13 The dermis shows a perivascular infil-
therapy, there is
trate of lymphocytes and histiocytes with variable numbers of eosinophils. spongiosis, dyskeratosis,
Eosinophils – although often emphasized in the literature as an important fea- and interface change
ture of drug reactions – can, in our experience, be very scanty or even absent. associated with
Sometimes marked edema is seen, particularly if an urticarial element is clini- lymphocytic exocytosis.
cally evident. Red cell extravasation may also be a feature in those lesions
that include a purpuric component.
By immunohistochemistry, the lymphocytes are largely CD3+ T-cells with
a predominance of CD4+ cells in the superficial perivascular infiltrate.14
Lymphocytes at the dermoepidermal junction and within the epidermis con-
sist of approximately equal numbers of CD4+ and CD8+ forms.14–19 These
latter cells regularly express human leukocyte antigen (HLA)-DR and a sub-
population also expresses CD25.19 There is an admixture of T-helper Th1
and Th2 cells.18 Occasionally, the infiltrate is almost entirely composed of
the CD4+ lymphocytes and, contrariwise in human immunodeficiency virus
(HIV) positive patients, the infiltrate may consist of CD8+ cells alone.14,17
CD1a+ dendritic cells and CD68+ histiocytes are also present.18 CD56+ nat-
ural killer (NK) cells may be identified.17 Cytotoxic pathways mediated by
Fig. 14.5
Exanthematous drug reaction: low power view showing focal parakeratois, mild
acanthosis and a heavy upper dermal inflammatory cell infiltrate.
perforin and granzyme B have been shown to be of particular importance in

exanthematous drug reactions.16,18,19 Fas/Fas-L cytotoxic mechanisms are not
thought to be of relevance.14
The features of drug-induced erythroderma are rather non-specific and
include parakeratosis and psoriasiform hyperplasia, sometimes accompanied
Fig. 14.3 by mild spongiosis. Eosinophils may be identified within the dermal chronic
Exanthematous drug inflammatory cell infiltrate.
reaction: early lesion
due to penicillin Differential diagnosis
showing slight interface
Exanthematous adverse drug reactions are a frequent feature in transplanta-
change, spongiosis, and
lymphocytic exocytosis. tion patients who are usually taking multiple medications and, therefore, must
There is a superficial be distinguished from acute GVHD. In reality, it is difficult, if not impossible,
perivascular lymphocytic to make this distinction histologically. Traditionally, the presence of eosino-
infiltrate, and one or two phils has been thought to support a drug reaction. However, a recent study
plasma cells are present. found tissue eosinophils in both graft-versus-host disease and drug reactions,
submucosal layers are affected, angioedema results.2–4 Urticaria can also be a

manifestation of serum sickness and anaphylaxis.
Urticarial reactions may be caused by a large number of drugs. Aspirin,
penicillin, ACE inhibitors, and blood products are particularly incriminated.5,6
Drugs which directly stimulate mast cell release of vasoactive substances such
as histamine can cause urticaria, include opiates, curare, vancomycin, and
polymyxin B.3,7,8 Radiocontrast media may have a similar effect.3 Urticarial
reactions due to aspirin and NSAIDs are thought to sometimes be a result of
abnormal arachidonic acid metabolism.3

The pathogenesis of urticarial drug reactions includes IgE-mediated type 1
reactions, immune complex mechanisms, and pseudoallergic phenomena
(non IgE-mediated).5,9,10
Histologically, urticaria is characterized by dermal edema and vascular
dilatation accompanied by a perivascular infiltrate consisting of lymphocytes
Fig. 14.6 and eosinophils (Fig. 14.8). Edema is often difficult to appreciate histologi-
Exanthematous drug cally but may be inferred by separation of collagen bundles. Mast cell degran-
reaction: in this high ulation may be present.3 Vasculitis is not a feature.
power view there Angioedema is characterized by edema extending into the deeper dermis
is parakeratosis, and subcutaneous fat.
focal spongiosis and
lymphocytic exocytosis.
A heavy dermal infiltrate
is present with one or
Serum sickness/serum sickness-like
two eosinophils. drug reactions
Clinical features
Serum sickness develops within 1–3 weeks after taking the serum or vac-
cine.1–8 It presents with an erythematous maculopapular or urticarial
response or with palpable purpura variably accompanied by fever, arthral-
gia, myalgia, arthritis, lymphadenopathy, glomerulonephritis, myocarditis,
and neuritis (Fig. 14.9).1–4 The cutaneous manifestations often commence
on the sides of the fingers, toes, and hands before becoming more gener-
alized.2 A wide range of drugs has been implicated in the development of
serum sickness-like drug reactions including phenytoin, phenylbutazone,
and carbamazepine. Antibiotics are also a common offender, with cefaclor
featured most prominently along with other antibiotics such as cefprozil,
ciprofloxacin, minocycline, penicillin V, amoxicillin, flucloxacillin, and co-
trimoxazole.6,9–19 More recently, therapy with monoclonal antibodies such
as rituximab, infliximab, and natalizumab has been associated with serum
sickness-like reactions.20–22
Fig. 14.7
Exanthematous drug
reaction: note the
interface change and
cytoid bodies.
making histological distinction impossible.20 A viral exanthem also commonly

enters the differential diagnosis – the histological findings are often indistin-
guishable although the presence of eosinophils may favor a drug reaction.
Urticarial reactions, angioedema

and anaphylaxis
Clinical features
Urticaria is the second most common adverse drug reaction.1 It is character- Fig. 14.8
ized by pruritic, erythematous, and edematous wheals. If accompanied by Urticarial drug reaction: high-power view showing a predominately perivascular
marked edema involving the deeper dermis and subcutaneous fat, or if the lymphohistiocytic infiltrate with one or two eosinophils.
Phototoxic and photoallergic reactions 595
Fig. 14.9
Serum sickness: there is a widespread erythematous and urticarial eruption.
Fig. 14.11
Phototoxic drug reaction:
Pathogenesis and histological features in this example there
Serum sickness is thought to represent an immune complex-mediated type are well-developed
3 reaction although the possibility of direct toxicity against vessel wall, auto- blisters arising on an
immunity, and cell-mediated cytotoxicity have been proposed as alternative erythematous base.
pathogenetic mechanisms.2 Direct immunofluorescence reveals immunoglob-
ulin and C3 in relation to blood vessel walls.6
The histological features are those of leukocytoclastic vasculitis (Fig. 14.10).23
Phototoxic and photoallergic reactions

Clinical features
There are two types of photosensitive drug reactions: phototoxic and photo-
allergic. Phototoxic reactions are more common; however, they are not neces-
sarily mutually exclusive and are not always clinically distinguishable.1–30 The
clinical appearances of acute phototoxic reactions mimic severe sunburn and
include erythema, edema, and blistering with subsequent desquamation and
postinflammatory hyperpigmentation (Figs 14.11, 14.12).6,7 Typically, only
exposed skin is affected and it occurs minutes to hours after sun exposure.
Phototoxicity has also been associated with onycholysis.21,25
Chronic phototoxicity presents with poikilodermatous features including
hyper- and hypopigmentation, epidermal atrophy, and telangiectasia. It is an
important feature of the porphyrias and the inherited photodermatoses such
Fig. 14.12
Phototoxic drug reaction: the lesions in this patient followed PUVA therapy.
as xeroderma pigmentosum, Rothmund-Thomson syndrome, and Bloom's

syndrome. It rarely results from drug treatment but may follow long-term
therapy with psoralen and UVA (PUVA therapy) where there is also an
increased incidence of actinic keratosis, basal cell carcinoma, squamous cell
carcinoma and, more rarely, melanoma.6,31–34
Drugs that are incriminated in acute phototoxic reactions include thi-
azide diuretics, sulfonamides, tetracycline antibiotics, NSAIDs (including
naproxen, diclofenac, and ketoprofen), phenothiazines (particularly chlo-
rpromazine), amiodarone, tars, and psoralens.6–13,19,20,23,24,29 Phototoxicity has
also been described with use of St. John's wort and following photodynamic
therapy.22,26 Porphyrins are potent phototoxic sensitizers.6 In this instance, the
damage affects the dermal constituents including the vasculature, leaving the
epidermis relatively unaffected.
The clinical appearances of photoallergic drug reactions are variable and
Fig. 14.10 include eczematous and lichenoid dermatitides (Figs 14.13, 14.14).14 The
Serum sickness: there is a florid leukocytoclastic vasculitis. rash usually develops 24 hours or more after sun exposure. Unlike phototoxic
Fig. 14.15
Phytophotodermatitis:
this variant represents
Fig. 14.13 an allergic reaction to a
Photoallergic drug reaction: note the obvious sparing of covered skin. By courtesy plant chemical. Linear
of the Institute of Dermatology, London, UK. lesions on the limbs are
characteristic and usually
follow gardening.
By courtesy of the
London, UK.
(Fig. 14.15).35 Members of the Umbelliferae, Rutaceae and Moraceae fami-

lies are implicated.36,37

Photosensitization has been described as a process whereby 'a reaction to
non-ionizing radiation occurs as a consequence of the introduction of a radi-
ation-absorbing reagent (the sensitizer), which induces another substance
(the substrate) to undergo chemical change'.1–6 There are two basic mecha-
nisms: phototoxic and photoallergic. While an enormous range of drugs has
been implicated in photosensitivity reactions, NSAIDS, phenothiazines, ami-
odarone, antibiotics, and antifungal agents such as griseofulvin appear to be
of particular importance.30
Two types of phototoxic reactions are recognized: photodynamic and non-
photodynamic.6
Fig. 14.14 • Photodynamic reactions are oxygen-dependent and result in singlet
Photoallergic drug oxygen or superoxide anions which cause injury to cellular constituents
reaction: this example such as cell membranes, cytoplasmic proteins and nucleic acids.
resulted from treatment
• Nonphotodynamic reactions are oxygen independent and damage DNA
with tetracycline.
or RNA directly.
By courtesy of the
Many drug reactions are photodynamic, whereas psoralen represents a
London, UK. nonphotodynamic reaction. Phototoxic reactions do not depend on prior
exposure to the drug and will affect all patients of the same skin type pro-
vided that sufficient bound drug is available for reaction with the appropri-
reactions, unexposed skin may also be affected in addition to exposed skin.7 ate radiation.1 The action spectrum for phototoxicity is UVA, and less often
Typically, the dermatitis resolves after withdrawal of the offending agent. UVB and visible light.
Rarely, a persistent light reaction may occur in which the photodermatitis Photoallergic drug-induced photosensitivity is immunologically mediated
persists despite removal of the photosensitizing chemical. This usually occurs and represents a delayed papular, vesicular or eczematous response.6 It is a
in the setting of photoallergic contact dermatitis. lymphocyte-mediated delayed hypersensitivity type 4 reaction. It typically
The majority of photoallergic reactions are induced by the application of requires previous exposure to the drug or chemical.1,5 Only a proportion of
topical medicaments and chemicals (contact photoallergy) including antihista- patients taking the drug will develop a reaction. Photoallergic reactions are
mines, local anesthetics, chlorpromazine, hydrocortisone sunscreens contain- usually induced by UVA.1,2
ing p-aminobenzoic acid, and halogenated phenolic compounds in soaps and The histological appearances of acute phototoxic reactions include con-
fragrances (e.g., 6-methylcoumarin and musk ambrette).2,7,15,17 Photoallergy spicuous apoptotic keratinocytes (sunburn cells) which in severe cases may
can also follow systemic administration of drugs including sulfonamides, affect the entire epidermis, with variable neutrophil exocytosis, dermal
griseofulvin, phenothiazines, tetracyclines, NSAIDs, chloroquine, and thiaz- edema, and a perivascular lymphohistiocytic infiltrate with small numbers of
ides.8,18 Diagnosis is best confirmed by a photopatch test. neutrophils and eosinophils (Figs 14.16, 14.17).38
Phytophotodermatitis represents a phototoxic drug reaction due to contact Chronic lesions are characterized by hyperkeratosis, hypergranulosis,
with plants containing furanocoumarins.35–37 Patients develop erythema fol- variable acanthosis and epidermal atrophy, increased melanin pigmenta-
lowed by postinflammatory hyperpigmentation. Rarely, blisters may develop tion, melanocyte hyperplasia, and pigmentary incontinence.38 Elastosis and
Anticonvulsant hypersensitivity syndrome 597
It can also be caused by other medications including allopurinol, azathio-

prine, dapsone, minocycline, sulfonamides, terbinafine, and more recently
efalizumab.12–17 The syndrome has been predominantly described in black
patients. There is no sex predilection.4 Children may be affected.18–22
Symptoms appear 1 to 8 weeks after starting the offending drug. Clinical fea-
tures include pyrexia, a maculopapular or erythrodermatous eruption, facial
or periorbital edema, strawberry tongue, tender lymphadenopathy, myosi-
tis and hepatitis associated with leukocytosis and eosinophilia (Figs 14.18,
14.19).4,5 Less often the cutaneous manifestations include localized or gener-
alized follicular pustules, erythema multiforme, and toxic epidermal necroly-
sis.4,6,22,23 In patients with the pustular variant, lesions present on the scalp
before becoming generalized.8,23,24 Conjunctivitis and/or pharyngitis may also
be present.2 Renal, pulmonary (interstitial pneumonitis), and hematological
(atypical lymphocytosis) involvement sometimes occur.5 The prognosis of this
syndrome is variable.25,26 The majority of patients recover but in those with
hepatitis, the mortality is approximately 20%.5,27
Fig. 14.16
Phototoxic drug reaction: this is a very severe reaction. Dermal edema has resulted
in subepidermal vesiculation.
Fig. 14.18
Anticonvulsant hypersensitivity syndrome: there is striking facial edema with
periorbital accentuation. By courtesy of C.C. Kim, MD, Department of Dermatology,
Fig. 14.17
Phototoxic drug reaction: note the multiple necrotic keratinocytes (sunburn cells).
The blister cavity is cell-free and the dermal papillae are preserved (festooning).
t elangiectatic vessels may be conspicuous, and in severely affected patients

stellate atypical myofibroblasts can be a feature. Epidermal disorganization
and dyskeratosis may also be present.6
The histological appearances of drug induced photoallergic reactions
includes spongiosis (often with vesiculation, lymphocytic, and eosinophil
exocytosis), accompanied by papillary dermal edema and an upper dermal
lymphohistiocytic infiltrate with variable numbers of eosinophils.38
Anticonvulsant hypersensitivity syndrome

Adverse drug reactions to phenytoin – which include erythematous maculo-
papular lesions, erythroderma, acneiform lesions, hypo- and hyperpigmenta- Fig. 14.19
tion, vasculitis, erythema multiforme, and toxic epidermal necrolysis – affect Anticonvulsant
up to 19% of patients taking this drug.1–7 Pseudolymphomatous drug reac- hypersensitivity
tions may also occur and these are discussed later in the chapter. syndrome: there is a
maculopapular eruption
A potentially fatal hypersensitivity syndrome develops in approximately 1
and pustules are present.
in 3000 patients receiving phenytoin.5,6 This is defined by a triad of pyrexia, By courtesy of C.C.
exanthematous skin rash, and evidence of systemic involvement.6 The acro- Kim, MD, Department
nym DRESS describes drug rash with eosinophilia and systemic symptoms. of Dermatology, Harvard
Administration of other antiepileptics including phenobarbital, carbam- Medical School, Boston,
azepine, primidone, and lamotrigine may result in an identical condition.8–11 USA.

The precise etiology of this syndrome is uncertain. It is thought to result
Lichenoid and interface drug reactions
from an inability to detoxify arene oxide anticonvulsant metabolites due to Clinical features
absence, possibly genetically determined, of specific hydrolases. The condi-
tion has been associated with reactivation of human herpes virus 6 and 7, Lichenoid drug reactions are clinically similar to lichen planus although lesions
Epstein-Barr virus, and cytomegalovirus.28–33 are often larger, Wickham's striae are usually not apparent, and mucosal
The histological features vary from spongiotic dermatitis to those of ery- involvement is commonly absent.1–4 In contrast to lichen planus, where
thema multiforme or toxic epidermal necrolysis. Pustular lesions are char- lesions are characteristically on the flexural surfaces of the forearms, the legs,
acterized by a subcorneal pustule associated with follicular infundibular and the genitalia, in lichenoid drug reactions the trunk and extremities are
dilatation (Figs 14.20, 14.21).8 more often affected (Figs 14.22, 14.23 ).4,5 The eruption may sometimes be
photodistributed and predominantly affect the hands and forearms although
other sun-exposed sites can be involved.4,6,7 The latent period between start-
ing the drug and the onset of the eruption is often long, months or even
years.4 Atypical features including eczematous and psoriasiform lesions are
sometimes seen and bullous or ulcerative variants are occasionally encoun-
tered.3,4,8 Postinflammatory hyperpigmentation may be very marked and is
Fig. 14.20
Anticonvulsant
hypersensitivity
syndrome: this example
shows a subcorneal
Fig. 14.22
pustule.
Lichenoid drug reaction:
lichenoid papules are
widely distributed about
the patient’s face and
upper chest.
Fig. 14.21
Anticonvulsant
hypersensitivity
syndrome: the
underlying dermis
shows a superficial
dermal perivascular
lymphohistiocytic Fig. 14.23
infiltrate with scattered Lichenoid drug reaction: lichenoid papules on the back. By courtesy of
eosinophils. B Al-Mahmoud, MD, Doha, Qatar.
Fixed drug eruptions 599
often persistent. Scarring alopecia is sometimes present and some patients

may develop anhidrosis.4
Although many drugs can cause a lichenoid reaction, those of particularly
importance include gold, antimalarials such as quinine and quinidine, pen-
icillamine, captopril, various beta-blockers (e.g., propranolol), lithium, thi-
azide diuretics, furosemide (frusemide),spironolactone, and ethambutol.4,7–19
More recently, the TNF-alpha inhibitors infliximab, adalimumab, and etan-
ercept have been associated with lichenoid eruptions.20–22
Contact with p-phenylenediamine by workers in the photographic color
developing process and hairdressers may also result in a cutaneous lichenoid
reaction. This is of two types:
• Continuous exposure to small amounts results in the appearance of
typical lichen planus.
• If exposed to a single large dose, the features are those of a lichenoid
contact dermatitis.4
Other causes of a contact lichenoid eruption include dental restorative
materials, musk ambrette, nickel, and gold.4
Captopril and cinnarizine may cause lichen planus pemphigoides-like
eruptions (see bullous drug reactions below).23,24
Fig. 14.25
Lichenoid drug reaction: In this example, the changes of hypertrophic lichen planus-
Histological features like lesions are evident. There is pseudoepitheliomatous hyperplasia and a dense
The histological features are frequently indistinguishable from typical lichen upper dermal lymphohistiocytic infiltrate.
planus although focal parakeratosis and spongiosis are sometimes present and
interface change may be patchy (Figs 14.24–14.26). The epidermis is often thin-
ner and hypergranulosis less marked.15 Cytoid bodies may be found in the upper
granular cell layer or even in the stratum corneum.5,7 Sometimes, eosinophils and
occasionally plasma cells are found in the dermal infiltrate.5 Focal interruption
of the granular cell layer, exocytosis of lymphoid cells into the upper epidermis
and a perivascular infiltrate in the deeper dermis are said to be additional helpful
diagnostic pointers.7 Photodistributed lichenoid drug reactions are said to more
closely resemble idiopathic lichen planus than nonphotodistributed variants.5 The
changes that allow distinction from lichen planus are often seen in hypertrophic
lichen planus. However, in lichenoid drug eruptions, prominent hyperplasia is
hardly ever present. With some drug reactions, interface changes are present in the
absence of a background of epidermal lichenoid features (Figs 14.27, 14.28).
Fixed drug eruptions

Clinical features
Fixed drug eruptions present as one or more circumscribed erythematous
to violaceous or brown plaques that show a predilection for the extremities
including the hands, feet, and external genitalia (Figs 14.29, 14.30).1–8 Fig. 14.26
Lichenoid drug reaction: focal interface change is present. Eosinophils are conspicuous.
Fig. 14.24 Fig. 14.27

Lichenoid drug reaction: there is hyperkeratosis, hypergranulosis with Interface drug reaction: more extensive lesion due to propranolol showing
interface change. Note the superficial bandlike infiltrate. The appearances are hyperkeratosis, widespread apoptosis, upper dermal edema, and a superficial
indistinguishable from idiopathic lichen planus. chronic inflammatory cell infiltrate.
Fig. 14.28 Fig. 14.30

Interface drug reaction: there are numerous apoptotic keratinocytes and severe Fixed drug eruption: early, sharply delineated erythematous lesion.
interface change is evident. By courtesy of the Institute of Dermatology, London, UK.

The mucous membranes may be affected, either alone or in association Fixed drug eruption is unique owing to the precise localization of the erup-
with cutaneous manifestations.3 Lesions – which may be pruritic or pres- tion and its recurrence at the same site on rechallenge. To understand this
ent with a burning sensation – typically recur at the same site on rechallenge process, initial research was directed towards identifying the site of cutaneous
with the offending drug. They usually develop within 30 minutes to 8 hours memory. Autotransplantation experiments in which normal skin was grafted
after taking the drug.3 Vesiculation and blistering are common. Resolution to a previously affected site and vice versa, followed by rechallenge with the
is typically marked by postinflammatory hyperpigmentation varying from causative drug, produced conflicting results. Some workers found that fol-
brown to brown-violet or even black.6 In cases with multiple lesions the lowing challenge, grafted normal skin was unaffected, whereas transplanted
multiple pigmented patches result in an appearance described as ‘Dalmatian previously affected skin developed erythema and became symptomatic.10
dog’. Occasionally, the eruption is generalized and resembles toxic epider- Others experienced quite the opposite results.11
mal necrolysis.9 Although the number of drugs that are capable of eliciting a Immunofluorescence studies have been equally conflicting. While some
fixed reaction is very large, those that are said to be more commonly incrimi- authors have documented in vivo bound immunoglobulin and complement
nated include barbiturates, phenylbutazone, ibuprofen, acetyl salicylic acid, in the intercellular region of the epidermis or at its basement membrane, the
sulfonamides, trimethoprim-sulfamethoxazole, tetracyclines, dapsone, phe- majority of investigations have been negative.12,13
nolphthalein, and quinine.2,3,6 It seems unlikely, therefore, that humoral immunity has a significant part
to play in the pathogenesis of fixed drug eruption. Current research is directed
towards understanding the role of cellular immunity. On initial exposure, the
drug appears to bind to the epidermal keratinocytes (thereby functioning as a
hapten) and is presented by Langerhans cells to lymphocytes within the der-
mis or in local lymph nodes. This stimulates an effector CD8+ lymphocyte
population which, on returning to the epidermis, produces various cytokines
including interferon-gamma (IFN-γ) and TNF-α which result in epidermal
necrosis.14,15 Keratinocyte death is believed to be mediated by both cytolytic
pathways (e.g., perforin, granzyme A, and granzyme B) and FAS-mediated
apoptosis.14–16 Resolution of the disease is thought to be due to recruitment of
CD4+ T cells into the epidermis which suppress CD8+ T-cell activation and
limit cell destruction, possibly via production of IL-10.17
Although the precise mechanism by which memory in fixed drug eruption
is achieved is incompletely understood, there is now considerable evidence
to suggest that an intraepidermal effector-memory CD8+ T-cell popula-
tion residing in the epidermis after the initial drug reaction is of particular
importance.13–20 Such cells are defined immunohistochemically by expression
of CD3, CD45RA, TCR-alpha beta, CD11a, and CD11b, and absence of
CD27, CD28, and CD62L.19,21 It has been demonstrated that they remain in a
state of activation (CD69+) in the unchallenged state and, following exposure
to the drug, rapidly up-regulate IFN-γ expression and induce FAS and FAS-
ligand expression, soon followed by epidermal necrosis.16,20
Fig. 14.29 Histologically, the acute fixed drug eruption is characterized by marked
Fixed drug eruption:
basal cell hydropic degeneration, with lymphocyte tagging along the dermoepi-
typical localized brown
plaque with a small dermal junction and individual keratinocyte necrosis (Figs 14.31–14.33).22
central blister. Marked pigmentary incontinence is typical. Subepidermal vesiculation may
By courtesy of the be a feature of advanced lesions. Lymphocytes, histiocytes, and neutrophils
Institute of Dermatology, are evident in the upper dermis. Eosinophils may sometimes be prominent. In
London, UK. late lesions, pigmentary incontinence may be the sole histological finding.
Drug-induced hyperpigmentation 601
Erythema multiforme
Although infectious agents (herpes simplex virus, Mycoplasma species) are
the most common cause of erythema multiforme (EM), medications, or a
combination of medications and viral infections, are implicated in a subset
of patients. Drugs with the strongest association include antibiotics, anticon-
vulsants, and nonsteroidal antiinflammatory agents.1 Sulfonamides, specifi-
cally trimethoprim-sulfamethoxazole, carry the highest relative risk. Other
causative antibiotics include aminopenicillins, quinolones, cephalosporins,
and tetracyclines. The anticonvulsants associated with EM most often are
phenobarbital, carbamazepine, phenytoin, and valproic acid. EM due to a
combined viral infections and drug exposure has been described with cyto-
megalovirus and Epstein-Barr virus.2,3
Stevens-Johnson syndrome and toxic

epidermal necrolysis
Fig. 14.31 In contrast to erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic
Fixed drug eruption: there is epidermal hyperplasia, interface change, and a epidermal necrolysis (TEN) are strongly associated with medication use.1 The
superficial dermal chronic inflammatory cell infiltrate. profile of implicated drugs is similar to that seen in EM (see above).2 Studies
on newer medications cite strong associations for nevirapine, lamotrigine and
weaker but significant associations for sertraline, pantoprazole and tramadol.3
Drug-induced hyperpigmentation
Clinical features
Cutaneous hyperpigmentation is a frequent complication of drug ther-
apy. It may result from increased melanin synthesis or deposition of the
drug or its metabolite within the skin.1–5 Heavy metals can also result in
skin pigmentation.4 Most often, however, it results from postinflammatory
hyperpigmentation.3
Long-term treatment with minocycline might result in usually reversible
(types I and II) cutaneous pigmentation.6–13 Three clinical variants of cutane-
ous minocycline pigmentation are generally recognized (Figs 14.34–14.36):
• Type I: blue-black macules localized to areas of scarring and
inflammation (e.g., facial acne scars),
Fig. 14.32
Fixed drug eruption: high-power view showing apoptosis and interface change.
Fig. 14.34
Minocycline
pigmentation: extensive
lesions involving the
cheek and periorbital
Fig. 14.33 region. By courtesy of the
Fixed drug eruption: in this example, the infiltrate has a predominantly perivascular Institute of Dermatology,
distribution. London, UK.
• Type II (most common): blue-black, brown or slate-gray pigmentation on thirds of the crown.16 Lesions of the oral mucosa are rare although pigmenta-
the shins, ankles and arms, tion has been described on the buccal mucosa, gingiva, tongue, and lips.17–21
• Type III: generalized muddy-brown pigmentation which may be The bones underlying the oral cavity (black bone disease) represent the single
exacerbated on sunlight-exposed regions. site most commonly affected by minocycline pigmentation.22 This is best visu-
A fourth variant affecting the lips and possibly representing a fixed drug alized by inspecting the maxillary and mandibular anterior alveolar mucosa.14
eruption has been described.14 The hard palate and lingual alveolar bone are also commonly affected.14
Nail pigmentation most often presents as a persistent slate-gray coloration The conjunctiva, sclera, thyroid (black thyroid), aorta, endocardium, and ath-
of the proximal nail bed.15 Additional features include longitudinal melanon- erosclerotic plaques may also be involved in minocycline pigmentation.23–29
ychia, diffuse nail pigmentation, and photo-onycholysis.15 Many other tetracyclines including methacycline and tetracycline hydro-
Minocycline may involve the teeth (causing a green–gray or blue–gray dis- chloride have also been associated with cutaneous pigmentation.30, 31
coloration) predominantly affecting the middle and occasionally the incisal Amiodarone, which is used primarily in the treatment of cardiac arrhyth-
mias, is associated with a phototoxic/photosensitivity reaction in up to 50% of
patients.32–38 In addition, cutaneous golden-brown to slate-gray or blue/viola-
ceous pigmentation predominantly affecting the exposed surfaces including
the face and the backs of the hands may develop, especially in those receiving
high doses over a protracted period of time (Fig. 14.37).32 Pigmentation is
also sometimes seen in the sclera and cornea.35
Antimalarials also result in abnormal skin pigmentation.39–42 Mepacrine
(quinacrine) typically produces a yellow coloration although local-
ized blue–black mucocutaneous lesions have been described (Figs 14.38,
14.39).42 Chloroquine and hydroxychloroquine cause yellow–brown to gray
Fig. 14.35
Minocycline
pigmentation: these
blue–black lesions
have developed in a
patient with pyoderma
gangrenosum. By
UK.
Fig. 14.37
Amiodarone pigmentation: note the slate-gray discoloration on the forehead, a
characteristic site. By courtesy of the Institute of Dermatology, London, UK.
Fig. 14.36
Minocycline
pigmentation; typical
pigmentation affecting
the shin. By courtesy
of the Institute of Fig. 14.38
Dermatology, London, Mepacrine pigmentation: a yellow discoloration is characteristic. By courtesy of the
UK. Institute of Dermatology, London, UK.
Drug-induced hyperpigmentation 603

The histological features of minocycline pigmentation are variable.7,10,11,14 In
types I and II variants, golden-brown to brown–black granules are found pre-
dominantly within macrophages distributed mainly around the vasculature
and sweat gland coils (Fig. 14.41). The pigment, which fluoresces yellow
under ultraviolet light, stains positively with both Masson-Fontana and Perl’s
Prussian blue reactions in type II variants (Figs 14.42, 14.43).11 The pigment
is periodic acid-Schiff (PAS) negative. In contrast, in type I, the pigment only
stains with Perl's reaction. It is believed to represent minocycline or its break-
down product chelated with hemosiderin, ferritin or iron.7 Calcium, sulfur,
and chlorine are also present but melanin is absent.11 Melanocytes and the
epidermis show no increase in melanin pigmentation in types I and II vari-
ants. Type III hyperpigmentation is characterized by an increase in epidermal
basal cell melanin pigmentation.6 The Perl’s stain is negative. Minocycline
pigmentation of the subcutaneous fat has recently been described in the clini-
cal setting of type II disease.52,53 Histologically, there is pigment within mac-
rophages and giant cells in the subcutaneous fat, with positive staining for
Masson-Fontana and variable staining with Perl’s reaction. One study also
described green–gray nonrefractile globules within macrophages in the fat.53
Fig. 14.39 Histologically, amiodarone pigmentation is characterized by macrophages
Mepacrine pigmentation: containing PAS-positive, yellow–brown lipofuscin-like granules located in a
in this patient the drug perivascular distribution (Figs 14.44, 14.45).32 Melanin pigmentation of the
resulted in black lesions.
By courtesy of the
London, UK.
igmentation.2,39–41 Sun-exposed skin is predominantly affected, although

p
mucosal pigmentation may also occur.43
In addition to causing photosensitivity and contact dermatitis, chlorpro-
mazine therapy (particularly when protracted and in high doses) can result
in cutaneous pigmentation, especially on sun-exposed skin such as the face,
dorsum of the hands, and the neck.2,44–47 Patients may present with a golden-
brown, tanned appearance while others develop a slate-gray, bluish or purple
appearance. The cornea and lens of the eye can also be involved.2
Long-term treatment with imipramine may result in photodistributed
hyperpigmentation affecting the face, neck, ‘V’ of chest, arms, and hands
(Fig. 14.40).48–50 The coloration varies from golden-brown to blue-gray or
slate-gray. The irises may also darken.
Photodistributed blue-gray pigmentation has been documented following
treatment with desipramine.51
Heavy metals including gold, silver, and mercury can all result in cutane-
ous pigmentation (see below).
Fig. 14.41
Minocycline pigmentation: note the presence of perivascular granular brown pigment.
Fig. 14.40
Imipramine pigmentation: note the intense brown pigment of the hands and
forearms in comparison with the chest. By courtesy of L. Cohen, MD, Cohen Fig. 14.42
Dermatopathology, Massachusetts, USA. Minocycline pigmentation: the pigment stains positively with Masson-Fontana.
Fig. 14.43 Fig. 14.46

Minocycline pigmentation: the pigment also stains with Prussian blue. Imipramine pigmentation: typical golden-brown granules. Note that the Prussian
blue reaction is negative. By courtesy of L. Cohen, MD, Cohen Dermatopathology,
Massachusetts, USA.
epidermis is not increased; indeed its absence in involved skin has recently
been documented.38 By electron microscopy, the granules are located within
lysosomes.33,37 Lamellar myelin bodies may also be identified.23 Similar
inclusions may be found in the hepatocytes, Kupffer cells, pulmonary mac-
rophages, and neutrophils.
In mepacrine (quinacrine) pigmentation, yellow–brown pigment is
found within the cytoplasm of histiocytes throughout the dermis.42 The
pigment is weakly positive with the Perl’s Prussian blue reaction for iron
and is Masson-Fontana negative.38,43 The histological findings in hydroxy-
chloroquine-related pigmentation have been described as yellow–brown
granular deposits within macrophages and extracellularly.54 These gran-
ules are nonrefractile and stain positively with Masson-Fontana and are
negative for iron.54
Histologically, chlorpromazine hyperpigmentation is characterized by
golden-brown macrophage-bound granules surrounding the superficial vas-
culature. The granules are positive with the Masson-Fontana reaction but
Fig. 14.44 do not stain with Perl’s Prussian blue.47 Ultrastructurally, the pigment is lys-
Amiodarone pigmentation: pigmented macrophages are present in a perivascular osome bound and present in endothelial cells, fibroblasts, Schwann, and
distribution. smooth muscle cells, in addition to macrophages.44,45 Increased melanin also
contributes to the cutaneous pigmentation.44
Histologically, imipramine and desipramine hyperpigmentation contain
Masson-Fontana positive golden-brown granules within the upper dermis,
lying both free and within macrophages (Fig. 14.46).48,49,51 Perl’s Prussian
blue is negative. Ultrastructurally, histiocytes contain melanosomes in addi-
tion to lysosomal-bound electron-dense granules.48
Vasculitic drug reactions

Adverse drug reactions are a common cause of vasculitis.1,2 An immune com-
plex mechanism mostly represents the pathogenesis in the majority of cases.
A wide range of drugs has been implicated, including anti-infective agents,
cancer chemotherapeutic agents and adjuvants, psychoactive and cardiovas-
cular drugs, diuretics, anticoagulants, beta-adrenergic receptor agonists, and
anticonvulsants.2 The more important agents include trimethoprim, peni-
cillin, sulfonamides, NSAIDs, and aspirin.3 Other implicated drugs include
cimetidine, clarithromycin, coumadin, furosemide (frusemide), hydralazine,
ibuprofen, iodides, phenacetin, phenothiazines, procainamide, rifampin, pro-
pythiouracil, and streptokinase (Figs 14.47, 14.48).4–13 More recently, anti-
TNF-alpha therapies have been linked to vasculitic reactions.14,15
Fig. 14.45 Granulomatous vasculitis has been described following treatment with
Amiodarone pigmentation: high-power view. chlorothiazide, allopurinol, phenytoin, and carbamazepine.4,16–18
Granulomatous drug reactions 605
Fig. 14.47 Fig. 14.49

Vasculitic drug reaction: hemorrhagic papules and plaques with central necrosis Purpuric drug reaction: there is massive subepidermal edema with red cell
complicating treatment with propylthiouracil. By courtesy of M. Mailberger, MD, extravasation.
Virginia Commonwealth University, Richmond, Virginia, USA.
reaction.2,3 This reaction pattern may also be related to a variety of systemic
illnesses including rheumatoid arthritis, hepatobiliary disease, diabetes mel-
litus, Crohn’s disease, and chronic infections such as hepatitis C, herpes
simplex/varicella-zoster, Epstein-Barr virus (EBV), and HIV.2 Patients pres-
ent with erythematous to violaceous, nonpruritic, irregular and sometimes
annular papules or plaques predominantly affecting the inner arms, inner
thighs, and the groins (Fig. 14.50).1 Erythroderma in a case of anticonvul-
sant-induced hypersensitivity syndrome has also been described.4
Histologically, the eruption is characterized by an interstitial infiltrate of
lymphocytes, histiocytes, eosinophils, plasma cells, and multinucleate giant
cells, sometimes associated with increased dermal mucin and showing more
than a superficial resemblance to interstitial granuloma annulare (Figs 14.51,
14.52). Fragmentation of collagen fibers and elastic tissue is commonly evi-
dent and phagocytosis of connective tissue debris by giant cells is typically
seen (Figs 14.53, 14.54). Discrete granulomata may also be identified and
granulomatous vasculitis has been documented.5 Flame figures and Churg-
Strauss-like granulomata have also been described.6,7 Atypical lympho-
Fig. 14.48 cytes with hyperchromatic, irregular and variably enlarged nuclei showing
Vasculitic drug reaction: there is acute vasculitis with thrombosis.
Purpuric drug reactions

Clinical features
Purpura may be a manifestation of an adverse drug reaction. Causes include
NSAIDs, diuretics, meprobamate, zomepirac sodium, ampicillin, pseu-
doephedrine, linezolid, and lidocine/prilocaine cream.1–4
The histological features are those of red cell extravasation in the absence of
changes of vasculitis (Fig. 14.49).
Granulomatous drug reactions

Clinical features
Interstitial granulomatous drug reactions are rare and have been associated
with a number of drugs including calcium channel blockers, ACE inhibitors, Fig. 14.50
beta-blockers, lipid-lowering agents, diuretics, NSAIDs, antihistamines, anti- Lichenoid and granulomatous dermatitis: note the flat-topped lichenoid papules.
convulsants, and antidepressants.1 More recently, IL-1 inhibitor (anakinra) This reaction developed during rituximab therapy. By courtesy of J. Francis, MD,
and adalimumab have been associated with an interstitial granulomatous Virginia Commonwealth University, Richmond, Virginia, USA.
Fig. 14.53
Granulomatous drug reaction: there is extensive elastophagocytosis (elastic van
Fig. 14.51 Gieson).
Granulomatous drug
reaction: there is a
marked infiltrate involving
dermis.
Fig. 14.54
Granulomatous drug reaction: phagocytosis of collagen may also be seen (Masson’s
trichrome).
Fig. 14.52 Drug-induced erythema nodosum

Granulomatous drug reaction: in this example there is an obvious interstitial
distribution reminiscent of granuloma annulare.
This topic is discussed in the chapter on panniculitis.
e pidermotropism are present in up to 50% of cases.1 The changes of interface

Drug-induced alopecia
dermatitis, sometimes with an associated lichenoid infiltrate, are found in the Drug-induced alopecia is usually reversible, predominantly nonscarring, and
majority of cases.1,5 affects females more often than males.1–4
Anagen effluvium, in which hair growth stops due to cessation of mitotic
Differential diagnosis activity, is a common feature of anticancer therapy and often develops days
Interstitial granulomatous drug reactions must be distinguished from granu- or a few weeks after starting the drug.1,2 The scalp and beard areas, which
loma annulare and systemic disease-associated lesions as described above. contain a high percentage of anagen follicles, are particularly affected.
Granuloma annulare is not usually associated with interface dermatitis, and It especially complicates combination chemotherapy and is likely to be severe.5
necrobiosis and mucin deposition are not features of granulomatous drug Although all anticancer drugs may be associated with some degree of alope-
reactions. Systemic disease-associated granulomatous dermatitis is usually cia, particular offenders include bleomycin, cyclophosphamide, dactinomy-
associated with vasculitic and/or thrombotic phenomena.7 In cases where cin, daunorubicin, doxorubicin, 5-fluorouracil, ifosfamide, and vindesine.1,2
significant lymphoid atypia is present, cutaneous T-cell lymphoma enters There is some variation in drug effect. Some cause alopecia in all individuals
the differential diagnosis. When elastophagocytosis is marked, granuloma- whereas others affect only a minority of patients.5
tous slack skin or an elastolytic granuloma may be important diagnostic Telogen effluvium, in which hairs are transformed into the telogen phase,
considerations. develops several months after commencing therapy.1 Anticoagulants, including
Bullous drug reactions 607
heparin and warfarin and dextran sulfate, cause telogen effluvium in up to 50%
of patients.3,5–11 Other causes include antithyroid drugs such as iodine, thiouracil
and carbimazole, oral contraceptives, lithium, interferons and retinoids.5,12,13
Alopecia areata may develop as a consequence of TNF-alpha inhibitors
such as adalimumab and etanercept.14,15
Drug-induced lupus erythematosus

Clinical features
Drug-induced systemic lupus erythematosus was first described as a com-
plication of hydralazine.1–8 It has also been reported in association with
procainamide, quinidine, sulfasalazine, chlorpromazine, penicillamine, meth-
yldopa, carbamazepine, acebutalol, isoniazid, captopril, propylthiouracil,
and minocycline.2,3 Therapy with TNF-alpha inhibitors has been associated
with a lupus-like syndrome.9,10 With the exception of hydralazine and pro-
cainamide (high risk) and quinidine (medium risk), the other associations are
low risk.2 Laboratory investigations reveal anti-Ro, anti-La, and antinuclear
antibodies (ANA) in the majority of cases.1 Subacute cutaneous lupus ery-
thematosus-like features have been described following treatment with ter- Fig. 14.55
binafine.11–13 More recently, localized cutaneous lupus lesions were described Bullous drug reaction: this subepidermal blister arose against a background of an
exanthematous drug reaction.
occurring at the site of IFN injection.14 Cutaneous lesions including malar
erythema, discoid lesions, photosensitivity, oral ulceration, and alopecia are
rare.2 Anti-TNF-alpha therapy-induced lupus may result in a higher incidence described following treatment with trimethoprim- sulfamethoxazole, penicil-
of cutaneous lesions, hypocomplementemia, and positive serology for dou- lin, phenytoin, somatostatin, lithium, amiodarone, captopril, cefamandole,
ble-stranded DNA as compared to other medications.13 Symptoms typically ceftriaxone, cyclosporin, IL-2, IFN-alpha, penicillin, amoxicillin, vigabatrin,
develop months to years after initiating therapy.15 Diagnostic criteria have and diclophenac.2,11–21 Cutaneous manifestations of vancomycin-induced
been defined as follows:2 linear IgA disease include pruritic, erythematous, urticarial, targetoid and
• continuous treatment with the suspected drug for 1 month or longer, bullous lesions with a predilection for the trunk, extremities, palms, and
• common presenting symptoms include arthralgias/arthritis, myositis, soles (Figs 14.56, 14.57).1 Morbilliform lesions have also been described.8
serositis, malaise and fever, Mucosal involvement is present in up to 40% of cases. As such, there can be
• antihistone antibodies frequent, particularly IgG anti-([H2A-H2B]-DNA), considerable clinical overlap with EM and TEN.2,9,10 Laryngeal involvement
• most importantly, clinical improvement within days or weeks after has been documented.20
stopping the suspected drug.
Histological features By definition, linear IgA deposition along the basement membrane region
The histological features of cutaneous lesions are indistinguishable from is present in all cases (Fig. 14.58). C3 is seen in approximately 20% of
those seen in the idiopathic forms.16 cases.7 Linear IgG may also very exceptionally be present, although distinc-
tion from drug-induced bullous pemphigoid can then be problematical.3,17
Such cases may, in fact, represent examples of drug-induced IgA-mediated
Bullous drug reactions bullous pemphigoid.21 Circulating IgA anti-basement membrane zone anti-
bodies are found in 25% of cases.1 Split skin studies predominantly localize
Blisters may develop within the setting of an adverse drug reaction either to the floor of the blister cavity.1,2 By immunoelectron microscopy, the results
as a consequence of severe spongiosis or marked interface change or they
may reflect drug-related autoimmune bullous disorders (Fig. 14.55). In this
section, only the last are discussed. These include drug-induced linear IgA
disease, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus
variants, and drug-induced pseudoporphyria. Many alleged drug reactions
are single case reports, particularly in patients taking multiple medications.
It is often difficult to determine which associations are therefore coinciden-
tal and which are genuine. In occasional reports, recrudescence following re-
exposure to the offending agent has been documented.
The precise mechanism of drug-induced blistering is unknown, although
multiple factors have been suggested:1
• direct toxicity to basement membrane constituents or intercellular
junctions with resultant autoantibody production,
• the drug may function as a hapten,
• the drug may be antigenically similar to a basement membrane or
intercellular junction constituent,
• perturbation of the immune system with inappropriate production of
anti-basement membrane antibodies,
• drug-induced abnormality of cell membrane calcium metabolism.
Drug-induced linear IgA disease Fig. 14.56

Drug-induced linear IgA disease: these blisters developed following treatment with
Drug-induced linear IgA disease is most often associated with intravenous vancomycin. By courtesy of B.A. Solky, MD, Department of Dermatology, Harvard
therapy with vancomycin.1–7,8–10 Similar eruptions, however, have also been Medical School, Boston, USA.
Fig. 14.57 Fig. 14.59

Drug-induced linear IgA disease: oral lesions were also present. By courtesy of B.A. Vancomycin-induced linear IgA disease: this case showed a neutrophil-rich
Solky, MD, Department of Dermatology, Harvard Medical School, Boston, USA. subepidermal blister.
Fig. 14.60
Fig. 14.58
Vancomycin-induced linear IgA disease: the adjacent skin showed neutrophil dermal
Vancomycin-induced linear IgA disease: immunofluorescence showed strong
papillary microabscesses.
basement membrane deposition of IgA.
are heterogeneous, IgA having been detected within the lamina lucida, lamina
densa, and in the sublamina densa.18–20 Western immunoblotting has detected
a number of antigens including a 230-kD antigen (bullous pemphigoid anti-
gen 1), a 97-kD antigen (an anchoring filament protein) and also a 250-kD
antigen corresponding to type VII collagen.19,20
Histologically, a neutrophil-rich subepidermal blister is seen in the major-
ity of cases but sometimes eosinophils are conspicuous (Figs 14.59–14.61).2
Drug-induced bullous pemphigoid

Clinical features
A variety of drugs including captopril, ciprofloxacin, chloroquine, furo-
semide (frusemide), ibuprofen, mefenamic acid, nifedipine, penicillamine,
penicillins, phenacetin, sulfasalazine, spironolactone, and enoxaparin have
been incriminated in alleged drug-induced bullous and mucosal pemphi-
goid.1–14 Of these, antirheumatics, cardiovascular drugs, and antimicrobial
drugs are the most important.6 Penicillamine is among the most commonly
incriminated (mucosal more than bullous), usually in rheumatoid arthritis
patients.6,15–17 Furosemide (frusemide) is believed to be an important cause of Fig.14.61
drug-induced bullous pemphigoid although recently this has been challenged, Vancomycin-induced linear IgA disease: conspicuous eosinophils may raise
the author suggesting that diagnoses of pseudoporphyria or epidermolysis suspicion for bullous pemphigoid if the clinical information is unavailable.
Psoriasiform drug reactions 609
bullosa acquisita may be more appropriate.6,18 The ACE inhibitors, capto- a change in prescribing habits to non-thiol related drugs, vulgaris-type cases
pril and enalapril, have both been associated with immunologically proven are more frequently seen.4 In most cases of imiquimod-induced pemphigus
bullous pemphigoid.2,8 The penicillins including amoxicillin and procaine foliaceus, disease is localized to the sites of application, although there is one
penicillin G are the most frequently implicated antibiotics.6 report of both localized and distant lesions.16 In the setting of radiotherapy,
Clinically, drug-induced bullous pemphigoid is similar to idiopathic disease all patients developed pemphigus at the site of radiation.18–21 One patient also
although the lesions are often polymorphic, mimicking other drug-induced had distant lesions.22
bullous dermatoses such as erythema multiforme, eczematous dermatitis, and
porphyria cutanea tarda.6 In drug-induced disease, mucous membranes are Pathogenesis and histological features
often involved, thereby blurring the distinction between bullous and mucosal Histologically, drug-induced and idiopathic variants are indistinguishable.23
variants of pemphigoid. In some patients there appears to be overlap between Intercellular IgG and circulating antibodies are variable in drug-induced pem-
bullous pemphigoid and pemphigus vulgaris.6 phigus, although in a series of 10 patients all had positive direct immunofluo-
rescence and 80% had circulating antibodies.4 Such antibodies may recognize
Histological features desmoglein 3 and/or 1.1,22
Drug-induced variants are characterized by linear IgG and C3 along the base-
ment membrane region on direct immunofluorescence.7,8 By indirect immu- Drug-induced pseudoporphyria
nofluorescence, the antibodies bind to the epidermal side (roof) of split
skin.2,5,6 Western immunoblotting has demonstrated that the antibodies react
Clinical features
with both the 230 kD and 180 kD bullous pemphigoid antigens.2,3
Histologically, drug-induced variants are similar to typical bullous pem- Pseudoporphyria is a rare blistering disease which clinically and histologi-
phigoid, being characterized by an eosinophil-rich subepidermal blister. cally mimics porphyria but which develops in the setting of normal porphy-
rin metabolism (Fig. 14.62). There are many causes including drugs, chronic
renal failure usually in the setting of dialysis, excessive sun exposure and
Drug-induced epidermolysis UVA. It has also been described following excessive use of sunbeds.1–15 The
bullosa acquisita most common medications include diuretics such as furosemide (frusemide)
and NSAIDs, particularly naproxen. Other drugs include isotretinoin and the
Drug-induced epidermolysis bullosa acquisita has been described following oral contraceptive. More recently imatinib (tyrosine kinase inhibitor) and
treatment with granulocyte–macrophage colony stimulating factor (GM-CSF) voriconazole have been implicated.14,15
and in a patient receiving vancomycin and gentamicin therapy.1,2 In both
patients, the blisters were subepidermal and eosinophil rich; direct immu- Pathogenesis and histological features
nofluorescence disclosed linear IgA and IgG deposits at the basement mem- The pathogenesis of pseudoporphyria is unknown but it may (at least in some
brane region. Split skin indirect immunofluorescence in the former patient patients) represent a phototoxic photosensitivity reaction.12
labeled the floor of the blister cavity and by immunoelectron microscopy the Histologically, pseudoporphyria is characterized by a subepidermal cell-
deposits were localized to the lamina densa and the sublamina densa region.1 free blister, typically with preservation of the dermal papillae (festooning).
In the latter patient, IgG antibodies against type VII collagen were recog- By immunofluorescence, immunoglobulin (most commonly IgG) is pres-
nized by an enzyme-linked immunosorbent assay (ELISA).2 An epidermol- ent at the dermoepidermal junction and also outlining the superficial dermal
ysis bullosa acquisita-like reaction has also been described after treatment vasculature.
with penicillamine. Histological features included a pauci-inflammatory sub-
epidermal blister. Linear deposition of C3, IgG and IgM are seen on direct
immunofluorescence, and IgG labels to the base of the blister on salt-spilt Psoriasiform drug reactions
direct immunofluorescence.3
A significant number of cases of vancomycin-induced linear IgA disease Clinical features
are characterized by antibodies which label the floor of split skin on indirect Psoriasis and psoriasiform dermatoses can be caused by a number of drugs
immunofluorescence. Many of these might represent examples of drug-induced including lithium, beta-blockers, NSAIDs, synthetic antimalarials, and tetracy-
epidermolysis bullosa acquisita.2 An epidermolysis bullosa acquisita-like blis- cline.1–5 Drug-induced disease may have variable presentations including:1,2
tering dermatosis has been described with penicillamine therapy but this has
not been confirmed with immunofluorescent or molecular data.3
Drug-induced pemphigus
Clinical features
Pemphigus may be related to a wide range of drugs, either directly as a caus-
ative factor or indirectly as a precipitating or triggering factor.1–14 The range of
drugs is quite wide but many belong to the thiol group of compounds (char-
acterized by the presence of an -SH group) including penicillamine, capto-
pril, bucillamine, and thiopronine.1,4 Thiol-induced acantholysis is mediated
by both immune and direct biochemical mechanisms.5 Penicillamine most
often induces pemphigus in the setting of rheumatoid arthritis.6 Although
foliaceus is most commonly encountered, vulgaris, erythematosus, and her-
petiform variants may occur.2,6–8 Other drugs that contain sulfur, which
can also form -SH groups, include gold compounds, penicillins, rifampicin,
and cephalosporins.4 Topical application of imiquimod has been reported
to cause pemphigus foliaceus and vegetans.15–17 Additionally, both pemphi-
gus foliaceus and vulgaris lesions have been described as a consequence of
radiotherapy.18–21 Clinically, drug-induced pemphigus can resemble vulgaris, Fig. 14.62
foliaceus, erythematosus, and vegetans variants, the first being most often Pseudoporphyria: trauma-induced blisters on the backs of the hands and fingers are
encountered.4 In the older literature, foliaceus variants were typical but with characteristic. By courtesy of the Institute of Dermatology, London, UK.
• exacerbation of pre-existing psoriasis,

• induction of new lesions in uninvolved psoriatic skin,
• precipitation of psoriasis de novo,
• resistance to treatment.
Lithium-induced psoriasis varies from exacerbation of pre-existing pso-
riasis to development of new disease.2 Manifestations vary from plaque
disease to generalized pustular psoriasis, palmoplantar pustulosis, scalp pso-
riasis, and psoriatic erythroderma.2,6–8 Latency varies from 1 week to years
or more.2
Beta-blockers (e.g. propranolol, oxprenolol, pindolol, alprenolol, and the
now discontinued practolol), antimalarials (e.g. chloroquine and hydroxy-
chloroquine) and NSAIDs (e.g. indometacin, phenylbutazone, oxyphenylb-
utazone, and ibuprofen) can also induce psoriasiform eruptions or result in
exacerbations and flares.1,2,9–15
The increasing use of TNF-alpha inhibitors is associated with new-onset
or exacerbated psoriasiform eruptions.16–21 Most patients develop palmo-
plantar pustulosis or plaque-type psoriasis.18–20 The average time to onset of
lesions is 6–10 months, although the range is variable.16–21 It is speculated that
inhibition of TNF-alpha increases levels of type 1 interferons which result in
psoriasiform lesions.21
A large number of other drugs have been linked with exacerbation of pso-
riasis or development of new disease. These include the antifungal agent ter-
Fig. 14.64
binafine, antibiotics such as penicillin and tetracycline, digoxin, amiodarone, Psoriasiform drug
IFN-α, recombinant IFN-α, and erlotinib (tyrosine kinase inhibitor).2,22–31 reaction: the capillaries
in the dermal papillae are
Histological features tortuous and dilated.
The histological features overlap lichen simplex chronicus and psoriasis.
Occasionally, they are indistinguishable from psoriasis vulgaris (Figs 14.63–
14.65). Psoriasis secondary to TNF-alpha inhibitors may also demonstrate
lichenoid inflammation and spongiosis.21
Pityriasiform drug reactions

Clinical features
Pityriasiform drug reactions may be particularly caused by ACE-inhibitors
and gold.1–4 Less often, terbinafine, omeprazole, benfluorex, arsenicals, bis-
muth compounds, isotretinoin, naproxen, acetaminophen, barbiturates,
and bacille Calmette-Guérin (BCG) therapy have been implicated.5–11 The
tyrosine kinase inhibitor imatinib has been associated with pityriasiform
dermatitis.12–14 Patients present with small erythematous lesions accompa-
nied by a peripheral scale, which may follow Langer's lines, giving rise to the
typical ‘fir tree’ appearance. The trunk and extremities are predominantly
affected.
Fig. 14.65
Psoriasiform drug
reaction: neutrophils are
present in the stratum
corneum.
Histologically, pityriasiform drug reactions are typically characterized
by patchy parakeratosis, focal spongiosis with lymphocytic exocytosis,
and a superficial perivascular lymphocytic infiltrate, sometimes associ-
Fig. 14.63 ated with red cell extravasation (Fig. 14.66)3,6 On occasions, clinically
Psoriasiform drug eruption: there is confluent parakeratosis with elongated, typical pityriasiform drug eruptions may demonstrate a more psorias-
broadened, and partially fused rete ridges. iform histology.9
Pustular drug reactions 611
Fig. 14.66 Fig. 14.68

Pityriasiform drug reaction: there is a focal parakeratotic scale associated with Acute generalized exanthematous pustulosis: tiny pustules are evident. There is
acanthosis and spongiosis. A perivascular chronic inflammatory cell infiltrate intense erythema. By courtesy of B.A. Solky, MD, Department of Dermatology,
surrounds the superficial vasculature. Harvard Medical School, Boston, USA.
While this disorder may occur as a feature of mercury toxicity or follow

Pustular drug reactions a viral infection (particularly enteroviruses) or spider bite, in the majority of
cases it represents an adverse drug reaction.3,12,13 In most patients, the eruption
Clinical features has followed antibiotic therapy including penicillin, amoxicillin, ampicillin,
Drug-induced pustules are a manifestation of reactions to corticosteroids, metronidazole, trimethoprim, and erythromycin.3,9 Analgesics (e.g. acetamin-
anabolic steroids, oral contraceptives, isoniazid, haloperidol, and lithium ophen), antiepileptics (e.g. carbamazepine), antidiabetics (e.g. carbutamide),
therapy (Fig. 14.67).1 In addition, they are a feature of the halogenodermas antifungals (e.g. terbinafine), antimalarials (e.g. hydroxychloroquine), and
(see below). many other drugs have also been implicated.3,11–19 The condition often devel-
Pustules are also the main feature of acute generalized exanthematous pus- ops rapidly following the administration of the drug – sometimes in a matter
tulosis (AGEP, toxic pustuloderma) (Fig. 14.68). This rare condition is char- of hours.3,7
acterized by the sudden onset of numerous small, nonfollicular pustules arising
against a background of pruritic or burning edematous erythroderma.2–11 The Histological features
eruption often starts on the face or in the intertriginous regions but soon The pustules are present in a subcorneal and/or intraepidermal location and
becomes generalized.3 The mucous membranes are affected in a minority of sometimes contain a few acantholytic keratinocytes in addition to large num-
patients.3 Facial edema, purpura, vesicles, blisters, and erythema multiforme- bers of neutrophils (Figs 14.69, 14.70).3,9 A background of spongiosis is
like lesions have also been described.3,6 Pyrexia is usually present. Although in usually evident. The dermal papillae are often edematous and occasionally
the majority of patients there is no history of significant previous skin disease, subepidermal vesiculation is a feature. A perivascular infiltrate of lympho-
in some there is a background of psoriasis.3 The eruption usually resolves rap- cytes and histiocytes with conspicuous neutrophils and variable numbers of
idly and is followed by widespread desquamation.9 Peripheral leukocytosis eosinophils is generally present in the superficial dermis. Leukocytoclastic
with high neutrophil levels and sometimes eosinophilia can be present.3,9 vasculitis may be a feature in a significant proportion of cases.3,9,11
Fig. 14.67 Fig. 14.69

Pustular drug reaction: numerous pustules are present on an erythematous Acute generalized exanthematous pustulosis: there is a subcorneal pustule. The
background. By courtesy of the Institute of Dermatology, London, UK. dermis is intensely inflamed.
Fig. 14.70 Fig. 14.71

Acute generalized exanthematous pustulosis: high-power view of pustule. Note the Drug-induced pseudolymphoma: this patient developed a maculopapular eruption
acantholysis. following treatment with phenytoin.
Differential diagnosis Nonanticonvulsant-related pseudolymphomatous reactions present simi-

larly with single lesions or multiple papules, plaques, and nodules. Associated
The differential diagnosis includes pustular psoriasis, subcorneal pustular
drugs include antihypertensives, antidepressants, tranquilizers, beta-blockers,
dermatosis, IgA pemphigus, pustular necrotizing angiitis, and acute general-
calcium channel blockers, diuretics, NSAIDs, and antibiotics.2,18–22 Sézary’s
ized pustular bacterid.20,21
syndrome-like features have also been documented.23
Lymphomatoid contact dermatitis is much less common and usually repre-
sents a T-cell reaction to a contact allergen that histologically shows features
Ichthyosiform drug reactions reminiscent of mycosis fungoides.2,24–31 Patients present with pruritic, local-
Clinical features ized to generalized scaly papules and plaques.2 A number of antigens have
been incriminated including matchbox striking surface antigens, ethylenedi-
Exceptionally, acquired ichthyosis following lipid-lowering agents (includ- amine dihydrochloride, isopropyl-diphenylenediamine, phosphorus, nickel,
ing triparanol and diazacholesterol) and kava consumption has been docu- cobalt naphthenate, and para-phenylenediamine.
mented.1–3 The clinical features may resemble ichthyosis vulgaris or lamellar B-cell lymphomatoid drug reaction is rare but has been described in asso-
ichthyosis. ciation with fluoxetine hydrochloride and amitriptyline hydrochloride.2,21,22
Patients present with solitary nodules, multiple infiltrative plaques, or mul-
Histological features tiple papules.
In ichthyosis vulgaris-like drug-induced variants, there is mild hyperkeratosis B-cell lymphomatoid contact reactions may be seen with gold and nickel
associated with a diminished to absent granular cell layer. A mild superficial earrings. Patients present with one or more firm, erythematous nodules at the
perivascular lymphohistiocytic infiltrate with occasional eosinophils may be site of piercing.32–34
present. B- and, less commonly, T-cell pseudolymphomatous reactions may
In the lamellar ichthyosis-like variant, there is marked hyperkeratosis, develop within tattoos.35–39 Papules and nodules localized to the tattoo occur
mild acanthosis, and a normal or thickened granular cell layer. months to years after tattoo placement. The most common culprit is red
pigment, although reactions to blue and green dyes have been reported.38,39
Both metals and organic synthetic pigments are implicated as antigens in
Drug-induced pseudolymphoma such reactions.
Clinical features Pathogenesis and histological features

Drug-induced pseudolymphoma includes pseudolymphomatous reactions to The pathogenesis of lymphomatoid drug reactions is not completely under-
systemically administered medications (lymphomatoid drug eruption) and stood, but is thought to be secondary to immune dysregulation. Studies show
the much less frequent contact variant associated with locally administered that medications implicated in drug-induced pseudolymphoma can induce
agents (lymphomatoid contact dermatitis).1–3 proliferation of T cells and inhibit suppressor T cells, both in vivo and in
Lymphomatoid drug eruptions are commonly a T-cell type, although B-cell vitro.40,41 This may lead to an increase in helper T cells as well as B cells,
lymphomatoid drug eruptions are also recognized. T-cell variants are divided resulting in T-cell and B-cell pseudolymphoma, respectively.
into anticonvulsant-related and nonanticonvulsant-related variants.2 Drug-induced T-cell pseudolymphoma most often presents as a dense
Anticonvulsant-related T-cell lymphomatoid drug eruption typically devel- superficial perivascular or bandlike infiltrate composed of lymphocytes, his-
ops within weeks or months of commencing treatment. Patients present with tiocytes, and atypical lymphoid cells with irregular, enlarged, and hyper-
pyrexia, lymphadenopathy, and an eruption of single or generalized lesions chromatic nuclei (Figs 14.72–14.76).42 Cerebriform variants may be seen
comprising erythematous, morbilliform maculopapules, plaques, nodules or and there is often associated epidermotropism. Pautrier-like microabscesses
tumors often associated with leukocytosis, circulating Sézary cells, eosino- reminiscent of mycosis fungoides, however, are only occasionally identified.
philia, hepatosplenomegaly, and variable liver dysfunction (Fig. 14.71).2,4–16 Eosinophils are frequently evident and often the epidermis shows significant
Vesicles and purpuric lesions have also been described.14 Sézary’s syndrome- spongiosis. Giant cells, collections of histiocytes, and epithelioid granulomata
like features may rarely be seen.17 A number of anticonvulsants have been may also be evident. Dense nodular and tumor-like variants more suggestive
implicated including phenytoin, primidone, mephenytoin, carbamazepine, of pleomorphic T-cell lymphoma may also be encountered (Figs 14.77–14.79).
Phenobarbital, and trimethadione.2 A follicular mucinosis-like variant has rarely been described.22
Drug-induced pseudolymphoma 613
Fig. 14.72
Drug-induced pseudolymphoma: there is an atypical superficial perivascular
lymphocytic infiltrate. Note the marked epidermotropism. The histological features Fig. 14.74
are suggestive of mycosis fungoides. Carbamazepine-induced
pseudolymphoma: in this
example, there is a dense
bandlike upper dermal
Fig. 14.73
Drug-induced
pseudolymphoma:
the lymphocytes are
surrounded by a well-
developed retraction Fig. 14.75
artifact and there Carbamazepine-induced pseudolymphoma: there is marked lymphocytic atypia.
is a small Pautrier Cerebriform cells are present. The features are very suggestive of plaque stage
microabscess. mycosis fungoides.
By immunohistochemistry, the infiltrate consists of CD3+ T cells. CD4+ In the limited number of cases in which T-cell receptor (TCR) gene rear-
cells most often outnumber CD8+ forms, and CD20+ B cells are either rangements have been documented, two have disclosed a polyclonal pattern
extremely sparse or absent. A CD8+ variant has, however, been recently while one has displayed a weak monoclonal band.26,29,31
described following treatment with gemcitabine.35 CD30 expression with B-cell lymphomatoid drug reactions are characterized by a nodular or diffuse
resultant confusion with an anaplastic large cell lymphoma has exceptionally pandermal infiltrate, often accompanied by extension into the subcutane-
been described.11,43–45 ous fat. The infiltrate consists of lymphocytes and histiocytes with variable
Reported T-cell receptor gene rearrangement studies have disclosed a numbers of plasma cells and eosinophils. Mitoses are sometimes numerous.
clonal population in only a small minority of patients.5,6,12,14 Blasts are often present and lymphoid follicles with germinal centers may be
Lymphomatoid contact dermatitis most often is reminiscent of mycosis evident.
fungoides and is characterized by a superficial dermal bandlike infiltrate By immunohistochemistry, the majority of the lymphocytes are CD20+ B
composed of atypical lymphocytes and histiocytes with variable lymphocyte cells although a subpopulation of CD3+ T-cells is also present. Identification
epidermotropism. The epidermis is typically acanthotic, and spongiosis may of CD21+ follicular dendritic cells may be helpful in confirming the pres-
sometimes be present. ence of poorly developed follicles. Kappa and lambda immunohistochemistry
Immunohistochemical analysis has been reported in a small number of invariably show no evidence of light chain restriction.
cases. The atypical lymphocytes usually express CD3 and CD4 with no loss Tattoo-associated pseudolymphomas may be of the B- or T-cell type, with
of CD5 and CD7. A CD8 predominant variant has been documented.29 a B-cell pattern being more common. In addition to the features described
Fig. 14.78
Drug-induced pseudolymphoma: scattered multinucleated giant cells are evident.
Fig. 14.76
Carbamazepine-induced
pseudolymphoma:
diagnosis depends upon
careful clinicopathological
correlation.
Fig. 14.79
Drug-induced pseudolymphoma: there is marked lymphocytic atypia. The nodules
melted away following withdrawal of drug.
Fig. 14.77 is withdrawal of the suspected drug. It is important that correlation always be
Drug-induced undertaken in any case of an unanticipated lymphoma in order that reactive
pseudolymphoma: this conditions do not receive inappropriate lymphoma treatment.
very dense dermal
infiltrate developed
following treatment Specific drug reactions
with an antidepressant.
Multiple cutaneous
nodules were present. Arsenic
Clinical features
above, there is tattoo pigment extracellularly and within macrophages. Arsenic exposure can be encountered under a variety of circumstances.1–7 It
Rarely, a lichenoid infiltrate is present.39 may be a constituent of proprietary medicines and is an active component
of pesticides and herbicides.3 Fowler's solution – once used in the treatment
Differential diagnosis of psoriasis and other dermatological disorders – contained 1% potassium
Distinction between cutaneous lymphoma and a drug-induced pseudolym- arsenate.1,3 The most common source of arsenic exposure now is through
phoma can be exceedingly difficult. Features that favor a drug-induced contaminated ground water. For many years (as a consequence of its use as an
process over mycosis fungoides include vacuolar alteration, keratinocyte insecticide) it was an ingredient in cigarette tobacco.2,4 High levels of arsenic
necrosis, spongiosis, and papillary dermal edema.40 However, there can be occur in the mining and smelting industries.3
considerable histological overlap and rare instances of a T-cell receptor gene Exposure to arsenic may cause acute arsenical dermatitis, although more
rearrangement necessitate close clinicopathological correlation. If cutaneous commonly patients are seen with long-term sequelae.2–7 The former presents
pseudolymphoma is suspected, the most effective way to make the distinction with a diffuse erythematous papular or pustular/bullous dermatosis that can
progress to exfoliative dermatitis.5 Transverse white nail striations may be a

feature.5 Chronic complications of arsenic exposure include pigmentary dis-
turbances and cutaneous tumors. Patients are also at increased risk of internal
malignancies.1,7 Other systemic manifestations include atherosclerosis, hepatic
fibrosis, peripheral neuropathy, respiratory disease, and diabetes mellitus.7
Characteristic of arsenicism is the ‘rain drops on a dusty road’ appear-
ance in which patients develop hyperpigmented macules containing foci of
hypopigmentation and areas of darker pigmentation.7–10 Lesions are often
seen on the trunk and in heavily pigmented regions such as the areola and
flexural creases.3 The cutaneous pigmentary changes are especially seen in
Asian populations.3
Palmar and plantar keratoses are common and present 2 years or more
after exposure.5 After many years they may be associated with malignant
transformation.7
Skin tumors are a late manifestation, are often multiple, and are particu-
larly found on non-sun-exposed sites. Bowen’s disease, squamous cell carci-
noma, and superficial basal cell carcinoma may develop.1,2
Patients with evidence of arsenic exposure should be investigated for vis-
ceral malignancies, particularly carcinoma of the lung, bladder, and kid-
ney.7,11,12 There are occasional reports documenting an association between Fig. 14.80
Iododerma: ulcerated vegetative plaques are present on the backs of the hands
arsenic and hepatic angiosarcoma.13,14
and fingers. By courtesy of the Institute of Dermatology, London, UK.

The mechanism of arsenic carcinogenesis is multifactorial. Arsenic is meth-
ylated as part of the metabolization process.6 This results in free radicals
which damage DNA, contribute to chromosomal aberrations, and increase
sister chromatid exchange.7 Arsenic also impairs the DNA repair process and
diminishes p53 activity.15 Transcription factors, cytokines, and cell signal-
ing pathways critical to regulation of cellular proliferation and differentia-
tion are also affected by arsenic and lead to uncontrolled cell growth and
de-differentiation.7,15,16
Histologically, cutaneous hyperpigmentation demonstrates increased mel-
anin synthesis, with excess pigment being present at all levels of the epider-
mis.3 There is no evidence of melanocytic proliferation. Skin cancers arising
as a result of arsenic exposure show no distinguishing features histologically
and are described elsewhere.
Iododerma
Clinical features
Potassium iodide is encountered in various settings. It is often included in Fig. 14.81
expectorants/bronchodilators and is used for treatment of thyroid disease and Iododerma: in this patient,
as a radiocontrast medium. nodules are conspicuous.
Superimposed pustules
Adverse reactions are rare.1–9 Acneiform papulo/pustular lesions are most
are evident. By courtesy
common and affect the face, neck, and back.3,4 Erythematous, urticarial,
of the Institute of
vesiculobullous, and pustular psoriasis-like lesions have been described.1,7 Dermatology, London,
Rarely, chemical burnlike changes develop in patients, often post-surgical, UK.
when there is concomitant occlusion and maceration.9 Lesions affecting the
lower limbs may be petechial, hemorrhagic or resemble erythema nodo-
sum.1,2 Nodular and ulcerated vegetative plaques constitute more extreme Differential diagnosis
forms. This latter variant affects the face, shoulders, trunk, and extremities
and presents as 1–7 cm disfiguring, crusted, erythematous lesions, sometimes Histologically, the nodular lesions of iododerma resemble an infective process
with central umbilication (Figs 14.80, 14.81).3 Healing may be complicated such as blastomycosis or an atypical mycobacterial condition. The presence
with scarring. of occasional eosinophils within the infiltrate and epidermal degeneration in
Iododerma is associated with multiple myeloma, polyarteritis nodosa, association with the abscesses may result in confusion with pemphigus veg-
lymphoma, and glomerulonephritis.3,7,10 Renal insufficiency may be a predis- etans. In early lesions, when the epidermis is normal thickness, the features
posing factor. can be mistaken for Sweet’s syndrome and pyoderma gangrenosum.
Pathogenesis and histological features Bromoderma

Although delayed hypersensitivity is believed to represent the underlying
pathogenesis, the precise mechanism is unknown. Acute lesions are char- Clinical features
acterized by an intense dermal neutrophil-rich infiltrate. With chronicity, Methyl bromide has been used as a pesticide and disinfectant and in the phar-
pseudoepitheliomatous hyperplasia and ulceration are common. Neutrophil maceutical, film, and dye industries.1–5 It may be found in sedative syrups
microabscesses may be seen in the epidermis and the dermis; in some cases, and expectorants. Although occupational exposure is associated with severe
there is focal leukocytoclastic vasculitis.3,5 respiratory effects including pulmonary edema, occasional reports of skin
contact have also been documented.3,4 Potassium bromide is used as an anti- Clinical features
convulsant in many parts of the world. Other sources of exposure include
Warfarin necrosis typically develops 3 to 6 days after starting anticoagu-
brominated pool disinfectants and brominated vegetable oil, a product used
lation therapy. Paresthesia is present initially and is followed by a painful,
in citrus-flavored drinks.6 Patients present with sharply circumscribed ery-
well-circumscribed, edematous, and erythematous plaque resembling peau
thematous lesions containing vesicles and bullae.4 Intertriginous regions and
d’orange with purpura.1,5 Large blood-filled blisters that rapidly break down,
sites of mechanical pressure are predominantly affected. Ingested bromide
accompanied by progressive necrosis of the underlying dermis and subcuta-
may give rise to hyperpigmentation, urticaria, acneiform/pustular lesions
neous fat, are later sequelae. Tissue destruction is often considerable and the
(acne bromica), vegetative and ulcerated plaques (vegetant bromoderma,
resultant scarring is very disfiguring. Occasionally, the onset of this condition
tuberous bromoderma), necrotizing panniculitis, and pyoderma gangreno-
is delayed for weeks or months although in most instances this reflects an
sum-like ulcers (Fig. 14.82).7–12 Lesions may be multiple or solitary. Vegetant
interrupted therapeutic regimen.9,10
bromoderma most often presents on the face, scalp, and legs and predomi-
The condition shows a predilection for obese females (85%) and pre-
nantly affects infants.7 It is commonly mistaken for an infection. A case which
dominantly affects the breasts, buttocks, and thighs.2 The reason for the
complicated bromine secretion in breast milk has been documented.13
female predominance is unknown. In males, the thighs and buttocks are
also affected and sometimes the penis is involved. Occasionally, lesions
Histological features are seen on the hands. Deeper soft tissues and internal viscera are not
Cutaneous lesions that develop following acute exposure to methyl affected.
bromide are characterized by spongiosis, keratinocyte necrosis, papil- Patients almost invariably have received anticoagulation for thrombophle-
lary dermal edema, and subepidermal blister formation.4 A perivascu- bitis (deep venous thrombosis) and/or pulmonary embolism. Patients who
lar inflammatory cell infiltrate containing neutrophils, eosinophils, and receive warfarin for treatment of cardiovascular disorders such as atrial fibril-
smaller numbers of lymphocytes and histiocytes is present in the super- lation only very exceptionally develop this condition.5
ficial dermis.
In vegetating lesions, there is striking pseudoepitheliomatous hyperpla-
sia with intraepidermal and dermal abscesses accompanied by an intense
neutrophil, eosinophil, and lymphohistiocytic infiltrate in the underlying Cutaneous necrosis rarely complicates therapy with warfarin. Although
dermis. hypersensitivity reactions and direct toxicity have been postulated as etio-
Urticarial lesions show papillary dermal edema accompanied by a neutro- logical factors, an imbalance in the ratio of procoagulative and anticoag-
phil and eosinophil-rich infiltrate.4 ulative factors is currently thought to be most important.5 In addition to
depressing the vitamin K-dependent clotting factors II, VII, IX, and X, war-
Differential diagnosis farin reduces the levels of naturally occurring anticoagulants including pro-
Vegetating lesions may be easily confused with deep fungal and atypical myco- tein C, protein S, and antithrombin III. It first affects protein C, which has
bacterial infections. Pemphigus vegetans also enters the differential diagno- an extremely short half-life, and until the anticoagulative effect comes into
sis. The diagnosis may be most easily reached by careful clinicopathological play with depressed levels of coagulating factors, the patient is paradoxi-
correlation.11 cally at increased risk of thrombosis. Why this should so rarely result in skin
necrosis is uncertain.
Congenital protein C deficiency is an important predisposing factor in
Warfarin some patients. This is a relatively common autosomal dominant condition
Warfarin (coumadin) may be associated with a number of adverse reactions that affects between 1:200 and 1:300 of the population. Protein C is acti-
including hemorrhage, alopecia, urticaria, maculopapular eruptions, der- vated by thrombin under the influence of the cofactor thrombomodulin.5
matitis, purple toe syndrome, and leukocytoclastic vasculitis.1–8 Cutaneous The activated form inactivates factors VIIIa and Va, which inhibit conver-
necrosis develops in 0.01–0.1% of patients and may cause severe morbidity sion of factor X to factor Xa and prothrombin to thrombin with resul-
and significant mortality.5 tant inhibition of coagulation.5 Protein C deficiency is, therefore, associated
with a thrombotic tendency.11 Approximately 30% of patients who develop
warfarin necrosis have an underlying protein C deficiency.2 Warfarin ther-
apy, therefore, tips the balance in an already protein C-deficient patient.
The proposed mechanism, however, by no means offers an explanation in
the majority of cases.
Acquired or congenital deficiency of protein S may also be of importance
in a small number of cases.12–15 Protein S is a vitamin K-dependent cofactor
for activated protein C.5 Acquired protein S deficiency may be encountered in
patients with renal failure or antiphospholipid syndrome, or who are under-
going hemodialysis.16,17
An episode of thrombophlebitis and/or pulmonary embolism leading to
the warfarin therapy seems to be of major etiological importance.1,2 It is
proposed that the vascular inflammatory changes play a role in precipitat-
ing the thrombotic tendency by reducing endothelial cell thrombomodulin
levels, inactivating protein S and decreasing fibrinolytic activity.1–4 Protein C
or protein S deficiency (inherited or developing as a consequence of warfarin
therapy) may then represent an additional predisposing factor. Other condi-
tions that predispose to the development of warfarin necrosis include reduced
antithrombin III levels, lupus anticoagulant syndrome, factor V Leiden, and
prothrombin gene mutation.18–20
Histologically, warfarin-associated skin necrosis is characterized by fibrin
thrombi in the small veins and venules of the dermis and subcutaneous fat,
Fig. 14.82 with widespread erythrocyte extravasation (Figs 14.83, 14.84). In advanced
Bromoderma: vegetant plaques and nodules are seen around the eye. Ulceration lesions, subepidermal blood-filled blisters are seen. In older lesions, the
is present. By courtesy of the late M. Beare, MD, Royal Victoria Hospital, Belfast, changes of infarction are superimposed; however, vasculitis is not a feature.
N. Ireland. Arteries are not affected.
occur at the injection site. There is a striking female predominance.2,11 Rarely,

blisters may develop, and exceptionally the erythema becomes generalized.10
Hemorrhagic vesicles have also been described in patients given low molec-
ular weight heparin.12,13 Reported patients have been elderly and received the
medication while hospitalized. Lesions develop distant from injection sites
and occur on the extremities.
HIT syndrome – in addition to definitional thrombocytopenia – is char-
acterized by thrombosis (venous more often than arterial) which account for
the high morbidity and potential mortality.4,6 Venous thrombosis results in
deep venous lesions in the lower legs in up to 50% of patients, and of these
25% may develop pulmonary embolism.6 Additional complications include
warfarin-induced limb gangrene, adrenal hemorrhage, and DIC.6 Arterial
thrombosis is more likely in catheterized or traumatized arteries and may
affect the aorta and ileofemoral arteries, resulting in peripheral gangrene,
myocardial infarction or stroke.4,6
Cutaneous necrosis develops in 10–20% of patients with the HIT syn-
drome.6,14 The injection site is predominantly involved but more distant
areas (thighs, abdomen, and buttocks) may also be affected in a minority of
patients.1,2,15–24 Initial lesions are painful or burning erythematous plaques fol-
Fig. 14.83 lowed by ulceration and tissue necrosis.2 The condition shows a predilection
Coumadin necrosis: there are thrombosed vessels throughout the superficial
for middle-aged females and the obese.2,15
dermis associated with epidermal regeneration.
Thrombocytopenia and thromboembolism are potentially life-threatening
complications.

The heparin-induced thrombocytopenia syndrome results from platelet acti-
vating HIT/PF4 antibodies induced in response to a platelet factor 4-heparin
complex.1,22,23 The resulting immune complexes bind to platelet Fc receptors
and activate platelets. In addition, the antibody reacts with surface endothe-
lial cell platelet factor 4-inducing endothelial cell injury and thrombosis.4,23
Only a minority of patients with HIT antibodies develops skin necrosis, and
it is postulated that additional prothrombotic factors such as protein C or S
deficiency are necessary for the development of thrombosis and its sequelae.1
Adverse side effects are more common and more severe in patients receiving
unfractionated as opposed to low molecular weight heparin.24
The histological features of the macular erythema are those of spongiotic
dermatitis. Within the superficial dermis is a perivascular lymphohistiocytic
infiltrate with variable numbers of eosinophils. The lymphocytes are predom-
inantly of the T-helper subclass.25
Heparin-induced cutaneous necrosis is characterized by widespread super-
ficial small vessel (capillary and venule) thrombi accompanied by hemorrhage
and necrosis.16,17 The presence of leukocytoclastic vasculitis is variable.2
Fig. 14.84
Bullous hemorrhagic lesions are intraepidermal blisters filled with
Coumadin necrosis: high-power view of Figure 14.83.
extravasated red blood cells.12,13 Perivascular lymphocytes, histiocytes, and
eosinophils are variably present. Leukocytoclastic vasculitis is absent. Direct
immunofluorescence studies are negative.
Identical histological features may be seen in a number of conditions includ-
ing antiphospholipid antibodies, hereditary hypercoagulation disorders (fac-
Penicillamine
tor V Leiden mutations, protein C or S, and antithrombin III deficiencies)
in the absence of warfarin therapy, heparin-induced thrombocytopenia syn- Clinical features
drome and disseminated intravascular coagulation (DIC). Cryoglobulinemia Penicillamine therapy is associated with various adverse reactions including
and cryofibrinogenemia may also have to be excluded. Calciphylaxis can be exanthematous eruptions, urticaria, lichenoid reactions, papulosquamous
excluded by the absence of vascular calcification. The diagnosis ultimately dermatoses, alopecia, hypertrichosis, nail changes, dermatomyositis, systemic
depends upon adequate clinicopathological correlation. lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus
erythema, and bullous and mucosal pemphigoid.1–12 The autoimmune blister-
Heparin ing dermatoses complicating penicillamine therapy are not dose dependent
and are seen particularly in patients with other immunologically mediated
Adverse side effects of heparin include hemorrhage, urticaria, anaphylaxis, diseases including rheumatoid arthritis and systemic sclerosis.9 Pemphigus is
macular erythema, and alopecia.1–3 Of greater significance, patients may by far the most common bullous disorder associated with penicillamine, pem-
develop thrombocytopenia, paradoxical thrombosis, and skin necrosis – phigus foliaceus being the most frequent variant encountered.4,9 Herpetiform
heparin-induced thrombocytopenia syndrome (HIT syndrome).1–6 pemphigus has also rarely been described as complicating the use of pen-
icillamine.10,11 Additional manifestations – particularly seen in patients tak-
Clinical features ing high doses in the treatment of Wilson’s disease and cystinuria – include
Urticarial reactions are exceptionally rare.7–9 Delayed hypersensitivity reac- penicillamine dermopathy, elastosis perforans serpiginosa, skin fragility with
tions are the most common of the adverse cutaneous responses to heparin, hemorrhages and milia formation on the extensor surfaces, wrinkling and
occurring in 7.5% of patients.9,10 Macular erythema and eczematous lesions anetoderma-like changes, cutis laxa, and pseudoxanthoma elasticum-like
appearances.13–19 Patients on long-term therapy may present with small yel-

low papules resembling a plucked-chicken appearance or disfiguring loose
folds of skin particularly affecting the flexures.16,17
Penicillamine acts by impairing cross-linking in newly formed collagen and
elastic fibers.13 The histological features include increased numbers of abnor-
mally formed elastic fibers in the reticular dermis (Fig. 14.85). These are
thickened with irregular serrated appearance on cross-section. When viewed
in a longitudinal plane, the fibers show conspicuous lateral projections
(Figs 14.86, 14.87).
Evidence of similar elastic tissue damage has been documented in the joint
capsules, lungs, intestine, and large elastic arteries.13
Gold
Clinical features
Gold therapy may result in eczematous, lichenoid, pityriasiform, and psorias-
iform dermatoses and stomatitis. Fig. 14.87
Cutaneous pigmentation which results from parenteral treatment with gold Penicillamine dermopathy: the changes can be highlighted by an elastic tissue stain.
salts is known as chrysiasis (auriasis, chrysoderma, hautaurosis).1–5 It is a pho-
todependent, irreversible condition most often documented in patients with
rheumatoid arthritis.2,3 Patients are at risk once a threshold of 50 mg/kg of
gold is reached.1 Disease severity correlates with the cumulative dose of gold.6
Coloration varies from mauve/blue to blue to slate-gray.2 The sun-exposed
skin of the face is particularly affected. In severe cases lesions may be seen on
the neck, front of chest, and backs of the forearms and hands (Fig. 14.88).2
In bald patients, scalp involvement is sometimes apparent. Pigmentation has
also been described in the sclera and buccal mucosa.2

The pathogenesis of chrysiasis is uncertain. It is probably related to an effect
of UV radiation on tissue-bound gold particles. Support for this hypothesis
is the observation that skin lesions can be induced by UVB irradiation of
sunlight-protected skin.7 Similarly, typical skin lesions have been described
following Q-switched ruby laser treatment in patients treated with gold.8–10
Chrysiasis is characterized by deposits of small black macrophage-
bound particles surrounding the vessels in the deeper reticular dermis and
around the sweat gland coils (Fig. 14.89).2 Perl’s Prussian blue (hemo-
siderin) and Masson-Fontana staining for melanin are negative. The gold
particles show orange–red birefringence with cross-polarized light.11 There
Fig. 14.85 is no inflammatory response. Epidermal melanin pigmentation usually
Penicillamine dermopathy: there are thickened, intensely eosinophilic elastic fibers appears normal.2
throughout the reticular dermis.
Fig. 14.88
Fig. 14.86 Chrysiasis: multiple foci of blue discoloration are present on the cheek. By courtesy
Penicillamine dermopathy: the serrated appearance is characteristic. of J. Kerner, MD, Department of Dermatology, Harvard Medical School, Boston, USA.
Fig. 14.89 Fig. 14.90

Chrysiasis: there are fine black granules both within macrophages and lying Argyria: there is striking slate-blue pigmentation; the eyes are also affected. By
free around the superficial vasculature. By courtesy of S. Lyle, MD, Beth Israel courtesy of the Institute of Dermatology, London, UK.
Deaconess Medical Center, Boston, USA.
By electron microscopy, the gold appears as granular, particulate, and fila-

mentous material, sometimes showing a starlike morphology within phago-
lysosomes (aurosomes). The diagnosis can be confirmed by electron/X-ray
probe microanalysis.2,4,12–14
Gold pigment must be distinguished from silver deposits (argyria), mercury,
and tattoo pigment.5,10 Silver pigment is predominantly deposited in relation
to basement membranes, particularly of the sweat glands. It does not show
orange–red birefringence with cross-polarized light.10 Mercury particles are
large (up to 340 μm in diameter) and brown-black in color. Tattoo usually
consists of a variety of different pigments of varying colors. Clinical history
should readily establish the diagnosis in the majority of cases.
Silver
Clinical features
Generalized tissue accumulation of silver (argyria) follows dietary, medici- Fig. 14.91
nal, and industrial exposure to silver compounds.1–9 Occupational exposure Argyria: note the fine silver granules outlining the basement membrane of the
may be encountered in silver mining and smelting, electroplating, and in the sweat gland epithelium.
photographic industries.3 Silver deposits are found in the skin and mucous
membranes in addition to internal viscera, particularly liver, spleen, adrenals,
muscle, and brain (Fig. 14.90).1 Argyria initially presents in the gingivae
as a slate-blue line due to deposition of metallic silver and silver sulfide.1–3 Mercury
Cutaneous manifestations affect the sun-exposed sites of the face, neck, and
backs of hands.6 The nails may also be involved. Ocular involvement presents Clinical features
as a bluish-gray to brownish-black coloration. Mercury exposure is encountered under a variety of circumstances.1–3
Localized argyria has been documented due to silver earrings, orthodon- It occurs in three different forms: metallic, inorganic, and organic
tic surgery, acupuncture, silver polishing, and the application of topical silver mercury.1
sulfadiazine.10–19 In the absence of clinical information, a diagnosis of blue • Metallic mercury, which is a liquid at room temperature, is present in
nevus may mistakenly be made.11 vapor from heating amalgam and paints and in mercury thermometers.4
• Inorganic mercurial salts may be present in laxatives, pesticides,
Histological features antiseptics and germicides.1,5
Argyria results from deposition of metallic silver and silver sulfide. Pigmentation • Organomercurials are used as industrial antifungal agents.4
is intensified by sunlight due to silver reduction analogous to photographic Dermatological reactions to metallic mercury include mercury granu-
processing.6 There is also increased epidermal melanin synthesis. loma and mercury exanthem (acute generalized exanthematous pustulosis).
Silver granules are found in association with the vascular and adnexal Mercury granuloma follows penetrating skin wounds as might result from a
basement membranes and adjacent to dermal elastic fibers (Fig. 14.91).2 broken thermometer, attempted homicide or suicide. Patients present with a
They measure less than 1.0 μm in diameter and appear brown–black in hema- flesh-colored to red or hyperpigmented nodule at the site of implantation.6–10
toxylin and eosin stained sections.6 Ultrastructurally, the silver granules may Membranous fat necrosis following subcutaneous mercury injection has also
be membrane bound within macrophage lysosomes or lie freely in the der- been documented.11 Mercury exanthem follows exposure to metallic mercury
mis.8 The diagnosis can be confirmed by X-ray microanalysis.6,9 (as may follow breaking a thermometer) in a previously sensitized patient.12–22
The eruption presents as a vivid erythema, which particularly affects the flex- Mercury exanthem is characterized by subcorneal and/or intraepidermal
ural sites of the body (so-called ‘Baboon syndrome’).17 An inverted V-shaped pustules which may contain acantholytic keratinocytes in addition to large
erythema affecting the upper anteromedial aspects of both thighs is charac- numbers of neutrophils.13 Background spongiosis is usually evident. The der-
teristic.12,16 Sterile pustules commonly develop and a purpuric element may mal papillae are often edematous and occasionally subepidermal vesiculation
develop. Pyrexia and peripheral leukocytosis are typically present. The der- is a feature. A perivascular infiltrate of lymphocytes and histiocytes with con-
matosis resolves by desquamation. spicuous neutrophils and variable numbers of eosinophils is present in the
Topical mercury cream has been used as a skin-bleaching agent.6,23,24 superficial dermis. Leukocytoclastic vasculitis may be a feature in a signifi-
Continuous and protracted use results in slate-gray pigmentation affect- cant proportion of cases.13
ing the flexures. The eyelids, nasolabial folds, and neck creases are sites of Cutaneous pigmentation following chronic local exposure to mercury is
predilection.25,26 characterized by increased melanin pigment in the epidermis accompanied by
Parenteral use of mercury results in pigmentation of the gingivae.26 mercury granules in the papillary dermis.26 Iron stains are negative.1
A lichenoid drug reaction has been documented following acute mercury Pink disease is characterized by sweat gland hyperplasia and a non-specific
poisoning.27 dermal inflammatory cell infiltrate.1
Dental workers are at risk of allergic contact dermatitis from exposure to
mercury or mercury salts.28 Bismuth
Mercury may also be associated with palmar/plantar peeling in chil-
dren (pink disease, acrodynia, erythredema), palmar/plantar hyperkeratosis,
and acanthosis nigricans-like skin lesions.29 Pink disease is rarely encoun-
Clinical features
tered nowadays due to control of mercury in medications and in the envi- Bismuth may be used for gastrointestinal complaints including gastritis and
ronment.30–32 The condition is still occasionally seen and may be a problem peptic ulceration.1–3 Adverse cutaneous reactions include erythroderma, exan-
in developing countries. It presents in infants and young children following themata, purpuric eruptions, stomatitis, and urticaria.2,3 Generalized pig-
chronic mercury exposure, for example in diaper powders, laxatives, paint, mentation may follow prolonged parenteral and oral use. Patients develop a
fluorescent light bulbs or other household sources.1 It is characterized by the generalized blue–gray pigmentation, which also affects the conjunctivae and
development of characteristic painful swelling and pink coloration of the tip oral mucosa.1 A blue–black line at the gingival margin is pathognomonic.1
of the nose, fingers, and toes.1,11 As the condition resolves, the palms and Transient black lingual pigmentation has also been reported.4
soles show intense sweating and desquamation.1 Sterility in males is a poten-
tial long-term sequel.31 Histological features
Lichenoid and granulomatous inflammatory reactions may complicate Bismuth appears as small dark granules in the dermis and within sweat gland
use of mercuric sulfide (cinnabar) to provide the red color in tattoos.33–35 basement membranes.3 Transfollicular elimination has been documented.2
Pseudolymphomatous reactions to mercury have also been documented.36,37
Amalgam tattoo reactions are discussed elsewhere.
Voriconazole
Clinical features
Mercury pigment is brown–black, round and opaque, and measures up to
340 μm in diameter (Fig. 14.92).5–7,38 The granules are found within mac- Voriconazole is a second-generation broad-spectrum triazole antifungal
rophages in addition to extracellular dermal deposition. They are localized that acts by inhibiting fungal cytochrome 450 enzymes. It is well tolerated
around the superficial vasculature and in association with the connective tis- and it is commonly used to treat fungal infections, particularly in immuno-
sue elements.38 compromised patients. It may be associated with a number of side effects
Mercury granulomata are characterized by local necrosis associated with including nausea, vomiting, diarrhea, visual disturbances, cheilitis, ery-
free mercury globules surrounded by an intense foreign body granulomatous thema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis,
reaction with lymphocytes, histiocytes, plasma cells, and varying numbers of pseudoporphyria, blistering, facial erythema, and mucocutaneous retinoid-
eosinophils.6,7,9 Ulceration is common and the epidermis may show pseudoep- like effects.1–4 One of the most important side effects is photosensitivity,
itheliomatous hyperplasia. initially reported to occur in around 1–2% of patients and after long-term
therapy.5–7 Although the photosensitivity subsides when the treatment is
stopped, photoaging also occurs and it persists. The latter is associated
with multiple lentigines and premature dermatoheliosis.5–7 Furthermore,
some patients, even children, have developed aggressive squamous cell car-
cinomas and, most recently, melanomas in-situ have been reported in two
adults.8–11
All the cutaneous manifestations of voriconazole therapy show the same his-
tological features of their counterparts not induced by drugs.
Lithium
Clinical features
Lithium therapy is associated with cutaneous side effects in up to 45% of
patients.1,2 It is known to precipitate or aggravate psoriasis, in particular
pustular lesions.3–6 Other cutaneous adverse affects include maculopapular
eruptions, seborrheic dermatitis, exfoliative dermatitis, atypical acneiform
lesions (predominantly affecting the forearms and legs), pustular erup-
tions, hidradenitis suppurativa, keratosis pilaris-like lesions, palmoplantar
Fig. 14.92 hyperkeratosis, bullous disorders, and hair, nail and mucosal changes.7–12
Mercury pigmentation: there are multiple round black deposits of mercury Exacerbation and the development of Darier’s disease has rarely been
associated with abscess formation. documented.13
Chemotherapeutic agents 621
Barbiturates and coma blisters develop as a result of mitosis inhibition with consequent temporary growth
arrest and may be due to bleomycin, cyclophosphamide, and doxorubicin.5
Onycholysis can follow treatment with docetaxel, fluorouracil, and mitoxan-
Clinical features trone.7 Transverse striate leukonychia (Mees’ lines), which result from peri-
Barbiturates may be associated with a wide range of adverse drug reactions odic disruption of nail plate keratinization, classically have been described in
including erythema multiforme, toxic epidermal necrolysis, hypersensitivity association with arsenic poisoning.9 Similar lesions have been documented
syndrome, and pseudolymphoma.1,2 with a number of agents including ciclosporin and daunorubicin.10,11
In company with many other sedative drugs, including chlorpromazine, imi- Maculopapular eruptions may be caused by several chemotherapeutic
pramine, and meprobamate, barbiturates, particularly when taken in overdose, drugs including azathioprine, 5-fluorouracil, chlorambucil, melphalan, and
may result in blisters (coma blisters), related especially to sites of trauma.3–8 hydroxyurea.6 These are frequently a source of clinical diagnostic difficulty,
as infectious diseases – including viral exanthemas and, in patients who have
Pathogenesis and histological features undergone transplantation, acute GVHD – are often within the differential
These lesions probably develop as a result of focal persistent hypoxia and diagnosis.
ischemia due to chronic localized pressure. They may develop in a coma- Cutaneous hyperpigmentation is a common complication of chemothera-
tose patient whatever the cause. Direct toxic effect may be of importance in peutic agents and often affects the hair, nails, and mucosae in addition to the
some patients, since similar blisters have complicated localized barbiturate skin.1–8,12–14 Hypopigmentation is less commonly seen.5 The mechanism for
extravasation. increased melanin synthesis by melanocytes is unknown. Alkylating agents
Histologically, the blisters are subepidermal in location and are often including busulfan, cyclophosphamide, ifosfamide, hydroxyurea, 5-fluorou-
accompanied by infarction of the overlying epidermis (Fig. 14.93). Sweat racil, and methotrexate are among the most often implicated agents.5,15,16 Nail
gland necrosis is characteristic. changes (including diffuse pigmentation, longitudinal and transverse banding
or streaks) are particularly seen with cyclophosphamide, daunorubicin, dox-
orubicin, 5-fluorouracil, and hydroxyurea.2,9 Cyclophosphamide also causes
Chemotherapeutic agents hyperpigmentation of the palms and fingers.14 Immediate or delayed tanning
following sun exposure is a frequent complication of 5-fluorouracil. Rarely,
Clinical features patients may develop linear erythema, complicated by pigmentation around
The rapid rate of epidermal and mucosal turnover results in a high degree an injection site, so-called serpentine supravenous hyperpigmentation.7,16,17–19
of susceptibility to the effects of chemotherapeutic agents. Among the most Similar lesions have followed treatment with actinomycin and nitrosourea.20,21
commonly encountered adverse responses are stomatitis, alopecia, and pig- Hair pigmentation can result from tamoxifen therapy.1,22 Bleomycin therapy
mentary changes.1–8 is associated with cutaneous pigmentation affecting between 30% and 60%
Stomatitis is very common and presents as burning erythema, followed by of patients.2,23 Pathognomonic linear flagellate streaks may develop on the
the development of extremely painful erosions and ulcers.2 Commonly impli- skin of the trunk and proximal extremities.24–31 It is suggested that lesions
cated drugs include cyclophosphamide, methotrexate, bleomycin, cytarabine, develop as a consequence of trauma-induced vasodilatation with resultant
doxorubicin, daunorubicin, dactinomycin, 5-fluorouracil, IL-2, hydroxyu- local increased concentration of bleomycin. An early inflammatory phase,
rea, and mercaptopurine.5,7 Secondary infection, such as with herpes simplex due to scratching, has occasionally been documented, suggesting that the pig-
virus or Candida albicans, is an important complication. mentation occurs as a consequence of postinflammatory changes. A simi-
Proliferating hair follicles are highly susceptible to chemotherapeutic agents lar problem of patterned hyperpigmentation has been documented following
and as a consequence anagen effluvium (in which there is loss of much of the treatment with thio-TEPA (triethylene thiophosphoramide). Localized occlu-
body hair) is a common and distressing complication.7,8 This is reversible once sion during treatment (as for example with adhesive bandages) may cause
treatment is completed although subsequent regrowth of hair may be accom- retention of thio-TEPA-rich sweat and subsequent reversible hyperpigmenta-
panied by a change in color or texture.1 Concomitant premature catagen and tion confined to the occluded surfaces.32,33 Transverse banding of hair shafts
telogen effluvium can result in total baldness.2 Drugs most often implicated following therapy with methotrexate – the so-called ‘flag sign’ – has also been
include bleomycin, cyclophosphamide, daunorubicin, docetaxel, doxorubi- documented.34
cin, etoposide, ifosfamide, mechlorethamine, methotrexate, mitoxantrone, Chemotherapeutic agents may interact with radiation therapy to result in
and paclitaxel.1 Nail changes, including pale transverse ridges (Beau’s lines) various unusual manifestations including photosensitivity, radiation enhance-
ment, radiation recall, and reactivation.
Photosensitivity may be induced by dacarbazine, 5-fluorouracil, hydroxyu-
rea, and vinblastine.7
Radiation enhancement, which may be a feature of both dactinomycin
and doxorubicin therapy, is due to impaired repair of radiation-induced sub-
lethal cellular damage.2,5 As a consequence, the effects of radiation therapy
are amplified. Clinical manifestations include increased erythema, hyper-
pigmentation, erosions, blistering, and necrosis at the site of radiation ther-
apy.32 Radiation enhancement has also been encountered following therapy
with adriamycin, bleomycin, cisplatin, 5-fluorouracil, hydroxyurea, and
methotrexate.5,7
Radiation recall presents as erythema, vesiculation, and desquamation
at the site of previous irradiation and may develop months or years after
completion of treatment.2 The mechanism is unknown. Dactinomycin is par-
ticularly incriminated.2 A similar response has also been reported following
therapy with adriamycin, bleomycin, cytarabine, doxorubicin, etoposide,
5-fluorouracil, hydroxyurea, melphalan, methotrexate, tamoxifen, and vin-
blastine.7,35,36 Recently, radiation recall reactions have been described follow-
ing treatment with paclitaxel, gemcitabine, docetaxel, IFN-α2b, dacarbazine,
acyclovir, and capecitabine.37–45
Fig. 14.93 Reactivation of ultraviolet light-induced erythema has been described as a
Coma blister: there is a subepidermal blister. Re-epithelialization along the floor is complication of methotrexate and suramin therapy.7,46 Manifestations include
present. vesiculation and erythema.
Inflammatory changes affecting pre-existing actinic keratoses and seb-

orrheic keratoses have been described following treatment with cispla-
tin, cytarabine, dacarbazine, dactinomycin, doxorubicin, 5-fluorouracil,
6-thioguanine, and vincristine.4,5 The affected keratoses become pruritic and
erythematous. It is suggested that such changes are analogous to radiation
recall phenomena.4
Hypersensitivity reactions (including urticaria, angioedema, serum sick-
ness, anaphylaxis, generalized dermatitis, and fixed drug eruption) are
uncommon complications of chemotherapy. Although a wide range of agents
may result in these responses, L-asparaginase, intravenous melphalan, and
cisplatin have been particularly incriminated.2,47,48 Cyclophosphamide,
daunorubicin, doxorubicin, methotrexate, and procarbazine have also been
implicated.48 Dacarbazine and procarbazine may cause fixed drug reactions.1
Immune complex-mediated reactions including vasculitis and some cases of
erythema multiforme or toxic epidermal necrolysis may rarely be a result of
treatment with hydroxyurea and mechlorethamine.5 Contact dermatitis is an
uncommon but important complication of topical mechlorethamine (mus-
tard) therapy.49
An interstitial granulomatous maculopapular eruption following low-dose
methotrexate in the treatment of collagen vascular diseases including lupus Fig. 14.94
Chemotherapy-related drug reaction: there are discrete palmar bullae with a rim
erythematosus and rheumatoid arthritis has been described.50 The buttocks
of erythema. The patient had been taking sorafenib. By courtesy of R. Lee, MD,
and limbs are commonly affected.
Virginia Commonwealth University, Richmond, Virginia, USA.
Newer chemotherapeutic agents have emerged which selectively target
specific cellular pathways. Their increasing use has also resulted in diverse
cutaneous side effects.51 One class of such drugs is the epidermal growth fac-
tor receptor (EGFR) inhibitors which are used to treat non-small cell lung
cancer, breast, colon, pancreatic, and squamous cell carcinoma of the head
and neck.52 Examples include cetuximab, gefitinib, and erlotinib. Since
EGFR is expressed in keratinocytes, follicular epithelium, eccrine glands, and
sebaceous cells, adverse effects on the skin and appendages are common.53
Acute folliculitis on the face and trunk is most common.51,52,54 Other poten-
tial side effects include dry skin, nail alterations (paronychia, ingrown nails,
nail fold fissures, onycholysis, splinter hemorrhages, pyogenic granulomas),
and hair changes (frontal alopecia, trichomegaly of eyelashes, altered hair
texture).51,52,55–57
Another class of medication is the tyrosine kinase inhibitor. Imatinib, dasa-
tinib, and nilotinib treat chronic myeloid leukemia (CML).51 Imatinib is also
approved for treatment of gastrointestinal stromal tumor (GIST) and some
cases of dermatofibrosarcoma protuberans. A wide range of cutaneous effects
have been reported with these medications, the more common being hyper-,
hypo- and de-pigmentation and macular–papular exanthems.51,58,59
Sorafenib and sunitinib are multikinase inhibitors currently approved for
treatment of renal cell carcinoma.51,60 Additional uses include hepatocellular Fig. 14.95
carcinoma and imatinib-resitant GIST for sorafenib and sunitinib, respec- Chemotherapy-related drug reaction: there are interface changes with basal cell
tively. A distinct cutaneous finding with both of these medications is hand– hydropic degeneration and apoptosis.
foot reaction developing in up to two-thirds of patients, typically 2 to 4 weeks
after initiating treatment, and characterized by painful erythema and edema of
the palms and soles (Fig. 14.94).51,53,61–63 There may be associated paresthesia
and desquamation. The lesions are discrete and accompanied by hyperkera-
tosis, in contrast to the acral erythema associated with traditional chemo-
therapeutic agents.53 Other cutaneous reactions linked to sorafenib include
pruritus, alopecia, actinic keratoses, and squamous cell carcinoma.51,60,64,65
Interface dermatitis represents the most frequently encountered histological
appearance in chemotherapy adverse drug reactions (Figs 14.95–14.97).66–69
In addition to the epidermis, both follicular and sweat gland/duct epithe-
lium may be affected. Appearances are variable, ranging from lichen planus-
like changes (including hyperkeratosis, hypergranulosis, acanthosis, basal cell
hydropic degeneration, and apoptosis) to lupus erythematosus-like reactions
in which the epidermis is markedly atrophic. The combination of interface
changes with severe maturation arrest (dysmaturation) is pathognomonic
of chemotherapy-related reactions. It is particularly a feature of patients
receiving long-term chemotherapy, high-dose chemotherapy, and multiagent
chemotherapy. In addition to impaired maturation, the epidermis appears Fig. 14.96
disorganized and individual keratinocytes are enlarged with pleomorphic Chemotherapy-related drug reaction: there is striking dyskeratosis and abnormal
nuclei containing conspicuous nucleoli. These changes are particularly maturation. The latter is a common feature of chemotherapy reactions.
Chemotherapy-associated eccrine gland reactions 623
Pustular folliculitis secondary to EGFR inhibitors demonstrates a dilated,

hyperkeratotic follicular infundibulum.63 The perifollicular infiltrate initially
contains lymphocytes and later becomes neutrophilic.
The histological features of hand–foot eruption seen with multikinase
inhibitors sorafenib and sunitinib include vacuolar interface alteration along
the dermal–epidermal junction, dyskeratotic keratinocytes, and a thin to
absent granular cell layer with variable parakeratosis.53,62 Mitotic figures
may also be seen predominantly in the spinous layer. Intraepidermal cleavage
occurs as a consequence of epidermal cell necrosis. Intradermal perivascular
inflammation is sparse and contains mononuclear cells with inconspicuous
eosinophils. Vasculitis is not seen.
Chemotherapy-induced acral erythema

Clinical features
Chemotherapy-induced acral erythema (acral erythema, hand-foot syndrome,
palmoplantar erythrodysesthesia syndrome, toxic erythema of the palms and
soles) in which the patient presents with circumscribed, extremely painful
Fig. 14.97 and tender erythematous macules on the palms, fingertips and soles has been
Chemotherapy-related drug reaction: close-up view. described following treatment with 5-fluorouracil, cyclophosphamide, cytar-
abine, daunorubicin, doxorubicin, and vincristine.1–12 Etoposide, mercap-
associated with bleomycin, busulfan, and hydroxyurea. Squamous metapla- topurine, methotrexate, and vinblastine have also been incriminated. Patients
sia of the dermal sweat ducts may be seen with methotrexate therapy.69 subsequently develop blisters followed by desquamation.
Etoposide, a podophyllin derivative, in addition to causing maturation
abnormalities, can cause metaphase arrest with characteristic fragmented Histological features
nuclear chromatin resulting in so-called ‘starburst cells’.70 The histological features include basal cell liquefactive degeneration, kerati-
Hyperpigmentation complicating busulfan therapy predominantly nocyte necrosis, and mild spongiosis.1–3,13 There is papillary dermal edema,
affects the basal layer of the epidermis but also may extend throughout the vascular dilatation, and a mild superficial perivascular lymphohistiocytic
full thickness and is often accompanied by pigmentary incontinence due infiltrate. Features of syringosquamous metaplasia and eccrine neutrophilic
to melanocyte toxicity.71 Similarly, bleomycin-induced hyperpigmentation hidradenitis are rarely seen.14,15
is characterized by epidermal hyperpigmentation and pigmentary incon- In one case, immunohistochemistry of the dermal lymphocytes disclosed a
tinence.72 Melanocytes are present in normal numbers. The early inflam- CD3+, CD16+, CD56+, leukocyte function antigen-1 positive phenotype sug-
matory phase is characterized by a superficial perivascular infiltrate of gestive of natural killer T-cells.16 The eccrine ducts expressed HLA-DR and
lymphocytes, histiocytes, occasional neutrophils, plasma cells, and eosino- intercellular adhesion molecule-1 (ICAM-1).16
phils. Some authors, however, have described basal cell pigmentation in the
absence of pigmentary incontinence.27,73 Lymphocytic vasculitis has also Differential diagnosis
been reported.28 The features are indistinguishable from graft-versus-host disease. Distinction
Thio-TEPA-induced pigmentation is similarly characterized by melanin is dependent upon clinicopathological correlation. Compared to hand–foot
pigment within all layers of the epidermis including the stratum corneum, reaction associated with multikinase inhibitors, there is no diminution of the
accompanied by basal cell hydropic degeneration and pigmentary incon- granular cell layer, parakeratosis or intraepidermal mitoses.17
tinence.32 A mild perivascular lymphohistiocytic infiltrate is present in the
superficial dermis. The melanocyte concentration is normal.
Radiation recall is characterized by epidermal atrophy, basal cell hydropic Chemotherapy-associated eccrine
degeneration, and superficial dermal vascular ectasia.
In addition to anagen alopecia and interface changes, pustular folliculi-
gland reactions
tis and allergic contact dermatitis (5-fluorouracil) may be a feature of che- Although there is some histological overlap between neutrophil eccrine
motherapy-associated adverse reactions, particularly with dactinomycin and hidradenitis and eccrine syringosquamous metaplasia, more often they present
5-fluorouracil.74,75 independently of one another and, as such, they are considered separately.
Hypersensitivity reactions including urticaria, angioedema, and maculo-
papular eruptions are histologically no different from other drug-induced
lesions (see above).
Neutrophilic eccrine hidradenitis
Dermal sclerosis may be a feature of bleomycin and docetaxel therapy.76
Extravasation of chemotherapeutic agents including cisplatin, dactino- Clinical features
mycin, daunorubicin, doxorubicin, etoposide, idarubicin, mechlorethamine, This rare eccrine gland reaction was initially reported in a patient receiv-
mithramycin, paclitaxel, vinblastine, and vincristine may result in chemical ing induction chemotherapy including doxorubicin and cytarabine in the
cellulitis and tissue necrosis.1 treatment of acute myelogenous leukemia.1 Subsequently, a similar erup-
Spongiotic dermatitis is rarely seen as a complication of systemic che- tion was described in patients with a number of other malignancies such as
motherapy but has been described following treatment with methotrexate, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, breast carcinoma, Wilms’s
5-fluorouracil, and dacarbazine.67,68 It is much more commonly encoun- tumor, osteosarcoma, and testicular tumors including embryonal carci-
tered following topical chemotherapeutic agents including 5-fluorouracil and noma and teratoma.2–7 Further cases developing in association with acute
mechlorethamine. myelogenous leukemia have also been documented.8,9 It was soon appreci-
The interstitial granulomatous reaction associated with low-dose metho- ated that additional chemotherapeutic agents including bleomycin, chloram-
trexate therapy is characterized by a largely histiocytic interstitial infiltrate bucil, daunorubicin, dactinomycin, vincristine, lomustine, mitoxantrone,
with small numbers of neutrophils.46 Vasculitis is not a feature. The histio- thioguanine, cis-platinum, vinblastine, topotecan, cyclophosphamide, and
cytes may surround neutrophil aggregates, and a characteristic feature is his- 5-fluorouracil might be responsible, although cytarabine has been most com-
tiocytes forming a palisade around collagen fibers.65 monly implicated.10 A case following the use of GM-CSF has been reported.11
It should be noted, however, that neutrophilic eccrine hidradenitis has also Differential diagnosis
been described as a prodromal manifestation of acute myelogenous leuke-
Idiopathic plantar hidradenitis (idiopathic recurrent palmoplantar hidradeni-
mia in the absence of chemotherapy.12 The condition has been described in
tis in children, neutrophilic eccrine hidradenitis in children) is a rare derma-
HIV-positive patients receiving zidovudine and as a complication of treat-
tosis in which tender, painful, erythematous papules, plaques, and nodules,
ment with acetaminophen.13–16
0.5–3.0 cm in diameter, develop on the soles of the feet of children.26–30
Clinically, patients (who are commonly febrile) develop a polymorphous
Pustular lesions have been reported.31 Less often, concomitant palmar involve-
eruption consisting of variably asymptomatic or tender erythematous to
ment has been documented.27 Recurrences are not uncommon. The condition
violaceous macules, papules, plaques, nodules, and pustules which most often
shows a predilection for females (2:1).26 Incidence shows seasonal variation,
presents within 1 or 2 weeks of starting chemotherapy.4 Lesions may be very
lesions developing most often in spring and autumn. Adults may also rarely
numerous and, although there does not appear to be a site predilection, the
be affected.32 Although trauma does not appear to be an etiological factor,
trunk and upper limbs are most often affected.5 Facial involvement may also
chronic pressure is probably of importance. Prolonged immersion in hot bath
occur, manifesting as periorbital edema, violaceous plaques, and lesions that
water preceded the development of lesions in a number of cases. Pyrexia is
mimic cellulitis.17–19 Ear involvement seen as bilateral tender erythema has
not usually present and the patients are otherwise well. The condition gener-
been documented.20 An atypical presentation with symmetrical, erythematous
ally clears spontaneously.
plaques isolated to the breasts has also been reported.21 The lesions desqua-
In contrast to eccrine neutrophilic hidradenitis, the changes are centered
mate and usually heal spontaneously within 1–3 weeks.4 Postinflammatory
on the coiled duct and proximal straight duct, the secretory apparatus usu-
hyperpigmentation and scarring are not usually features. Recurrence follow-
ally being spared or only minimally affected.26 There is an intense neutrophil
ing the reintroduction of chemotherapy has been documented.1,8 Clinically,
infiltrate surrounding and involving the ductal epithelium associated with
an infectious condition, leukemia cutis, bullous pyoderma, atypical pyoderma
epithelial degenerative changes and necrosis. Abscess formation may also be
gangrenosum or Sweet’s disease is most often suspected.8
a feature. Eccrine syringosquamous metaplasia is not seen.
Rarely, neutrophilic eccrine hidradenitis may represent a primary infec-
Pathogenesis and histological features tious process, for example Serratio spp., Enterobacter cloacae, Staphylococcus
The pathogenesis of this condition is unknown but it has been proposed that aureus, and Nocardia asteroides.33–35
the drug may be concentrated in the sweat glands, thereby exerting a direct
toxic effect on the secretory epithelial cells.1,2 Alternatively, the condition
may represent part of the spectrum of acute neutrophilic dermatoses which
Eccrine squamous syringometaplasia
also includes Sweet’s syndrome and pyoderma gangrenosum.4 Presentation
as a prodromal manifestation of leukemia before the introduction of chemo- Clinical features
therapy and its development in an otherwise healthy person as a probable Eccrine squamous syringometaplasia (syringosquamous metaplasia) is a his-
complication of prolonged pressure suggests that the etiology is likely to be tologically distinctive eruption that may rarely develop following chemo-
multifactorial.12,16 therapy.1–3 Patients present with erythematous papules often in a generalized
The most significant histological features are seen in the deeper reticular distribution following the administration of a number of chemotherapeutic
dermis and subcutaneous fat where a dense neutrophil polymorph infiltrate agents including bleomycin, cytarabine, daunorubicin, doxorubicin, and cis-
surrounds the eccrine secretory coils (Fig. 14.98). The coiled and straight der- platinum (Fig. 14.99). A similar response has been seen more recently with
mal ducts are typically unaffected. Leukocytoclasis is sometimes evident.4,22 the kinase inhibitors sunitinib and imatinib.4,5 Pustules and vesicles are some-
The glandular epithelium shows neutrophil infiltration, nuclear pyknosis, times seen. Presentation as acral erythema has also been documented.6,7
cytoplasmic eosinophilia or vacuolation and often appears sloughed off into
the lumen of the gland.7 Syringosquamous metaplasia may additionally be Histological features
present; rarely, necrosis of the eccrine gland is seen in the absence of signifi- The changes primarily affect the upper portion of the eccrine duct and con-
cant inflammation.8,17,23,24 The periadnexal fibroadipose tissue stroma typi- sist of squamous metaplasia associated with apoptosis of the lining epithe-
cally shows mucinous degeneration and a variable infiltrate of neutrophils, lium (Figs 14.100, 14.101).1 Periductal edema and fibrosis may also be seen.
lymphocytes, histiocytes, and eosinophils.8 Recently, it has been shown that A perivascular infiltrate consisting of lymphocytes and occasionally neutro-
the apocrine glands may be affected in addition to the eccrine glands.25 There phils is present in the surrounding dermis.
is no evidence of vasculitis.
Fig. 14.98 Fig. 14.99

Neutrophil eccrine hidradenitis: there is a neutrophil infiltrate involving the eccrine Eccrine squamous syringometaplasia: there is an erythematous patch with a dusky
gland. Note the sparing of the duct in the center of the field. center on the thigh and in the inguinal fold.
Adverse reactions to cytokine therapy 625
Granulocyte colony-stimulating factor (G-CSF, filgrastim; a glycopro-

tein that stimulates proliferation and differentiation of neutrophils) therapy
has been associated with a number of dermatological conditions including
bullous pyoderma gangrenosum, folliculitis, leukocytoclastic vasculitis, and
Sweet’s syndrome.2–9 G-CSF and GM-CSF have also been incriminated in
exacerbation of pre-existent leukocytoclastic vasculitis, psoriasis, a general-
ized erythematous eruption, erythematous plaques, and a localized lichenoid
reaction.10–15
A number of adverse reactions have been described following treatment
with GM-CSF (a growth factor which stimulates proliferation and differ-
entiation of neutrophils, monocytes, and eosinophils) including localized
angioedema, facial flushing, and generalized erythematous, maculopapu-
lar, exfoliative, urticarial, pruritic and pustular cutaneous reactions.2,16–19
Localized pustular and vasculitic reactions, generalized folliculitis, epider-
molysis bullosa acquisita, and alopecia have also followed treatment with
GM-CSF.2,7,18–21
The use of IFN-α may be followed by localized erythema and less often
skin necrosis. It is followed by the development of alopecia in up to 10% of
patients.22 Psoriasis, pyoderma gangrenosum, localized granulomatous and
Fig. 14.100 suppurative lesions, ulcers, vasculitis, systemic lupus erythematosus, eosino-
Eccrine squamous syringometaplasia: the eccrine ductal wall is replaced with
philic fasciitis, eczematous lesions, photosensitivity, and paraneoplastic pem-
squamous epithelium.
phigus have also complicated its use.2,23–29 Sarcoidosis induced by IFN-α is
also well documented.30,31 Cutaneous and systemic disease may occur as a
consequence of enhanced helper T-cell type 1 (Th1) immune response, result-
ing in granulomatous inflammation.
Pegylated IFN-α, used increasingly for its improved bioavailabity com-
pared to traditional interferon, has been linked to hyperpigmentation.32–34
Expression of α-melanocyte stimulating hormone receptors is increased by
interferon, and is thought to be the cause of lingual and cutaneous darkening.
Cutaneous lesions are reported to occur at sites of injection and elsewhere,
including the face, trunk, extremities, and nails. Lesions develop weeks to
months after starting therapy.
Single case reports have documented instances of fatal pemphigus vulgaris
and allergic facial contact dermatitis following treatment with IFN-β.35,36
Erythematous plaques, cutaneous ulceration, necrosis, vasculitis, scleroder-
miform lesions, and lobular panniculitis have also been documented.37–43
IFN-γ may induce psoriatic plaques at the injection site and its use has been
shown to induce erythema nodosum leprosum in patients with leprosy.44,45
IL-2, which is produced by activated T lymphocytes, stimulates the pro-
duction of a number of cytokines including IFN-γ, tumor necrosis factor and
GM-CSF in addition to inducing differentiation of an activated killer cell
population which has a cytotoxic effect on tumor cells.46,47 Dermatological
Fig. 14.101 complications of recombinant IL-2 (r IL-2) therapy include a desquamating,
Eccrine squamous syringometaplasia: high-power view.
diffuse erythematous macular eruption, pruritus, purpura, telogen effluvium,
mucositis with aphthous ulcers, and glossitis.2,46 Toxic epidermal necrolysis-
like blistering dermatoses, pemphigus vulgaris, linear IgA disease, vitiligo,
Differential diagnosis and erythema nodosum have also been reported.2,29,48–52 IL-2 therapy may be
Eccrine squamous syringometaplasia may occur in a wide variety of settings. associated with exacerbation of psoriasis.53,54
It may be found adjacent to cutaneous ulcers, following severe burns, as a Pruritus, facial edema, and a transient acantholytic dermatosis-like erup-
feature in panniculitis, linear scleroderma, and pyoderma gangrenosum, in tion affecting the chest, back, and proximal extremities have been described
fibrous hamartoma of infancy, in recall phenomenon, in association with following treatment with IL-4 and there is a case report describing the devel-
tumors including squamous cell carcinoma and keratoacanthoma, and in opment of vitiligo in association with recombinant IL-4 therapy.55,56
infections including herpes virus, cytomegalovirus, and human immunodefi-
ciency virus.8–15 It has also been described as a complication of benoxaprofen
therapy.16 Histological features
Histologically, the erythematous lesions associated with G-CSF show epi-
dermal acanthosis, parakeratosis, eosinophilic spongiosis with abscess for-
Adverse reactions to cytokine therapy mation, and interface changes.14 The lichenoid eruption is characterized by
hyperkeratosis, dyskeratosis, and interface change accompanied by a lym-
Clinical features phocytic infiltrate.15 An atypical dermal histiocytic infiltrate characterized by
A very wide range of adverse reactions to the large number of recombinant nuclear pleomorphism and mitotic activity has recently been documented.57
cytokines available as therapeutic agents has been described.1 These are very The erythematous maculopapular eruption associated with GM-CSF is
comprehensively documented in the review article of Asnis and Gaspari.2 The characterized by edema and a superficial perivascular and interstitial inflam-
majority of these agents have to a greater or lesser extent been associated with matory cell infiltrate composed of T-helper lymphocytes, histiocytes, eosino-
local injection site reactions (painful or pruritic erythematous wheals).2 Only phils, and conspicuous neutrophils accompanied by epidermal spongiosis
a limited number of cytokines, which may be associated with more specific and lymphocyte/neutrophil exocytosis.16–18 Focal dyskeratosis may also be a
dermatological manifestations, are included in this section. feature.16
The histological features of hyperpigmentation from pegylated IFN-α Histological features

include increased melanin along the basal layer of the epidermis and papil-
Amalgam tattoos, which consist of mercury and silver, sometimes accompa-
lary dermal melanophages.33 There is no associated iron deposition.
nied by tin, present as fine to globular, brown to black deposits lying free or
Lobular panniculitis associated with IFN-β demonstrates a spectrum of
within macrophages and also deposited on the elastic tissue fibers and blood
changes.43 Early on, there is a neutrophil-rich lobular panniculitis with sterile
vessels within the lamina propria.2–4
microabcess formation. Intravascular thrombi without vasculitis, increased
interstitial mucin, and microcalcification may be seen. Areas of fat saponi-
fication with microcalcification are typical and must be distinguished from Tumor necrosis factor-a inhibitors
pancreatitis-associated panniculitis. As lesions become longstanding, there is
less inflammation, predominantly comprised of mononuclear cells with septal The use of tumor necrosis factor-α (TNF-α) inhibitors has rapidly expanded
fibrosis and calcification surrounding adipocytes. over the past decade. Etanercept, infliximab, and adalimumab are FDA
IL-2 skin reactions are characterized by interface vacuolar degeneration approved for treatment of plaque-type psoriasis, rheumatoid arthritis, and
with rare necrotic keratinocytes accompanied by lymphocyte exocytosis and ankylosing spondylitis. Other indications for its use include Crohn’s disease,
focal spongiosis.3,46,54 Papillary dermal edema is present with a superficial ulcerative colitis, and juvenile idiopathic arthritis. As use of these medications
perivascular lymphohistiocytic infiltrate. Rarely, epidermal necrosis may be has increased, so too has the side effect profile.
extensive.46 The most common adverse dermatological effect is injection site reaction,
The infiltrate consists predominantly of CD3+/CD4+/CD25-/HLA-DR+ occurring in up to one-third of patients.1,2 Erythematous, edematous, eczem-
T-helper cells with a small subpopulation of CD8+ lymphocytes. Endothelial atous lesions are described most commonly, although discoid lupus erythe-
cells and keratinocytes express ICAM-1.46 matosus and localized vasculitis have been reported.1–3 Generalized vasculitis
Histologically, the transient acantholytic dermatosis-like eruption associ- may also occur, either following localized lesions or de novo, involving the
ated with IL-4 therapy is characterized by acantholysis and suprabasal cleft skin and other organ systems (kidneys, central and peripheral nervous sys-
formation with dyskeratosis, spongiosis, and a superficial perivascular lym- tems, serosa, myocardium, lung, gall bladder).4,5
phohistiocytic infiltrate with rare eosinophils.55 Immunofluorescence studies Paradoxically, a common cutaneous side effect seen distant from the injec-
have not been performed. tion site is psoriasis.6 Both psoriasis vulgaris and palmar-plantar pustular pso-
riasis have been described, predominantly in patients treated for rheumatoid
arthritis, ankylosing spondylitis and Crohn’s disease (Figs 14.102–14.104).7
Cutaneous reaction of lymphocyte recovery Most psoriasiform reactions occur 6 to 10 months after starting therapy.7,8
The proposed mechanism is increased IFN-α production by plasmacytoid
Clinical features dendritic cells (PDC) as a consequence of TNF-α inhibition, which has been
shown to induce psoriasis lesions.9–11
This unusual condition follows return of lymphocytes to the general circula-
There is clinical overlap between the psoriasiform and lichenoid derma-
tion and skin after induction or augmentation chemotherapy.1,2 It has been
titides associated with the TNF-α inhibitors. The clinical appearance of the
described most often following combined cytarabine and daunorubicin treat-
lichenoid eruptions may resemble lichen planus, psoriasis, or be non-specific
ment and also following treatment with amsacrine, etoposide, interferon,
erythematous macules and papules.12 The mechanism for development of
cyclophosphamide, and vincristine.3 Patients present with a pruritic, ery-
these lesions is not well understood but is thought to be a consequence of
thematous maculopapular eruption associated with pyrexia.1 The eruption
cytokine imbalance.13 The eruption begins weeks to months after starting
resolves with desquamation.2
TNF-α inhibition therapy.
Histological features Cutaneous infections are a well known risk with TNF-α inhibitor ther-
apy and include folliculitis, herpes simplex, tinea corporis, and tinea
The histological features include mild spongiosis with lymphocyte exocytosis versicolor.14–16
associated with interface change, keratinocyte atypia with impaired matura- An emerging reaction seen in the setting of TNF-α inhibition is granu-
tion (chemotherapy effect) and minimal dyskeratosis.1,2 There is vascular dil- lomatous inflammation. Case reports describe cutaneous, pulmonary, and
atation and a perivascular lymphocytic infiltrate is present in the superficial
dermis. Eosinophils are absent.2 Exceptionally, epidermal lymphocyte infil-
tration may be very marked so as to mimic mycosis fungoides.4
The infiltrate is composed of CD3+/CD4+ T-helper cells with a smaller
subpopulation of CD8+ cells.2 The lymphocytes may also express CD25.4
Epidermal Langerhans cells are reduced in number and there is minimal to
absent keratinocyte HLA-DR and ICAM-1 expression.2,4
Nuclear pleomorphism with hyperchromatism and expression of CD30,
CD25, and HLA-DR has been described in the eruption of lymphocyte recov-
ery in patients who have also received human recombinant cytokines includ-
ing GM-CSF and IL-3.5
The features are indistinguishable from exanthematous drug reactions, viral
infections, and acute graft-versus-host disease.6
Dental amalgam tattoos

Clinical features
Dental amalgam tattoos develop following the accidental implantation of
dental amalgam into the soft tissue of the mouth following a dental proce-
dure. Lesions, which are most commonly found on the buccal, gingival, and Fig. 14.102
alveolar mucosa, measure from 0.10 to 1.5 cm and present as flat gray to Tumor necrosis factor-α inhibitor reaction: there are thin psoriasiform plaques on
blue–gray or slate-colored lesions.1 the lower legs.
Esthetic microimplants 627
Fig. 14.103 Fig. 14.105

Tumor necrosis factor-α inhibitor reaction: erythematous, psoriasiform plaques Tumor necrosis factor-α inhibitor reaction: there is hyperkeratosis, hypergranulosis,
are present on the lower leg. Courtesy of J. Nunley, MD, Virginia Commonwealth psoriasiform hyperplasia, and interface change with a superficial perivascular
University, Richmond, Virginia, USA. lymphohistiocytic infiltrate.
Fig. 14.104
Tumor necrosis factor-α inhibitor reaction: there are tense palmar pustules identical Fig. 14.106
to those seen in palmar-plantar psoriasis. Tumor necrosis factor-α inhibitor reaction: in this example, the features are
indistinguishable from sarcoidosis.
nodal sarcoidosis which improves upon discontinuation of therapy.17,18

Additional reports include interstitial granulomatous dermatitis and granu- infiltrate of mononuclear cells, melanophages involving a hyperplastic epider-
loma annulare.19,20 mis, hyperkeratosis, and hypergranulosis.12 Psoriasiform hyperplasia may be
Lupus-like syndromes may also occur as a consequence of therapy with superimposed (Fig. 14.105).
TNF-α inhibitors.21 TNF-α inhibitor associated sarcoidosis is characterized by noncaseat-
ing granulomata in the dermis and/or subcutis (Figs 14.106, 14.107).17
Histological features Necrotizing foci are rarely described. Interstitial granulomatous dermatitis
demonstrates a diffuse intradermal infiltrate of histiocytes and lymphocytes
Injection site reactions are characterized by dermal edema, a perivascular
with a variable number of eosinophils and occasional neutrophils.19 There is
lymphocytic infiltrate with eosinophils.1–3 Immunohistochemical studies dem-
no increased dermal mucin or vasculitis. Interface changes occur but are not
onstrate CD8-predominant T cells.1
common.
Vasculitis in the setting of TNF-α inhibitor therapy may involve small or
medium sized vessels with leukocytoclastic changes.7 Necrotizing features
and extravascular granulomatous inflammation have been described. Esthetic microimplants
Psoriasis induced by TNF-α inhibitors resembles typical psoriasis, with
variable presence of spongiosis and lichenoid inflammation.10 The dermal Cosmetic dermatology is a rapidly evolving industry. The demand for ‘non-
infiltrate contains mononuclear cells, although eosinophils may be present.10 surgical’ rejuvenation has seen a rise in the number of implants and inject-
The few histological descriptions of TNF-α inhibitor-associated lichenoid able materials available to patients. Unfortunately, inflammatory reactions to
dermatitis available closely resemble lichen planus, with a lichenoid these agents occur.
Fig. 14.107 Fig. 14.108

Tumor necrosis factor-α inhibitor reaction: high-power view. Restylane nodules: linear arrangement of nodules along the neck creases.
There are several categories of fillers which may be permanent or resorb-

able (Table 14.1). Fillers are either polymers, which function as volumizers, As a consequence of the ban on silicone, bovine collagen was developed.
creating effect by taking up space, or a combination of degradable polymer There is a 1–3% rate of allergic reactions, despite double skin testing.4 Many
and microparticles.1 The microparticles serve as a lattice upon which the host’s such reactions are localized erythema and edema which occur in the first
response (often collagen induction) contributes partially or completely to the weeks to months after injection, although recurrent inflammation, years later,
filler’s effect. The microparticles may or may not be degraded over time. has been described. Other potential complications include localized glabellar
Silicone was one of the first agents used for soft tissue augmentation, in necrosis, granulomata, and abscess formation.5 Granulomata present as ery-
the 1950s. It was banned in the United States in 1982 due to concerns over thematous nodules at the site of treatment and are seen within a few months
adverse effects such as migration to distant locations.2,3 Inflammatory nod- following injection. Sometimes, lesions are seen years later. Abscesses typi-
ules (‘siliconomas’) may also develop, sometimes years later. Presently, two cally occur weeks to months after injection.4
new forms of liquid silicone are available, Silikon 1000 and Adatosil 5000, Hyaluronic acid is commonly used to correct facial creases and wrinkles.
for treatment of retinal detachment.1 The former is more easily injected and There are two types of hyaluronic acid fillers: nonanimal, derived from fer-
is used off-label for cosmetic purposes. Polydimethylsiloxane/polyvinyl pyr- mentation of bacteria (Streptococcus equi) and animal, derived from chicken
rolidone (Bioplastique) contains particles of solid silicone and is available for combs.6 Hypersensitivity reactions, although rare, have been reported in
injection into the subcutaneous fat (Fig. 14.108).4 up to 0.8% of patients.4,7 Injection site reactions are most common, with
temporary erythema, edema, and bruising within the first 14 days follow-
ing injection.8 Delayed reactions are less common and present as erythema-
Table 14.1 tous, firm nodules along the sites of injection weeks to months later.6–11 There
Esthetic microimplants
are two types of nodules: granulomatous and nongranulomatous. The etiol-
ogy of the granulomatous response is unclear. There is speculation that it
Chemical Ingredient Product Name(s) could be secondary to impurities related to the fermentation process in the
Resorbable: nonanimal-derived form.12 Additional side effects to hyaluronic acid include
Bovine collagen Zyderm, Zyplast sterile abscesses, hyperpigmentation, and a livedoid, reticular pattern in the
Human collagen Cosmoderm, Cosmoplast, area of injection.7
Cymetra Foreign-body granulomata have also been seen following injection with
Porcine collagen Evolence
poly-L-lactic acid (Newfill, Sculptra) and polyacrylamide gel (Aquamid).4,5
Hyaluronic acid (non-animal) Restylane, Captique, Perlane,
Juvederm
Hydroxy-polyethylene/hydroxyl-polypropylene (Profill) is also associated
Hyaluronic acid (animal) Hylaform, Hylaform plus with lipoatrophy.4
Poly-L-lactic acid Newfill, Sculptra Polytetrafluoroethylene (Gore-Tex) has been used for lip augmentation
Hydroxy-polyethylene/ Profill and has resulted in ulcerated nodules with pustules.14
hydroxyl-polypropylene Immediate-type reactions such as erythema, edema, and bruising have also
Calcium hydroxylapatite Radiesse, Radiance been described with other fillers, including hydroxy-polyethylene/hydroxyl-
Permanent: polypropylene (Profill), polyacrylamide-containing products, and poly-L-lactic
Bovine collagen/polymethyl Artecoll, Arteplast, Artefill, acid.4,13
methacrylate microspheres (PMAA) Metacril Infection is a potential complication following any cosmetic procedure.13
Hyaluronic acid/ DermaLive, DermaDeep Early infections, occurring within 2 weeks, are typically secondary to bac-
polyhydroxyethylmethacrylate (HEMA) / teria such as Staph. aureus or Streptococcus.3,13 Later infections may be due
ethylmethacrylate (EEMA) to atypical mycobacteria such as Mycobacteria chelonae, M. fortuitum, and
Silicone (dimethyl polysiloxane) Silikon 1000, Silskin, Adatosil abscesses.13
5000
Polydimethylsiloxane /polyvinyl Bioplastique
pyrrolidone Histological features
Polyacrylamide gel (PAAG) Aquamid Silicone nodules contain multiple vacuoles in the dermis, subcutis, and
Polyacrylamide and polyvinyl acid Evolution skeletal muscle.3,4,13 Vacuoles are variable in size and shape and resemble
Polyalkylimide gel BioAlcamid Swiss cheese. These are actually empty spaces where silicone was lost dur-
Polytetrafluoroethylene Gore-Tex ing processing. They are surrounded by giant cells and histiocytes which
Esthetic microimplants 629
contain intracytoplasmic vacuoles. Additionally, impurities in the silicone Ulcers caused by polytetrafluoroethylene (Gore-Tex) demonstrate variably
result in birefringent foreign material within giant cells.3,4 Surrounding sized threads of material surrounded by neutrophils and granulation tissue
fibrosis may also be noted.3 The silicone particles in polydimethylsiloxane/ (Fig. 14.111).14
polyvinyl pyrrolidone are too large to be phagocytosed by histiocytes.1 The Infectious lesions demonstrate variable findings depending on the caus-
material induces a foreign body giant cell reaction and fibrosis. The par- ative organism. Mycobacterial infections may present as granulomatous nod-
ticles are identified as translucent, jagged structures within cystic spaces.4 ules, and appropriate tissue stains and culture are necessary.
Bovine collagen is distinguished from human collagen by its lighter eosino-
philic color, thicker bundles, and more amorphous, acellular appearance.4
When recurrent inflammatory reactions develop in hypersensitive patients, Alpha-melanocyte stimulating hormone
there is a perivascular mononuclear cell infiltrate with a mixture of neutro- analogues (melanotan I and II)
phils, mononuclear cells, and eosinophils within implanted collagen.4
Early granulomatous nodules are comprised of a mixture of mononuclear Melanotan I and II are superpotent analogues of alpha-melanocyte stimulat-
cells, giant cells, eosinophils, neutrophils, and plasma cells surrounding but not ing hormone that have photoprotective effects. They appear to be increas-
infiltrating the collagen implant.4 Later lesions have a denser and deeper infil- ingly used by patients who want to develop a prominent tan. Although they
trate. Birefringent material is not seen. In contrast, nodules due to bovine col- are not licensed for this purpose, they can be obtained through the Internet.
lagen with polymethyl methacrylate microspheres (PMAA) (Artecoll) contain Their administration not only induces prominent tanning but also induces
a diffuse and nodular granulomatous infiltrate which surrounds cystic spaces, enlargement and darkening of pre-existing nevi. Histology of these nevi has
mimicking fat cells and with a Swiss cheese appearance.3 Located in the cen- not been described in detail but the few removed lesions in two patients did
ter of the spaces are nonbirefringent, round, translucent, well-circumscribed not show evidence of malignancy.1
foreign bodies (Fig. 14.109). This foreign material is the PMMA microsphere
which also induces surrounding fibrosis. The fibrosis contributes to the fill-
ing-effect. Hyaluronic acid with polyhydroxyethylmethacrylate (HEMA)/eth-
ylmethacrylate (EEMA) (DermaLive, DermaDeep) reactions are very similar
histologically to Artecoll, as they also contain methacrylate microspheres.3
Calcification of the foreign material has been described with DermaLive.1
Asteroid bodies may be present in both reactions.
Abscesses seen as a consequence of collagen implants show a dense neutro-
philic infiltrate with admixed plasma cells, histiocytes, and mononuclear cells.4
Giant cells surround implanted collagen, and granulomata may be present.
Nongranulomatous inflammatory nodules related to hyaluronic acid
injection are characterized by a superficial and deep perivascular and peri-
adnexal infiltrate of mononuclear cells with several eosinophils.13 Implanted
hyaluronic acid is not seen. In contrast, the granulomatous nodules con-
tain a striking nodular infiltrate of foreign body giant cells, histiocytes, and
eosinophils surrounding pools of basophilic foreign material which stain with
Alcian blue (pH 2.7).4,13 Polyacrylamide gel (PAAG) (Aquamid) has similar
features, but is distinguished from injected hyaluronic acid by the presence of
necrotic tissue admixed with the basophilic foreign material.13
Poly-L-lactic acid (Newfill, Sculptra) nodules are granulomatous and are
distinguished by spiky, long translucent bodies within giant cells.4,13 They are
irregular in shape and birefringent.
Reactions to bioAlcamid (polyalkylimide gel) display palisading granulo- Fig. 14.110
mas with scattered giant cells and a central area of amorphous material that Reaction to Bioalcamid: the central necrobiosis with a surrounding rim of
may mimic deep granuloma annulare or rheumatoid nodule (Fig. 14.110). histiocytes shows a striking resemblance to granuloma annulare.
Fig. 14.109
Reaction to Artecoll: note the foreign body granulomatous reaction and the typical Fig. 14.111
swiss cheese appearance. Reaction to Gore-Tex: the mesh is surrounded by dense fibrous tissue.
latter changes may mimic epidermolysis bullosa (Fig. 14.112). By electron

EMLA cream (prilocaine-lidocaine microscopy, the appearances mimic a lysosomal storage disorder with empty
emulsion) lisosomal inclusions.6 The latter change has been attributed to the castor oil
contained in EMLA cream.
Clinical features
EMLA is a eutectic mixture of prilocaine and lidocaine that is used widely
as a cream to provide local anesthesia, particularly in children and in adults
in genital areas. Very few side effects occur with its application, among them
a petechial eruption, contact urticaria, allergic contact dermatitis, and irri-
tant contact dermatitis.1–4 For dermatopathologists, however, what is more
important about EMLA are the subtle changes that it can cause at a micro-
scopic level, leading to difficulties in interpretation.5 These changes appear to
be related to the time that the cream is applied to the patient and they may
be more common in skin in which the biopsy is performed as a result of an
inflammatory process.
In cases of irritant contact dermatitis, the features consist of confluent necro-
sis of the upper layers of the epidermis, focal interface change with hydropic
degeneration of basal cells and clefting at the dermoepidermal junction and
an upper dermal mixed inflammatory cell infiltrate with neutrophils.4 The
changes mimic a necrolyic erythema or graft-versus-host disease. In cases
with no clinical evidence of a side effect, there is vacuolization of the gran- Fig. 14.112
ular cell layer and upper stratum spinosum and focal areas with hydropic Reaction to EMLA cream: in this example, there are multiple small foci of
degeneration of basal cells and clefting at the dermoepidermal junction.5 The subepidermal vesiculation.
Neutrophilic and eosinophilic Chapter
See
for references and
additional material
dermatoses
15
Pyoderma gangrenosum 631 Seabather’s eruption and coelenterate Eosinophilic cellulitis 649
stings 643
Acute febrile neutrophilic dermatosis 636 Eosinophilic pustular folliculitis 651
Erythema marginatum rheumaticum 644
Neutrophilic dermatoses associated Incontinentia pigmenti 652
with gastrointestinal and hepatobiliary Still's disease 644
Toxic erythema of the neonate 655
disease 639
Urticaria 645
Hidradenitis suppurativa 655
Rheumatoid neutrophilic dermatitis 640
Papular urticaria 649
Arthropod and arachnid bite reactions 641
Hypereosinophilic syndrome 649
They may be solitary or multiple, and occur most often on the lower limbs,
Pyoderma gangrenosum although other sites such as the trunk, face, arms, and buttocks are sometimes
affected (Fig. 15.3).29–30 Rare sites of involvement include the oropharyngeal
Clinical features region, hand, eyelid, eye, vulva, penis, scrotum, and the cervix.31–44 The ulcers
Pyoderma gangrenosum is an uncommon disease of obscure etiology.1–11 It are painful and tender, and may persist for months or years. Complications
appears to be somewhat more common in women and, although it may occur usually result from the site of the lesion and include cranial osteolysis and nasal
at any age, most patients are in their fourth or fifth decade.4 Presentation perforation.17,45 Recurrent attacks are not uncommon.2 Cribriform scarring
in children is uncommon, but it has been seen even in infants,12–21 and rare often follows healing. Systemic involvement has rarely been documented,
familial cases have been documented.22–24 The disease may also present in affecting the lungs, liver, bone, joints, pancreas, and heart.46–51
pregnancy and in this setting it is associated with an underlying disease
process in about 50% of the cases.25–28 Large, necrotic ulcers, often 10 cm or
more in diameter, characterize the disease (Fig. 15.1). Lesions may arise from
acneiform pustules or on a background of erythematous nodules. Typically,
the ulcers have undermined edges and red–purple borders (Fig. 15.2).
Fig. 15.2
Pyoderma gangrenosum:
this shows an area of
ulceration with a typical
undermined purplish
Fig. 15.1 border. By courtesy
Pyoderma gangrenosum: this unusually severe example is associated with very of R.A. Marsden, MD,
extensive tissue destruction resembling necrotizing fasciitis. By courtesy of R.A. St George’s Hospital,
Marsden, MD, St George’s Hospital, London, UK. London, UK.
632 Neutrophilic and eosinophilic dermatoses
or a tattoo.4,82–85 Pressure from use of seat belts in automobiles has been

associated with subsequent lesion development.86 Presentation has even been
documented at the location of a spider bite.87 One case reports involvement
of the scalp after receiving hair highlights at a salon, which could be due to
physical and/or chemical trauma.88
A few publications have implicated drugs in the etiology of the disease,
including:
• alpha-2b interferon (IFN-α2b),
• isotretinoin,
• sulpiride,
• propylthiouracil.89–94
In a single case report, pyoderma gangrenosum developed after
combination therapy with cytosine arabinoside, aclarubicin, and granu
locyte colony-stimulating factor for myelodysplastic syndrome.95 Another
single report associates gefitinib, an EGFR inhibitor, with pyoderma gan
grenosum.96 A granulomatous and suppurative dermatitis that may mimic
pyoderma gangrenosum has been documented at the site of interferon-
alpha (IFN-α) injections.97 Sclerotherapy has also been complicated by
Fig. 15.3 pyoderma gangrenosum on rare occasions.98 Association with sunitinib
Pyoderma gangrenosum: an extensive lesion with marked crusting and was reported in a single case study.99
undermining in the proximal and medial margins. By courtesy of R.A. Marsden, MD, Of particular importance is the known association of pyoderma gangreno
St George's Hospital, London, UK. sum with a variety of conditions4,11,100 (in up to 50% of patients2) as outlined
in Table 15.1. Of these, inflammatory bowel disease (both Crohn’s disease
and ulcerative colitis) and arthritis show the most well-established links.101–103
Pyoderma gangrenosum is reported to complicate around 1–2% of inflam
Occasionally bullous or pustular variants are encountered.4,52–60 One large matory bowel disease patients.104–106 In one study, 27% of patients had asso
study found that bullous lesions are more common on the upper extremities ciated inflammatory bowel disease and 20% of patients had arthritis.4 In this
and they appear to be more frequently associated with hematological same study, 27% of patients with superficial ‘atypical’ pyoderma gangrenosum
malignancy.4 Such lesions are sometimes designated atypical pyoderma gangr had an associated hematological disorder.4 In another large study, idiopathic
enosum.4,53 A vegetative form has also been described.61–65 pyoderma gangrenosum and that associated with chronic inflammatory
A particularly interesting feature seen in as many as 50% of cases is bowel disease were found to be more common in females, whereas pyoderma
development of lesions in traumatized areas (pathergy).4,66,67 Lesions may gangrenosum associated with hematological malignancy was more common
occur at sites of surgery and have been reported after cholecystectomy, breast in males.5 While pyoderma gangrenosum can fluctuate with inflammatory
reduction or augmentation, splenectomy, hysterectomy, cesarian section, fol bowel disease activity, it may also be a presenting or heralding feature. The
lowing aortic valve replacement, at the site of a fasciocutaneous flap, a lap presence of pyoderma gangrenosum as a complication of inflammatory bowel
aroscopic port insertion site, and in an amputation stump (Fig. 15.4).68–81 disease does not appear to be an independent predictor of severity of the
They also occur following rather trivial trauma such as injection or intrave bowel disease.107,108 Although pyoderma gangrenosum lesions may improve
nous access site, arteriovenous dialysis shunt, blood-drawing, acupuncture as inflammatory bowel disease is brought under control, specific treatment
is usually required.109 Most of the other numerous, rare associations men
tioned in Table 15.1 are likely to be fortuitous, as a report of simple coex
istence does not strictly imply a meaningful association.110 In any event, a
diagnosis of pyoderma gangrenosum should always prompt an evaluation for
an underlying disease association. Pyoderma gangrenosum-like lesions have
been reported as the presenting feature of antiphospholipid antibody syn
drome.111 Other underlying conditions causing lesions that mimic pyoderma
gangrenosum are also well described including inflammatory and infectious
processes, vasculopathies, and malignancies, stressing the importance of care
ful c linical investigation.112–122
The disease may also occur in association with other neutrophilic derma
toses including Sweet’s syndrome.123–125
Pyoderma gangrenosum is one of the components of a recently
described autosomal dominant syndrome known as PAPA (pyogenic ster
ile arthritis, pyoderma gangrenosum and acne).126 This syndrome has been
mapped to chromosome 15q and is associated with mutations in the gene
CD2BP1/PSTPIP1.127–131 These mutations increase the binding affinity of
this gene product to pyrin, overcoming the autoinhibition of this homotrimer
and allowing activation of the downstream innate immune response.132–134
Ultimately, this mutation leads to an increase in caspase-1 activation, an
underlying feature of multiple inherited autoinflammatory syndromes.135
Cases lacking a mutation in this gene have also been reported.136 These find
Fig. 15.4 ing indicate that pyoderma gangrenosum may be best regarded as an autoin
Pyoderma gangrenosum:
flammatory or autoimmune disease and the pathways being studied in PAPA
multiple early lesions
at the site of previous
syndrome may also eventually shed light onto the pathogenic mechanisms of
surgery. By courtesy sporadic pyoderma gangrenosum.
of R.A. Marsden, MD, Para- and peristomal involvement in patients with ileostomy or colostomy
St George’s Hospital, for inflammatory bowel disease is a well-recognized phenomenon.4,137–141 In a
London, UK. large series, 13% of patients had peristomal pyoderma.4 Both Crohn’s disease
Pyoderma gangrenosum 633
Table 15.1 Superficial granulomatous pyoderma is believed to represent a superficial

Conditions associated with pyoderma gangrenosum (alphabetical order) and rare variant of pyoderma gangrenosum.3,143–148 Patients develop single
or sometimes multiple superficial ulcerated lesions with vegetative borders
• Acne fulminans, acne conglobata and hidradenitis suppurativa184–188 (for this reason this variant is sometimes referred to as ‘vegetative variant of
• Acquired ichthyosis189
pyoderma gangrenosum’) as a consequence of trauma, frequently surgical
• Acute myeloid leukemia190
(Fig. 15.5). Pain is an occasional feature. The ulcers have a cleaner base than
• Allergic contact dermatitis from rubber191
• Anaplastic large cell lymphoma192 those seen in classic pyoderma. Lesions are most commonly found on the
• Antineutrophil cytoplasmic antibodies193–195 trunk and upper extremities and heal with cribriform scarring (Fig. 15.6).
• Arthritis (either seronegative or rheumatoid arthritis), ankylosing Draining sinuses are occasionally evident. Often there is no evidence of under
spondylitis and osteoarthrosis 4,196–198 lying systemic disease. Superficial granulomatous pyoderma is more likely to
• Autoimmune neutropenia of infancy199 follow a chronic course compared with classic pyoderma gangrenosum.149
• Behçet’s disease200 So-called ‘malignant pyoderma’ is a controversial designation which we
• Bullous systemic lupus erythematosus201 believe should be avoided. Some authors have used the term to describe a vari
• Burns / scalding202,203 ant of pyoderma gangrenosum predominantly affecting the head and neck.150–
• C7 deficiency204 152 More recently, however, it has been postulated that at least some cases
• Chronic idiopathic myelofibrosis205
of so-called malignant pyoderma more likely represent cutaneous Wegener’s
• Chronic myelomonocytic leukemia206
• Chronic renal failure207 granulomatosis.153
• Chlamydia pneumoniae208 One study found that over 50% of patients with pyoderma gangreno
• Cogan’s syndrome (interstitial keratitis and vestibuloauditory sum required long-term therapy to control their disease.5 The disease may be
dysfunction) 209
• Collagenous colitis210, 211
• Colorectal carcinoma212
• Cutaneous T-cell lymphoma213
• Cryofibrinogenemia214
• Cryoglobulinemia6
• Diverticular disease215
• Essential thrombocythemia 216
• Fanconi’s anemia217
• Factor V Leiden deficiency214
• Gastric carcinoma154,218
• Grave's disease219
• Glomerulonephritis220
• Hepatitis, autoimmune and viral156, 221–225
• Human immunodeficiency virus (HIV) infection226–228
• Hypertrophic osteoarthropathy229
• Hypogammaglobulinemia230, 231
• Inflammatory bowel disease: both ulcerative colitis and Crohn’s disease2,4,104
• Juvenile idiopathic arthritis232
• Kartagener’s syndrome233
• Klinefelter's syndrome234
• Lupus anticoagulant235
• Monoclonal gammopathy (most often IgA); usually benign but may
lead to multiple myeloma2,54,196,236 Fig. 15.5
• Multiple sclerosis237 Superficial granulomatous pyoderma: crusted superficial lesion with a cribriform
• Myelodysplastic syndrome238,239 appearance. By courtesy of the Institute of Dermatology, London, UK.
• Myelofibrosis240
• Myeloid leukemia54,56,155,241
• Osteomyelitis12,242
• Paroxysmal nocturnal hemoglobulinuria243
• Polycythemia rubra vera198
• Psoriasis244
• Renal transplant245,246
• SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis)247,248
• Sarcoidosis249
• Sjogren syndrome250
• Subcorneal pustular dermatosis251,252
• Systemic lupus erythematosus253
• Systemic sclerosis254
• Tuberculosis255
• Varicella (chickenpox)256
• Vasculitis, including Takayasu’s disease, erythema elevatum diutinum
and Wegener’s granulomatosis257–263
and ulcerative colitis are associated with this complication.4,140,142 It should be

noted that peristomal pyoderma gangrenosum has been seen in the absence
of inflammatory bowel disease.137,138 It has been documented in patients with
ostomy for gastrointestinal carcinoma and diverticular disease.137,138 Pyoderma Fig. 15.6
gangrenosum may also occur at urostomy sites following cystectomy for Superficial granulomatous pyoderma: this field shows extensive ulceration of the
bladder carcinoma.138 breast. By courtesy of R.K. Winkelmann, MD, Mayo Clinic, Scottsdale, Arizona, USA.
fatal in some cases, particularly if diagnosis is delayed.6,154 In another study,

2 of the 21 patients reported died of pyoderma gangrenosum secondary to
pulmonary involvement.6

The precise pathogenesis of pyoderma gangrenosum is uncertain. The current
state of knowledge suggests that it is due to immune dysfunction, perhaps
innate, and/or that it develops on a vasculitic basis.10,128,155–160 A variety of
immunological abnormalities have been described including:
• absent delayed hypersensitivity reactions to common antigens such as
mycobacteria and Candida albicans,
• defective neutrophil chemotaxis,
• impaired neutrophil phagocytosis,
• diminished lymphokine (migration inhibition factor) production,155,156,158
• overexpression of interleukin-8, a potent chemotactic polypeptide for
neutrophils, has been reported in lesional tissue and may be an important
pathogenetic factor,161,162
• reduction in interleukin-8 and related molecules has been noted following
successful therapy,163 Fig. 15.8
• aberrant neutrophil trafficking and metabolic integrin β2-CR3 and -CR4 Pyoderma gangrenosum: early acneiform lesion showing a subcorneal pustule.
oscillations in lesional tissue,164,165
• elevated levels of HIF2a and downstream effectors VEGF and Ang-2 aking recognition difficult has been described in one patient.180 Early lesions
m
have been noted in disseminated disease, suggesting that angiogenesis may present with subcorneal pustulation (Fig. 15.8). Although the histological
in improper control of the neutrophil oxidative burst may be features of both leukocytoclastic and lymphocyte-mediated vasculitis have been
involved,166 described, it is our experience that any vasculitis present is usually located within
• elevated TNF-α, MMP-9, and MMP-10 have also been noted,167 the floor of the ulcer or in the immediate adjacent tissues and is, therefore, more
• TNF-α may have some of its effects mediated by keratinocyte likely to be a consequence, rather than a cause, of the lesion (Fig. 15.9).1,181
secretion of elafin, an elastase inhibitor.168 Indeed anti-TNF-α Giant cells appear to be a common feature of pyoderma gangreno
therapy has been described to show some efficacy;169–173 however, a case sum in patients with Crohn’s disease.7 In one study, they were present in
has also been described in association with TNF-α antagonists used to 6 of 13 patients with associated inflammatory bowel disease; of these,
treat rheumatoid arthritis and the relationship may be complex.174 5 had Crohn’s disease and 1 had ulcerative colitis.7 Giant cells were not
The results of immunofluorescence studies in large series of patients have found in any biopsies from 22 patients without associated inflammatory
revealed both immunoglobulins (usually IgM) and complement in blood ves bowel disease.
sel walls in the dermis of the leading edge of the ulcer.175,176 Another study, Superficial granulomatous pyoderma is characterized by a zoned inflamma
however, failed to substantiate this finding.2 There is no evidence to support tory infiltrate in the superficial dermis.3 Focal and sterile abscesses are surrounded
an infective pathogenesis.177 by a zone of granulomatous inflammation bordered by a rim of lymphocytes and
Expanding T-cell clones in both the skin and circulation have been plasma cells (Figs 15.10–15.12).3 Hemorrhage is often present and eosinophils
described in a small series of patients indicating that T-cell response plays may be evident. Any vasculitic change is thought to be secondary. The adjacent
a role in the disease and may be triggered by a local stimulus in the skin.178 tissues may show scarring. Acanthosis and pseudoepitheliomatous hyperplasia
T-cell clonality has been described in pyoderma gangrenosum in the absence are frequently noted. Foreign material including starch, sutures, vegetable mat
of an underlying myeloproliferative disease.179 ter, wood, and hair has been identified in a large proportion of these cases.3
In general, the histopathology is that of non-specific ulceration with abscess It should be noted that not all cases of pyoderma gangrenosum with granu
formation (Fig. 15.7). The adjacent dermis shows acute and chronic inflam lomatous inflammation are limited to the superficial dermis. Some cases show
mation. A pseudo-Pelger-Huet phenomenon with hyposegmented neutrophils involvement of the deep dermis and even subcutaneous tissue.
A B
Fig. 15.7
(A, B) Pyoderma gangrenosum: in this biopsy from the edge of an ulcer, there are massive intradermal inflammatory changes, with abscess formation.
Pyoderma gangrenosum 635
Fig. 15.9 Fig. 15.12

Pyoderma gangrenosum: acute necrotizing vasculitis. It is likely that any active Superficial granulomatous pyoderma: high-power view showing multinucleate giant
inflammation of the blood vessel walls is a result of the surrounding inflammation cells. There are also conspicuous plasma cells.
rather than its cause.
The histopathological findings in pyoderma gangrenosum are non-specific
and the diagnosis is primarily one of exclusion.182 Since surgery is used to
manage some of the disorders considered in the histological and clinical dif
ferential diagnosis – but is contraindicated in the treatment of pyoderma
gangrenosum – early and accurate diagnosis is critical. Surgery, which tends
to exacerbate the disease, is generally contraindicated in pyoderma cases
because of the pathergic response. The mainstay of therapy is medical man
agement, such as corticosteroids. Unfortunately, patients with pyoderma are
often misdiagnosed early in the course of their disease and the diagnosis is
sometimes made only after multiple unsuccessful (and damaging) surgeries
have been performed. In one study, an average of five physicians had exam
ined the patient before a correct diagnosis was rendered.29 To avoid this error,
obtaining accurate clinical information on wounds and debridement speci
mens is essential.
Culture is required to exclude infection (bacterial, mycobacterial, fun
gal). Necrotizing fasciitis tends to affect deeper fascial and subcutaneous
Fig. 15.10 tissue, while pyoderma is centered in the dermis (albeit some spillover
Superficial granulomatous pyoderma: low-power view showing an undermining ulcer. into the subcutis may be seen). Usually, sheets of bacteria are evident
in untreated necrotizing fasciitis. Distinguishing these two conditions
is critical since the treatments are diametric opposites with surgery and
antibiotics for necrotizing fasciitis and avoidance of surgery with sys
temic anti-immune treatment and supportive wound care for pyoderma
gangrenosum.183
Sweet’s syndrome is generally not associated with ulceration and shows
more prominent karyorrhexis relative to the number of neutrophils. Bite
reactions, particularly resulting from the brown recluse or other spiders,
may show similar histological features. Clinical information is necessary
to distinguish pyoderma from many other forms of ulcer such as those due
to trauma.
Although some authors have noted lymphocytic or neutrophilic vascu
litis in lesions of pyoderma gangrenosum, this finding, in our experience,
is limited to areas adjacent to the ulcer and likely represents a second
ary finding.5 Indeed, it has been our experience that ‘secondary’ vasculitis
is frequently present at the border of ulcers of many different etiologies
in patients without any genuine underlying ‘primary’ vasculitic process.
Evaluation for vasculitis as a cause of ulceration therefore depends upon
examination of blood vessels in areas of dermis and subcutaneous tissue
away from the ulcer.
Fig. 15.11 It cannot be overemphasized how important accurate clinical information
Superficial granulomatous pyoderma: the zoned inflammatory reaction is clearly is in establishing the correct diagnosis. Failing to recognize this disease early
seen. Note the central abscess and surrounding granulomatous inflammation. in its course can be disastrous for the patient.
Occasionally, the lesions may become bullous or pustular.32,33 The

Acute febrile neutrophilic dermatosis plaques vary from about 1 to 4 cm in diameter and typically heal without
scarring. Recurrences develop in approximately one-third of patients and
Clinical features postinflammatory hyperpigmentation is sometimes seen.34,35 Pathergy and
Acute febrile neutrophilic dermatosis (Sweet’s syndrome) is an uncommon koebnerization are occasional features and necrosis with ulceration may
disease of unknown etiology and pathogenesis.1–11 It is associated with a rarely be encountered.7,36–38 Sweet’s syndrome may present with lesions
marked female predilection (5:1) and most patients affected are in their third mimicking palmoplantar pustulosis and sometimes erythema nodosum-like
through sixth decades. It may, however, occasionally be seen in children and lesions are present.32,39,40 A Sweet’s syndrome-like eruption has been described
a few cases presenting in infancy have been documented.12–22 Infant broth in a ssociation with exposure to light.41
ers who both had Sweet’s syndrome have been reported.23 Patients present Sweet’s syndrome often follows an upper respiratory tract infection. In
with variable numbers of asymmetrically distributed, frequently bilateral, cir some cases it is a complication of drug treatment, for example carbamazepine,
cumscribed, tender and painful red plaques or nodules, particularly on the furosemide, hydralazine, co-trimoxazole, abacavir, azathioprine, ofloxacin,
face, neck, and upper and lower limbs (Figs 15.13–15.15). An acral form doxycycline, clindamycin, minocycline, trimethoprim-sulfamethoxazole, bort
of this condition is now termed neurophilic (or pustular) dermatosis of the ezomib, lenalidomide, imatinib mesylate, nilotinib, etanercept, granulocyte
dorsal hands (Fig 15.16).24–31 Whether this represents a distinct disease or a colony-stimulating factor (G-CSF), radiocontrast agent, some vaccines, oral
peculiarly localized variant of Sweet’s syndrome is uncertain. contraceptives, all-trans retinoic acid, isotretinoin, nitrofurantoin, diazepam,
clozapine, and celecoxib.32,33,42–69 The temporal relationship with administra
tion, development of symptoms, and resolution with withdrawal of the offend
ing drug establishes the cause in drug-induced cases.42,65 The disease has also
been reported after chemotherapy in patients with acute myeloid leukemia.70,71
Fig. 15.13
Sweet’s syndrome: an erythematous plaque on the forearm. By courtesy of R.A.
Fig. 15.15
Sweet’s syndrome: close-up view of typical plaques. By courtesy of the Institute of
Fig. 15.14
Sweet’s syndrome:
characteristic edematous
red plaques (some
showing ulceration and
pustulation) are widely
distributed on the trunk
and proximal limbs. By
courtesy of R.A. Marsden, Fig. 15.16
MD, St George’s Hospital, Sweet’s syndrome: acral lesions on the dorsal surface of the hands and fingers, some
London, UK. with a hemorrhagic appearance. By courtesy of J.C. Pascual, MD, Alicante, Spain.
Acute febrile neutrophilic dermatosis 637
Sweet’s syndrome can be broadly reviewed as falling into three general Table 15.2
categories: Conditions associated with Sweet’s syndrome
• classic (and often idiopathic), Common associations
• malignancy-associated (paraneoplastic),
Drugs58
• drug-induced.10
Hematologic malignancies (and myelodysplastic syndrome)91
Patients may also have conjunctivitis, episcleritis, iritis, polyneuropathy,
Hepatitis B142
oral involvement (superficial ulcers), and arthralgias.32,72–76 The larger joints Inflammatory bowel disease (including ulcerative colitis and Crohn’s
are usually affected and involvement tends to be migratory.5 Patients with disease) 143,144
concurrent Sweet’s syndrome and erythema nodosum have been described Non-tuberculous mycobacterial infection145,146
and it is possible that these two disorders share common pathogenetic mecha Pregancy147
nisms.77 Dyssynchronous and synchronous Sweet’s syndrome and erythema Sarcoidosis148,149
nodosum may occur.78–81 Scrofuloderma150
Sweet’s syndrome is of particular importance since 10–40% of cases are Sjögren’s syndrome151
associated with hematological malignancy such as leukemia (monocytic or Tuberculosis152
myelomonocytic, including leukemia cutis), myelodysplasia, lymphoma, and Upper respiratory tract infection10
multiple myeloma.82–93 Development of the disease may herald a relapse of the Rare associations
leukemia.94 Sweet’s syndrome has also been reported in patients with mono Bacille-Calmette–Guérin (BCG) vaccination153
clonal gammopathy and myelodysplasia in the absence of frank leukemia or Pigmented villonodular synovitis154
lymphoma.95 Hemophagocytic syndrome is also a reported association.96 The Behçet’s disease155,156
clinical lesions of Sweet’s syndrome are said to be more severe in patients with Bronchiolitis obliterans157
underlying hematological disease.88 An association with urticaria pigmentosa Celiac disease158
has also been documented.7 Chronic granulomatous disease159
Dermatomyositis160, 161
Solid tumors may also be associated with Sweet’s syndrome in up to 7%
Encephalitis162
of patients, including:
Erythema nodosum80
• testicular, Generalized granuloma annulare163
• bladder, Hashimoto thyroiditis164
• gastrointestinal, Infection with Apnocytophaga canimorsus, Chlamydia pneumoniae,
• breast, Coccidiodes immitis, Cytomegalovirus, Francisella tularensis,
• lung, Helicobacter pylori, Hepatitis C, human immunodeficiency virus (HIV),
• ovary, Pasteurella multocida, Salmonella enteritidis, and Staphylococcus
• prostate.7,32,35,79,82–85,88,95,97–99 epidermidis and Staphylococcus aureus165–178
Association with oral squamous cell carcinoma has been reported,36,100 Polycythemia rubra vera179,180
Prothrombin gene (G20210A) mutation181
as has a rare case following treatment of herpes simplex in a patient with
Relapsing polychondritis182, 183
metastatic breast carcinoma.101 Sweet’s syndrome has been described in
Sarcoidosis184
conjunction with numerous conditions, some of which are listed in Table Solid tumor malignancy87, 97
15.2. While its association with hematologic and internal malignan Still’s disease185
cies, upper respiratory tract infections, drugs, and certain inflammatory Surgery186
disorders such as erythema nodosum, rheumatoid arthritis, and sarcoido Subacute and systemic cutaneous lupus erythematosus187–189
sis appears repeatedly, many of the others listed in the literature could be Thyroid disease (Grave’s disease and Hashimoto’s thyroiditis)190
coincidental. Urticaria pigmentosa7
Systemic involvement may be a feature of Sweet’s syndrome with lesions
described in the eye, lung, kidney, central nervous system, vagina, liver, gas
trointestinal tract and skeletal muscle.7,86,102–110 Neural involvement appears
to be strongly associated with HLA-Cw1.110 An exceptional case with gin One study demonstrated clonality in the skin infiltrate of a patient with
gival hyperplasia and myositis in the absence of cutaneous involvement has Sweet’s syndrome and acute myelogenous leukemia, undergoing treatment
been documented.111 with G-CSF.119 The authors concluded that Sweet’s syndrome in patients with
Associated features include pyrexia, neutrophilia, and a raised ESR. In myelogenous leukemia may result from therapy-induced differentiation of
one study, six of seven patients had antineutrophil cytoplasmic antibodies neoplastic cells.119 However, a further study has demonstrated clonality in
(ANCA).112 Other studies, however, have not found an association between four patients in the absence of myeloproliferative disease.120
Sweet’s syndrome and ANCA.7 This finding has not been further explored in Histologically, the epidermis in Sweet’s syndrome is usually unaffected
the more recent literature. although occasionally slight spongiosis is present; rarely, vesiculation and
spongiform pustules have been described.32 Necrotic keratinocytes are also
sometimes evident.32 The cardinal feature, however, is an intense neutrophil
Pathogenesis and histological features polymorph infiltrate within the reticular dermis (Fig. 15.17).3,121 This may be
The etiology of Sweet’s syndrome is unknown; however, the disease most prob diffuse or perivascular in distribution and often surrounds the sweat ducts.
ably represents an unusual hypersensitivity reaction.113 Cytokine mediation Typically, leukocytoclasis is marked (Fig. 15.18). Admixed with the neutro
is likely, as anti-inflammatory agents are generally useful.113 The occasional phil polymorphs are variable numbers of eosinophils, lymphocytes, and his
presence of immune complexes in blood vessel walls may have pathogenetic tiocytes. Ingestion of nuclear debris by histiocytes is sometimes a conspicuous
significance.32 It has been suggested that neutrophils are activated by interleu feature. A histiocyte-rich form of the disease has increasingly been recog
kin (IL)-1 and that Sweet’s syndrome represents a cytokine-mediated inflam nized.32,122–130 This is more likely to represent a stage in the evolution of the
matory reaction to a wide variety of different antigens including bacteria, disease rather than a specific variant of Sweet’s syndrome. It has been pos
viruses, drugs, and malignancies.114–116 Demonstration of elevated serum tulated that the histiocyte-like cells seen represent immature granulocytes.130
IL-1α, IL-1β, IL-2, and interferon-gamma (IFN-γ) but not IL-4 suggests that Awareness of this form of presentation is important to avoid a misdiagno
type 1 (but not type 2) helper T cells (Th) play a role in the pathogenesis.117 sis. Given the presence of a mononuclear cell infiltrate in these cases, it is
Not surprisingly, since exogenous treatment with G-CSF is associated with extremely important to exclude leukemia cutis.
Sweet’s syndrome, endogenous G-CSF has been shown to be elevated in some Often, the papillary dermis shows very marked edema, which sometimes
cases.118 results in subepidermal vesiculation (Fig. 15.19). Rarely, the presence of
Fig. 15.17
Sweet’s syndrome: an intense inflammatory cell infiltrate is present in the dermis. Fig. 15.20
Sweet’s syndrome: the
occasional presence of
dermal papillary neutrophil
microabscesses can
result in confusion with
dermatitis herpetiformis.
dermal papillary neutrophil microabscesses may cause diagnostic confusion

with dermatitis herpetiformis (Fig. 15.20).121 In Sweet’s syndrome the blood
vessels are dilated and may show endothelial swelling but changes of frank
vasculitis are generally absent in our experience (and certainly not promi
nent). However, others have reported features of vasculitis such as nuclear
dust, extravasation of erythrocytes, and fibrin deposition in and around ves
sels walls in the majority of their series of 31 cases and thus argue that the
presence of vasculitis should not exclude this diagnosis.131–133 Purpura, how
ever, is sometimes evident.134 Immunofluorescence examination of skin biop
sies in Sweet’s syndrome is usually negative for immunoreactants in the walls
of the vasculature. Recently, a case associated with leukocytoclastic neutro
philic lobular panniculitis has been reported.135
Fig. 15.18 In some cases, an inflammatory infiltrate is noted within subcutaneous tis
Sweet’s syndrome: the infiltrate consists largely of neutrophils. There is edema and sue. This infiltrate may be composed of lymphocytes and histiocytes and, less
marked leukocytoclasis. commonly, neutrophils.121,129 Sweet’s syndrome has also been associated with
an erythema nodosum-like panniculitis.136 Elastophagocytosis and cutis laxa
have been reported with resolution of Sweet’s syndrome lesions.137–140
The presence of prominent fibrinoid vascular change can distinguish necrotiz
ing vasculidities such as leukocytoclastic vasculitis, erythema elevatum diuti
num, and granuloma faciale from Sweet’s syndrome; the clinical presentation
and distribution of disease are also extremely helpful. In granuloma faciale,
fibrinoid necrosis is often minimal and eosinophils tend to be prominent. Late
lesions of erythema elevatum diutinum and granuloma faciale show fibrosis,
a feature not seen in Sweet’s syndrome. Clinically, the presence of character
istic large ulcers helps distinguish pyoderma gangrenosum from Sweet’s syn
drome. Also, pyoderma gangrenosum does not usually show the extent of
karyorrhexis that is a typical feature of Sweet’s syndrome. A Gram stain and
periodic acid-Schiff (PAS) or culture may be necessary to exclude infection.
Distinction from some other forms of neutrophilic dermatosis including
bowel bypass syndrome may be a definitional issue since the clinical setting
determines the terminology applied.7 Behçet’s disease may also be associated
with lesions similar to those seen in Sweet’s syndrome. Clinical correlation
should ensure the correct diagnosis. CD30-positive forms can sometimes be
Fig. 15.19 found in Sweet’s syndrome, raising the possibility of lymphomatoid papulosis.
Sweet’s syndrome: marked papillary dermal edema is commonly present and However, neutrophils are usually rare in the latter condition and the number
sometimes this is associated with subepidermal vesiculation. of CD30-positive cells in lymphomatoid papulosis is not prominent.141
Neutrophilic dermatoses associated with gastrointestinal and hepatobiliary disease 639
Neutrophilic dermatoses associated with

gastrointestinal and hepatobiliary disease
Clinical features
Pyoderma gangrenosum, the most common neutrophilic dermatosis affect
ing patients with gastrointestinal disease (particularly ulcerative colitis), is
discussed above. The spectrum of lesions described in this section shares
many histological (and likely pathogenetic) features with pyoderma gan
grenosum but lack the characteristic progressive ulceration. Neutrophilic
dermatoses associated with gastrointestinal disease may best be regarded
as a continuum, with pyoderma gangrenosum representing an extreme end
of the spectrum.
A syndrome of arthritis and pustular skin lesions was initially
described in patients with inflammatory bowel and liver disease, and also
in patients who have undergone jejunoileal bypass or Billroth II surgery
for morbid obesity, but now has been described in other gastrointesti
nal disorders.1–7 Up to 20% of patients with jejunoileal bypass develop
this condition.4,8 It has also been noted in association with peptic ulcer Fig. 15.21
(A, B) Neutrophilic
ation, appendicitis, and diverticular disease.9,10 An increasing number of
dermatosis associated
papers call this process bowel-associated dermatosis-arthritis syndrome with gastrointestinal
(BADAS); this terminology currently appears to be that preferred by the disease: there is
majority of authors. an intense dermal
The skin lesions may be papular or vesicular, or form large necrotic neutrophilic infiltrate
lesions resembling pyoderma gangrenosum. They are usually found on A indistinguishable from
the trunk or extremities. Oral involvement has also been described.2 Sweet’s syndrome.
Associated panniculitis, which may resemble erythema nodosum, is a fea
ture in some patients. Cutaneous manifestations often recur with exacer
bation of the associated gastrointestinal disease.4 Some patients have an
elevated ESR.4 The disease occasionally responds to antibiotic or steroid
therapy.
A recurring vesiculopustular eruption may be seen in patients with hepa
tobiliary disease.11 The lesions – which can be pruritic and sometimes heal
with an atrophic scar – often present on the extremities. In some patients
the eruption represents a necrotizing folliculitis.11 Occasionally, the cutaneous
lesions precede the features of the hepatobiliary disease.
Of interest, patients with Crohn’s disease complicated by disseminated
abscesses (involving the spleen, lymph nodes, liver, pancreas, and brain)
have recently been described.12 In some of these, the abscesses occurred
before the diagnosis of Crohn’s disease. Histologically, a granulomatous ele
ment was commonly present. Successful treatment with immunosuppressive
therapy suggests that such lesions may represent an unusual extraintestinal
manifestation of Crohn’s disease.12
The description of these entities suggests that they are overlapping or B
perhaps represent a disease continuum. BADAS is the most rigorously defined
among these and this terminology can probably be employed for all of the
conditions mentioned above. Differential diagnosis
The main differential diagnoses include infection, Sweet’s syndrome, pyoderma
Pathogenesis and histological features gangrenosum, and rheumatoid neutrophilic dermatitis. Clinical history is essen
The presence of circulating immune complexes in occasional patients has led tial to distinguish these conditions.
some authors to postulate a pathogenic role.13,14 It is postulated that bacterial The literature relating to bowel-associated dermatosis-arthritis and
overgrowth may play a role in the development of such circulating immune Sweet’s syndromes is often confusing and it seems likely that some patients
complexes.4 who have been reported as the former would actually have been better clas
The histopathological findings, which are non-specific, are those of a neu sified as the latter. Contrariwise, occasional patients who presented with
trophilic dermatosis. The lesions show variable dermal edema and necrosis features more typical of bowel-associated dermatosis-arthritis syndrome
associated with a perivascular and interstitial neutrophilic infiltrate. Variable have, in fact, been reported as Sweet’s syndrome.17,18 In many patients
numbers of lymphocytes and histiocytes may also be present. Abundant kary such a distinction is semantic. In others, however, the clinical lesions are
orrhexis gives rise to a histological pattern similar to acute febrile neutrophilic quite inconsistent with Sweet’s syndrome and in these patients a designa
dermatosis (Sweet’s syndrome) (Fig. 15.21). Leukocytoclastic vasculitis and tion of bowel-associated dermatosis-arthritis syndrome is probably more
pustular vasculitis have also been documented.15,16 The inflammation is often appropriate.
limited to the dermis but in some patients it may be seen to involve the sub Pyoderma gangrenosum is another neutrophilic dermatosis which patients
cutaneous fat, resulting in erythema nodosum or an erythema nodosum-like with gastrointestinal disease are at risk of developing. Clinically, it may be
panniculitis. distinguished by the progressive expansile nature of the cutaneous ulcers.4
The small number of cases described in patients with hepatobiliary disease Since the biopsy findings may be similar, clinical correlation is essential
has shown bullae associated with a dermal neutrophilic infiltrate, sometimes to distinguish this condition from bowel-associated dermatosis-arthritis
accompanied by eccrine hidradenitis or folliculitis.11 syndrome.
It is likely, given the histological and clinical spectrum encountered in the e osinophils may be present; abscess formation is sometimes a feature.2,3,5
neutrophilic dermatoses associated with gastrointestinal and hepatobiliary Occasionally, the inflammatory infiltrate extends into the subcutaneous
disease, that they result from similar or shared pathogenetic mechanisms. fat.3,7 The overlying epidermis may show spongiosis and intraepidermal
Clearly, more research may clarify their precise pathogenesis and contribute vesiculation.5
to a more satisfactory classification system.
Infection must be considered in the differential diagnosis, particularly as
Rheumatoid neutrophilic dermatitis patients are often at risk of infection as a result of immunosuppressive ther
apy. Furthermore, the cutaneous eruption may be treated with steroids, and
Clinical features failure to diagnose an underlying infective process could have disastrous
Rheumatoid neutrophilic dermatitis is an uncommon eruption seen in consequences. Gram, AFB/acid fast, and silver stains for microorganisms
patients with rheumatoid arthritis.1 It presents most often as papules, nod should be routinely performed and the diagnosis made only after infection
ules, and plaques on the extensor surfaces of the extremities, neck, and has been excluded. We have encountered several patients with rheumatoid
trunk. In some patients it may clinically resemble urticaria.2–7 Bullous lesions arthritis on steroid therapy who developed pustular infiltrates associated with
have also been described.8,9 The lesions, which can ulcerate, are often pru Mycobacterium chelonei infection.
ritic or painful, and sometimes show an annular configuration.3,10 The dis Pyoderma gangrenosum may show similar, if not identical, features but
ease is uncommon, as evidenced by documentation in just two of 142 and differs by progressive ulceration. It should be remembered that patients
two of 215 patients with rheumatoid arthritis seeking medical attention for with rheumatoid arthritis may also develop pyoderma gangrenosum.4
skin disorders in academic clinics in Japan and Turkey, respectively.4,11 The Clinical correlation is necessary to distinguish these entities. Pyoderma
presence of rheumatoid neutrophilic dermatitis correlates with the severity gangrenosum may form part of a continuum that may eventually prove
of the patient’s joint disease.4 to share similar pathogenetic mechanisms. To those who hold this view,
Typically, lesions last for up to several weeks.2 In some patients, the condi documentation of a patient with concurrent typical features of both
tion resolves spontaneously; in others, it responds to steroid, dapsone or sul pyoderma gangrenosum and rheumatoid neutrophilic dermatitis should
famethoxypyridamine therapy.2,5,10 not be surprising.20
Patients with seronegative arthritis but with cutaneous findings similar to Some authors have pointed out that rheumatoid neutrophilic derma
rheumatoid neutrophilic dermatitis have recently been reported.12–15 titis might be classified as a variant of Sweet’s syndrome.2 Certainly, the
Magro and Crowson have described sterile neutrophilic folliculitis biopsy findings may be very similar. The lack of fever and the general mal
associated with a Sweet’s syndrome-like histology in a setting of systemic aise that accompany Sweet’s syndrome are distinguishing clinical findings.
disease including rheumatoid arthritis, Crohn’s disease, connective tissue The presence of gastrointestinal disease distinguishes rheumatoid neutro
disease, hepatitis, Behçet’s disease, atopy, hematological dyscrasia, and philic dermatitis from bowel-associated dermatosis-arthritis syndrome.
mycobacterial infection.16,17 A similar folliculocentric acute inflammatory As with pyoderma gangrenosum, one might consider Sweet’s syndrome
process has also been documented in patients with ulcerative colitis.18,19 and rheumatoid neutrophilic dermatitis to form a spectrum of disease.2
It would seem probable that these reports reflect a similar condition It is the characteristic clinical settings that allow these disorders to be
or spectrum of disease that likely shares common histopathogenic distinguished.
mechanisms. Patients with rheumatoid arthritis may sometimes develop lesions
which show histological overlap with rheumatoid neutrophilic dermatitis
Pathogenesis and histological features but which can be distinguished by the presence of a palisading necrobiotic
The pathogenesis of rheumatoid neutrophilic dermatitis is not understood and granulomatous component (termed palisaded neutrophilic granuloma
but some authors have suggested that it may represent an immune complex- tous dermatitis).21 This spectrum, also includes interstitial granulomatous
mediated disease.3,5 dermatitis encountered in a setting of systemic disease (including rheuma
Histologically, it is characterized by a dermal neutrophilic infiltrate with toid arthritis). Patients, predominantly adults, present with papules and
variable karyorrhexis (Fig. 15.22). In some cases, however, karyorrhe nodules which particularly affect the extremities or trunk; these are often
xis is minimal or absent. Variable numbers of histiocytes, plasma cells, and distributed in a linear pattern.22,23 The presence of necrobiosis associated
A B
Fig. 15.22
(A, B) Rheumatoid neutrophilic dermatitis: there is an intense upper dermal neutrophilic infiltrate with conspicuous karyorrhexis. By courtesy of J. Cohen, MD,
Dermatopathology Laboratory, Tucson, USA.
Arthropod and arachnid bite reactions 641
with a histiocytic response reminiscent of granuloma annulare or necrobi

osis lipoidica in addition to acute inflammation and variable karyorrhexis
helps distinguish these lesions from typical rheumatoid neutrophilic
dermatitis.
Lesions in which the neutrophilic infiltrate is associated with dermal pap
illary abscess formation may be mistaken for dermatitis herpetiformis, linear
IgA disease, and bullous systemic lupus erythematosus. Immunofluorescence
staining may be necessary in problematic cases.
The presence of vascular necrosis and fibrinoid change distinguishes rheu
matoid neutrophilic dermatitis from vasculitis.24 It must be emphasized that
a careful search for evidence of vasculitis is not simply an academic exercise,
since patients with rheumatoid arthritis are also at risk of developing vas
culitis. In fact, patients with rheumatoid arthritis may present with lesions
histologically showing extravascular palisading granulomas, diffuse neutro
philic infiltrates or vasculitis (neutrophilic, lymphocytic or granulomatous).
The different patterns may overlap and classification should be based on the
dominant histological pattern.
Fig. 15.24
Arthropod and arachnid bite reactions Spider bite: note the central eschar and surrounding erythema. Courtesy of
Al Mahmoud, MD, Doha, Qatar.
Clinical features
The vast majority of insect bites pose little more than a minor annoyance. The
reaction that results from a given bite depends on the nature of the offend ulceration, often progressing to a large necrotic lesion, is a feature.6 Chronic
ing insect and the patient’s immune response. The clinical response to a bite ulceration mimicking pyoderma gangrenosum may rarely ensue.7 The brown
may vary from a trivial erythematous papule to a large nodule associated recluse is most commonly encountered in rural areas of the Midwest, south-
with marked pruritus and ulceration. Vesicles are sometimes seen in severe central, and southeastern United States and is easily identified by a violin-
reactions (Fig. 15.23). Careful inspection will often reveal a punctum at the shaped marking on the cephalothorax that gives it its vernacular name of
site where insect mouth parts entered skin. ‘fiddleback’ spider.8 However, other spiders are often misidentified as brown
While arthropod bites are rarely of clinical importance, reactions following recluse and the diagnosis may be overused as the spider is often not identi
the bite of certain arachnids can lead to a more serious clinical lesion fied at the time of the bite.9–13 This makes much of the existing literature
(Fig. 15.24). Many different species of spiders may bite humans, and reac suspect.14
tions to the most significant and well described – the brown recluse and the Sphingomyelinase-D in the venom of the brown recluse spider is
black widow – are detailed below.1–4 thought to be responsible for the extensive necrosis that results in some
patients.15 Spider bites may be associated with morbilliform rash, malaise,
Brown recluse spider fever, nausea, hemoglobinuria, arthralgias, and vomiting.6,16–18 More seri
The brown recluse spider (Loxosceles reclusa) bite begins as a painful bluish ous complications (e.g., renal failure, shock, disseminated intravascular
macule, papule or nodule, often with a bruise-like appearance. A central coagulation, acute hemolytic anemia, and intravascular hemolysis) have
punctum is commonly observed. The lesion is often trivial. The thigh was the also been described.16,19,20 Many of the effects of the venom appear to
involved site in almost 50% of cases with the arm and abdomen accounting be dose-dependent rather than idiosyncratic.21,22 ELISA-based assays to
for most of the remainder in a large series from a single center of more than detect the Loxosceles venom at the site of the bite are available and can
50 patients with presumed bites.5 However, in some patients, blistering and be helpful to confirm the diagnosis, as detectable toxin may persist for
more than 2 weeks.23–27 Anti-loxoscelic sera are available for use in severe
cases.28,29
Widow spiders
The five species of widow spiders found in the United States, including the
notorious black widow (Latrodectus mactans), are most commonly encoun
tered in the southern states. Compared with the brown recluse, bites by
widow spiders are much less commonly encountered by healthcare provid
ers. Many presumed or self-reported arachnid bites are ultimately discov
ered to be skin and soft tissue infections.30 The bite often shows a targetoid
appearance with a pale center surrounded by an outer erythematous rim.31
A bite from a black widow spider is commonly associated with severe pain
in the vicinity of the bite as well as systemic symptoms such as general mal
aise, abdominal pain, nausea, headache, and muscle spasms.6,16,31 Priapism
has been noted as a rare complication.32 Occasionally, patients die as a result
of the bite.19,33
Alpha-latrotoxin is an active component of the venom that binds to pre
synaptic nerve terminals and stimulates massive neurotransmitter release.
The neurological symptoms are termed latrodectism and consist of pain,
Fig. 15.23 diaphoresis, and non-specific systemic symptoms sometimes combined with
Bullous insect bite reaction: there are large fluid-filled bullae in this close up view additional autonomic or neurological dysfunction.34 Equine-derived antisera
from the lower leg. From the collection of the late N.P. Smith, MD, the Institute of is available and effective as a treatment.35 Recombinant antisera are under
Dermatology, London, UK. development.36
Hobo spider
Recently, the Hobo spider (Tegenaria agrestis) has been implicated as a
cause of significant bite reactions in the Pacific Northwest with migration to
Montana and Colorado and evidence of continuing eastward expansion.37,38
While bites from this spider are believed to cause dermonecrotic injuries,
additional study is necessary to confirm this impression.39,40
Just as there is a spectrum of clinical response to an insect bite, the histo
pathological features also vary.
The typical arthropod bite reaction, such as follows a mosquito bite, is
characterized by a wedge-shaped polymorphic inflammatory cell infiltrate
composed of lymphocytes, histiocytes, eosinophils, and sometimes neutro
phils (Figs 15.25, 15.26). Spongiosis (occasionally with vesicle formation)
and variable dermal edema are also seen (Figs 15.27–15.30). Ulceration
with scale-crust commonly forms in excoriated lesions. In some cases,
insect mouth parts are identified in the center of the lesion. In our experi
ence, this is more common in biopsies from tick bites than arachnid bites
Fig. 15.26
(Figs 15.31–15.33). Arthropod bite reaction: note the conspicuous eosinophils.
As with arthropod bite reactions, the histological sequelae from arach
nid bite are variable. Compared with the former, arachnid bite reactions are
typically associated with more extensive necrosis and suppurative inflam
mation. Necrosis may extend to involve the subcutaneous fat and muscle.6
Variable numbers of eosinophils and lymphocytes are present and marked
dermal edema is often a feature.6 Secondary vasculitis, involving vessels
within the lesion or in the immediate surrounding tissue, may be a feature
in some cases. Injection of brown recluse spider venom into rabbits results
in ‘mummified’ coagulation necrosis, a mixed inflammatory cell infiltrate,
and vasculitis.41
The histological findings in biopsies of insect bites, short of identifying
mouth parts in the specimen, are non-specific. The main differential diagno
sis includes hypersensitivity reactions. The characteristic wedge shape of the
infiltrate is an important clue to the diagnosis. The presence of large atypical
lymphocytes helps distinguish lymphomatoid papulosis from an arthropod
bite reaction. Bite reactions with a dense eosinophil-rich infiltrate may be
Fig. 15.27
Bullous arthropod bite reaction: massive subepidermal edema has resulted in a
multiloculated subepidermal blister.
Fig. 15.25
Arthropod bite reaction:
there is a heavy Fig. 15.28
perivascular and interstitial Bullous arthropod bite reaction: eosinophilic spongiosis is present at the edge of
infiltrate. the lesion.
Seabather’s eruption and coelenterate stings 643
Fig. 15.29 Fig. 15.32

Bullous arthropod bite reaction: there is a lymphocytic and eosinophilic perivascular Tick bite reaction: high-power view showing tick parts and multiple flame figures.
and interstitial infiltrate.
Fig. 15.30 Fig. 15.33

Bullous arthropod bite reaction: high-power view showing a flame figure. Tick bite reaction: there is a dense infiltrate of lymphocytes, histiocytes, and
conspicuous eosinophils.
indistinguishable from Wells’ syndrome. The occasional presence of flame

figures heightens the similarity. Clinical correlation may be necessary to
distinguish these two conditions.
The histological findings associated with arachnid bite are also non-spe
cific. Arachnid bites must be distinguished from pyoderma gangrenosum,
factitial disease, primary vasculitis, and infections including cellulitis and
necrotizing fasciitis. Arachnid envenomation appears to be over-reported;
thus, some cases have been reported in regions where the spiders have never
been documented to exist. ELISA-based assays may be helpful to confirm
the diagnosis. Without definitive evidence of involvement of an arachnid,
the diagnosis must be considered one of exclusion so as not to overlook
important clinical alternatives with a different treatment approach.
Seabather’s eruption and coelenterate

stings
Fig. 15.31
Clinical features
Tick bite reaction: low-power view showing a heavy dermal inflammatory cell Seabather’s eruption, sometimes referred to as ‘sea lice’, is attributed
infiltrate. Tick parts are seen in the center of the field. to stings from larval forms of coelenterates, often the thimble jellyfish
(Linuche unguiculata scyphomedusae).1–4 Typically, patients develop a Pathogenesis and histological features
papular eruption in areas covered by the bathing suit, often accentuated The pathogenesis of rheumatic fever is incompletely understood. It appears
where the suit is tight fitting, such as the waistline.5 The eruption is usu likely that it results from a hypersensitivity reaction triggered by streptococ
ally pruritic and may cause a burning sensation. Patients sometimes expe cal infection. Specifically, patients develop autoantibodies that cross-react
rience systemic symptoms such as malaise, fever, nausea, diarrhea, and with streptococcal antigen due to molecular mimicry.9 For example, autoan
vomiting. tibodies cross-react with cardiac muscle, causing carditis. Mice immunized
Reactions to coelenterates such as jellyfish vary from minor irritation to with the streptococcal M protein develop myocarditis.9 Bradykinin in dense
fatal reactions following stings by highly venomous species such as the ‘box deposits can be seen in stromal and endothelial tissues, suggesting it may
jellyfish’ (Chironex fleckeri and Chiropsalmus quadrigatus).6 Jellyfish stings mediate some facets of this condition.10
are often erythematous and show a ‘whiplash-like’ appearance.6,7 Certain spe Variable numbers of neutrophils (sometimes associated with leukocyto
cies may have more serious consequences, such as the Portugese man-of- clasis) and mononuclear cells are present in the infiltrate.7,11 Importantly,
war (Physalia physalis), where systemic effects from neurotoxins can be seen, however, there is no evidence of vasculitis. Dermal papillary neutrophil
including cramping of muscles, respiratory distress, profound hypotension, microabscesses have occasionally been described.7
and even death in extreme cases.8–11 It has been reported that rare cases are devoid of neutrophils and the
A topically applied envenomation inhibitor based on the mucous coat of infiltrate is instead composed of lymphocytes and histiocytes.12
clown fish is effective in dramatically reducing both some coelenterate stings
and seabather’s eruption, though it may lack efficacy against certain coelen
terate species.12,13
The biopsy findings in erythema marginatum are non-specific. Similar his
tological features may be seen in patients with Still’s disease and acute lupus
Histological features erythematosus. Careful search for vascular damage is necessary to exclude
Biopsy of papules of seabather’s eruption shows a non-specific perivascular leukocytoclastic vasculitis. Special stains and culture to rule out an infec
inflammatory cell infiltrate composed of variable numbers of lymphocytes, tious etiology are sometimes required. Urticaria can demonstrate perivascular
eosinophils, and neutrophils.2 Epidermal changes are apparently not usually neutrophils but additionally it shows significant dermal edema, and an
a feature.2 interstitial inflammatory cell infiltrate, including neutrophils, eosinophils,
Only few authors have reported the histological findings following reac and lymphocytes
tion to coelenterate stings. Non-specific perivascular inflammation with
lymphocytes and variable numbers of eosinophils appear to be characteris
tic. Some cases show dense, sheetlike aggregates of lymphocytes and histio Still's disease
cytes.14 Variable dermal edema may be an additional feature. Spongiosis and
vesicle formation are also sometimes described.14–16 One fatal case showed Clinical features
only vascular congestion without significant inflammation, a histological Juvenile rheumatoid arthritis or systemic juvenile idiopathic arthritis (Still’s
picture that likely reflects the fact that the patient died only 40 minutes disease) is a heterogeneous group of disorders which share in common an
after being stung.6 Only occasionally are nematocyst capsules and tubes inflammatory arthritis with many features similar to rheumatoid arthritis in
identified.6,16 adults. Juvenile rheumatoid arthritis patients, however, are seronegative for
rheumatoid factor.1 There are marked differences in prevalence from region
to region. Whites in Europe, the United States, and Australia (4 per 1000)
Differential diagnosis have the highest prevalence.2,3 One study has suggested that the incidence of
The histological differential diagnosis of reactions to coelenterates includes the disease is decreasing.4 This same study also documented incidence peaks
other hypersensitivity reactions. Short of finding nematocysts, the diagnosis indicating a possible cyclical pattern.4 Other studies have found seasonal
depends entirely on clinical correlation. variation in certain regions such as the Canadian prairies.5 However, such
seasonal onset has not been apparent in other areas of Canada, in Denmark
or in Japan.5–8
Juvenile rheumatoid arthritis is classified into three variants: pauciarticular,
Erythema marginatum rheumaticum polyarticular, and systemic onset.
• The pauciarticular (oligoarticular) form is characterized by arthritis
Clinical features involving up to a maximum of four joints. Systemic manifestations are
Once a common disease, it was thought that, with the effective antibiotic uncommon. Uveitis, however, is frequently present.
treatment of the causative infection, rheumatic fever would become of histor • The polyarticular form is manifest by symmetrical arthritis typically
ical interest only. However, there has been a resurgence of the condition over involving the knees, wrists, and ankles. Fever and hepatosplenomegaly
the past few decades, particularly in developing countries.1–5 are sometimes present.
Rheumatic fever is an immunologically mediated disease that follows an • The systemic-onset form is a severe variant in which lymphadenopathy,
infection with Lancefield group A beta-hemolytic streptococcus. The infec fever, and rash precede development of polyarteritis which most often
tion causes pharyngitis and carditis. Additional features include polyarthritis, affects the knees, ankles, and wrists.9 Additional features may include
a neurological movement disorder known as Sydenham’s chorea, and sub hepatosplenomegaly and effusions. In general, the term Still’s disease is
cutaneous nodules.6 Carditis, characterized by a valvular disease, is a major restricted to this form of juvenile rheumatoid arthritis; however, some
cause of morbidity and mortality. authors use it for any of the variants. The majority of patients with the
Erythema marginatum rheumaticum is the designation given to the dis systemic form have the characteristic rash in contrast to the pauci- and
tinctive annular or polycyclic eruption of rheumatic fever. The lesions are polyarticular variants in which only 20–40% are affected.9
nonpruritic, multiple, flat, erythematous maculopapules which change The rash of Still’s disease is evanescent, and is characterized by a faint
and spread over hours, and are often recurrent. The trunk and proximal erythematous (salmon-colored), sometimes pruritic, macular eruption involv
extremities are most frequently affected.2 The hands and face may also be ing the trunk, extremities, head, and neck.9–11 Often, there is an association
involved.4 By definition, erythema marginatum rheumaticum is associated between onset of rash and febrile episodes, particularly in the late afternoon
with rheumatic fever, but occurs in only 1–18% of patients.1 Some studies or evening.9,11 The rash is typically present for only a short period of time,
have failed to identify significant human leukocyte antigen (HLA) associa usually a matter of a few hours; however, some lesions persist for more than
tions.3,7 However, there are conflicting reports of certain HLA subtypes and 24 hours.9,11 It characteristically reappears without regard for its former dis
the disease.8 tribution.11 Macules are often only a few millimeters in size but frequently
Urticaria 645
become confluent to form larger lesions. Central pallor is sometimes a feature The influence of various HLA alleles and their association with juve
of the latter.10 The eruption – which may persist for weeks to years – tends to nile rheumatoid arthritis has been an area of considerable interest and has
localize to areas of mild trauma and pressure.9,11 yielded a complex picture of the relationship between certain HLA alleles and
Laboratory abnormalities include elevated ESR and C-reactive protein. risk of disease.29 HLA-A2, DR8, DR5, and DPB1*0201 are associated with
Serum immunoglobulins may also be raised. Patients sometimes have leuko increased risk of pauciarticular disease early in life.31 While B27 and DR4
cytosis, anemia, and thrombocytosis. Occasional patients have rheumatoid may be protective in the early years, these alleles seem to confer increased risk
factor and some authors consider this to represent bona fide juvenile rheu of disease later in life.30
matoid arthritis. Antinuclear antibodies are commonly found in patients with CD4-reactive T lymphocytes are the predominant cell type in the inflamed
pauci- and polyarticular variants of the disease.8 In contrast, antinuclear anti synovium.31 As with other autoimmune disorders, production of predomi
body is usually not present in the systemic-onset form. nantly Th1 cytokines (IFN-γ and IFN-β) has been observed in the synovium
It is very difficult to predict the outcome of this disease in the individual of juvenile rheumatoid arthritis patients.31,32
patient. Approximately 50% of patients experience symptoms into adulthood. The biopsy findings are non-specific and variable. There is often a perivas
Progression of juvenile rheumatoid arthritis to systemic lupus erythematosus cular neutrophilic infiltrate.10 In some cases, mononuclear cells are the pre
(SLE) has been documented.12 Serious complications including uveitis, dominant cell type.9,11 A neutrophilic panniculitis may be associated with
cardiac tamponade, portal vein thrombosis, liver failure, and disseminated the disease.33 In adult-onset Still’s disease, distinctive histologic features have
intravascular coagulation have been documented.13–17 been described particularly in the persistent papules and plaques sometimes
Despite the name juvenile rheumatoid arthritis, Still’s disease is not lim seen in the disease.24 The epidermis displays dyskeratotic keratinocytes in
ited to the pediatric population. Adult onset is well described in the literature single units or aggregates. They tend to be present mainly in the upper layers
(Fig. 15.34).18–22 Patients with the adult form of the disease may develop per of the epidermis and even in the stratum corneum.23,34 Other changes include
sistent papules and plaques and hyperpigmentation.23 Lesions are mainly seen subcorneal pustules, upper dermal lymphocytes and neutrophils and, in a
on the face, neck, trunk, and extensor surfaces of the extremities. single case report, excess dermal mucin.23,34
Pathogenesis and histological features Differential diagnosis

The pathogenesis of juvenile rheumatoid arthritis is poorly understood. It would The histological findings, as indicated above, are variable and non-specific.
seem likely, however, that the various subtypes have different etiologies. Thus: Clinical correlation is necessary to establish the diagnosis. The differential
• IL-2 mRNA is detected more often in pauciarticular juvenile rheumatoid diagnosis includes infection, and culture and stains for microorganisms should
arthritis than in the polyarticular form.24 be performed when necessary. The absence of fibrinoid change and necrosis of
• IFN-γ mRNA may be detected in 33% of systemic-onset juvenile blood vessel walls distinguishes the lesions from leukocytoclastic vasculitis.
rheumatoid arthritis in contrast to 85% in the other forms.24 IL-6 and
other cytokines can also be involved.25
Recently, it has been suggested that nucleotide-binding and oligomerization Urticaria
domain (NOD)-like receptors (NLR) that detect microbes and help constitute
the inflammasome (a complex of proteins which initiates an inflammatory Clinical features
reaction) may be involved in autoimmune disease generally and in Still’s dis Urticaria is an extremely common group of disorders that share common
ease in particular.26 clinical and histological features.1 The lifetime incidence approaches 1 in 5
Data suggesting that the incidence of the disease is decreasing with cyclical people.2 As will be seen later, urticaria has many different etiologies but, more
peaks raise the possibility that environmental factors could play a role in the often than not, the cause remains unknown and the disease is then classi
pathogenesis.4 Demonstration of T-cell oligoclonal expansions within synovial fied as idiopathic. In some patients, more than one stimulus may elicit symp
tissue suggests that an antigen or group of antigens may trigger the disease.27 toms.3 The clinical common denominator in urticaria is the development of
The nature of such triggering factors, however, has not yet been identified. ‘hives’ or ‘wheals’ – raised edematous lesions – which are often surrounded
The prevalence of autoimmune disease is increased in relatives of patients by a zone of erythema and are commonly pruritic (Figs 15.35–15.37).4,5
with juvenile rheumatoid arthritis compared with control subjects, suggesting Dermatographism – pressure or light scratching resulting in linear urti
that shared susceptibility genes may be of importance in the pathogenesis of carial lesions – is a common symptom. Urticaria may develop in only sec
juvenile rheumatoid arthritis and other autoimmune diseases.28 onds. Lesions usually resolve in less than a few hours. By definition, lesions
Fig. 15.34 Fig. 15.35

Still’s disease in an adult: there are multiple erythematous macules. By courtesy of Urticaria: erythematous, edematous, coalescing plaques on the trunk and proximal
J.C. Pascual, MD, Alicante, Spain. extremities of an infant. By courtesy of J.C. Pascual, MD, Alicante, Spain.
Solar urticaria
Solar urticaria is characterized by development of wheals and pruritus at sites
exposed to light (Fig. 15.38).7 A sensitizing agent, such as a drug, may be
necessary.8 In some patients lesions even arise in areas covered by light cloth
ing.9 ‘Fixed solar urticaria’ is a designation given to a rare form of urticaria
seen in patients who develop lesions at the same sites with repeated light
exposure.10,11 Solar urticaria has also been described following exposure to
infrared and ultraviolet radiation.12,13
Aquagenic urticaria
‘Aquagenic urticaria’ is a bizarre variant of physical urticaria in which patients
develop lesions following exposure to water (regardless of temperature).14,15
Extracutaneous manifestations such as migraine headache and familial occur
rence has been described on rare occasion.16–18 Thankfully, patients do not
develop symptoms from drinking water.5,19 Application of petrolatum oint
ment or other barrier cream prior to water exposure helps to prevent lesion
development.14,20 It has been postulated that a water-soluble epidermal anti
gen may be responsible for such symptoms, since aqueous extracts of callus
cause symptoms in patients’ skin but not in that of controls.21 Increased water
Fig. 15.36 salinity has also been implicated.22
Urticaria: in this patient,
the erythematous border Cold urticaria
is well demonstrated. Placing an ice cube on the skin of patients may elicit a wheal – a condition desig
By courtesy of the nated ‘cold urticaria’.5,23 Some patients, however, develop symptoms only after
generalized cooling of the body.5,24 Occasionally, drinking cold liquids or bath
London, UK.
ing in cold water elicits symptoms.5 The condition can be associated with other
types of physical urticaria. Very rarely, there is associated cryoglobulinemia and
in some cases the condition follows a viral infection or drug ingestion.23,25,26
Familial cold urticaria (familial cold autoinflammatory syndrome) which
follows exposure to cold is an autosomal dominant condition characterized by:27–30
• urticaria,
• fever,
• arthralgias,
• arthritis,
• conjunctivitis,
• leukocytosis.
Patients with this syndrome develop symptoms with a decrease in body
temperature but do not develop wheals at the site of an ice cube applied to
skin. Recently, patients have been shown to have mutations in the NLRP3
gene (also known as CIAS1) on chromosome 1q44 encoding the protein cryo
pryin. This protein is part of the cytosolic inflammasome protein complex and
involved in its activation.31–38 Interestingly, Muckle-Wells syndrome is associ
ated with the same gene and consists of periodic fever, frequent sensorineural
Fig. 15.37
Urticaria: in this extreme
example there is intense
erythema. By courtesy
of the Institute of
in patients with chronic urticaria, however, persist over a period in excess of

6 weeks.5,6 In addition, individual lesions in patients with chronic urticaria
often last longer – up to 36 hours.4
Given that urticaria is best viewed not as a single disease but as a group of
related disorders, it comes as no surprise that the natural history of urticaria
is highly variable.2 Resolution is seen in 50% of patients within a few years
of onset; however, in some patients the disease persists for decades.2,5 The
severity of symptoms is also variable. For many patients, the disease is a
minor annoyance; for others, however, severe reactions may be associated
with life-threatening anaphylaxis. Fig. 15.38
Physical causes of urticaria include sunlight, cold, heat, pressure, and Solar urticaria: in this patient, urticaria developed after exposure to sunlight.
vibration. By courtesy of the Institute of Dermatology, London, UK.
Urticaria 647
hearing loss, amyloidosis, and recurrent urticaria not linked to cold expo Physical urticaria, secondary to vibration, cold, and sunlight, as well as
sure.32,39 In addition, neonatal-onset multisystem inflammatory disease also contact (type I) hypersensitivity reaction and cholinergic urticaria may be
maps to this gene.40 The spectrum of autoinflammatory disorders is now associated with angioedema.57
referred to as the cryopinopathies.41
Urticaria induced by heat has rarely been documented.42–44 Urticarial vasculitis
Urticarial vasculitis is an uncommon condition which combines clinical
Delayed pressure urticaria features of chronic urticaria and histological findings of leukocytoclastic
Patients with ‘delayed pressure urticaria’ develop lesions at sites of pressure, venulitis.59–62 A type III hypersensitivity reaction (caused by antibody–antigen
such as areas of tight clothing.5,45 This form of urticaria is seen in 40% of complexes) appears to be the underlying etiology in a subset of patients.63,64
patients with chronic urticaria (see below).5,46,47 In many patients, however, no underlying cause is discovered.
Urticarial vasculitis is associated with a female predominance (2:1)
Cholinergic urticaria and is most often seen in young to middle-aged adults. Urticarial lesions
Cholinergic urticaria – one of the most common subtypes of urticaria – is tend to last 24–72 hours and may be associated with pruritus, a burning
thought to result from release of cholinergic substances by nerves.48–50 Evidence sensation or pain.65,66 The frequency of attacks varies from daily to monthly.
in support of this theory includes the observation that wheals may be elicited Hyperpigmentation can be present at resolution.
by the injection of cholinergic compounds, and injection of anticholinergic The spectrum of illness ranges from mild symptoms to a serious systemic ill
agents blocks wheal formation.48 Furthermore, wheals do not develop in skin ness.67 In addition to urticarial skin lesions, patients can also have angioedema,
innervated by nerves injected with local anesthetic, and application of sco gastrointestinal symptoms, and evidence of renal involvement. Necrotic skin
polamine to skin prevents aquagenic urticaria.19,48 Common causes of cho lesions are not usually seen. Other systemic manifestations/associations include
linergic urticaria include increase in body temperature (e.g., following a hot joint pain, stiffness, and swelling; however, frank arthritis is extremely rare. Some
bath or shower), emotional stress, exercise or consumption of spicy food (Fig. patients have proteinuria and hematuria. Rarely, renal biopsy reveals the features
15.39).5,48,51 Familial cases of cholinergic urticaria have been reported.52 of focal or diffuse proliferative glomerulonephritis. Crescentic glomerulonephri
tis and mesangial and membranous nephropathy have been described in some
Contact urticaria patients.67–69 The erythrocyte sedimentation rate (ESR) is frequently raised.
Rarely, urticarial vasculitis has been documented in association with malig
Contact urticaria may be divided into two main subtypes: allergic and irritant.5 nancy, a relationship which may be coincidental.67,70–75
• Allergic contact urticaria is a hypersensitivity reaction following Hypocomplementemia is seen in many patients and the presence of this sign
exposure to an allergen such as chemicals, foods, latex, plants, fruits and correlates with systemic involvement and a high prevalence of autoantibod
vegetables, and animal-derived antigens.53,54 Not surprisingly, this form of ies to endothelial cells.63,67,76–78 Patients with Schnitzler’s syndrome have urti
urticaria often occurs in patients with a history of atopy.53,55 carial vasculitis and monoclonal IgM gammopathy.79–86 Hepatosplenomegaly,
• Irritant contact urticaria is a nonimmunologically mediated form of elevated ESR, raised white blood cell count, fever, and joint pain are charac
urticaria secondary to a wide variety of substances found in cosmetics, teristic features.80–82 Occasional patients have an associated lymphoprolifera
food and medications.53 tive disorder.79 This disease is associated with anti-C1q autoantibodies which
likely mediate the disease.87
Urticarial angioedema Urticarial vasculitis (especially the hypocomplementemic variant) is often asso
Patients with urticaria often develop angioedema characterized by edematous ciated with or precedes development of a variety of systemic diseases, including
swelling of the lips, eyelids, and tissues of the oropharynx.5,56,57 Two main sub myeloma, hepatitis B and C, SLE, arthritis, interstitial lung disease, pericarditis,
types of angioedema are recognized: hereditary and nonhereditary (acquired). mixed connective tissue disease, inflammatory bowel disease, serum sickness,
• Hereditary angioedema is rare, autosomal dominantly inherited, and due polyarteritis nodosa, Wegener’s granulomatosis, viral infections, Sjögren’s syn
to C1-esterase inhibitor deficiency.58 drome, cryoglobulinemia, polycythemia rubra vera, reaction to drugs, and as a
• Acquired angioedema is caused by drug reactions, allergic reactions, response to sunlight.67,76,77,88–96 Urticarial vasculitis has also been documented in
reaction to physical agents, hypereosinophilia, and acquired association with pregnancy, exercise, and cocaine use.97–99 Ocular disease (includ
(nonhereditary) C1-esterase deficiency.57 ing uveitis, scleritis, conjunctivitis or episcleritis) is a very common feature.67,100
An idiopathic variant is also recognized. Patients with hypocomplementemia appear to be at risk of developing more
severe disease.88 Obviously, a diagnosis of urticarial vasculitis in any patient
should initiate an evaluation for underlying disease.101
Drug-induced urticaria
Drug-induced urticaria is fairly common. It is present in 0.16% of medical
inpatients and in 9% of cases of chronic urticaria or angioedema seen in der
matology outpatient departments.102,103 The drugs most commonly implicated
are sulfonamides, penicillins, and non-steroidal anti-inflammatory medica
tions.102 Aspirin may induce acute urticaria, worsen chronic urticaria or act
as a cofactor to induce anaphylaxis.104 Other less common drug associations
include antipsychotics, alendronate, recombinant IFN-β, cetirizine, bleomycin,
and IL-3.105–110 Many of these reactions are mediated by IgE antibodies, but
some result from direct activation of mast cells or interact with another path
way that augments the urticaria reaction.111 In this last category, modulation
of arachidonic acid metabolites by aspirin and other agents can help initiate or
exacerbate urticaria.112 Specifically, in some cases polymorphism in the leukot
riene C4 synthase gene can be associated with aspirin-induced urticaria.113–115
Other urticarial associations

Urticaria has also been documented in association with autoimmune pro
Fig. 15.39 gesterone dermatitis, dermatophytosis, candidiasis, parasites (anisakiasis),
Cholinergic urticaria: in this variant, urticaria follows heat, emotional stress or a consumption of tonic water, nicotine, alcohol consumption, and hepatitis
spicy meal. By courtesy of the Institute of Dermatology, London, UK. B vaccination (Table 15.3).116–122
Table 15.3 histamine, eosinophil chemotactic factor, prostaglandin, leukotrienes, platelet

Classification of urticaria subtypes (presenting with wheals and/or activating factor, and enzymes.53,123,124,126,127 Similarly, IgE-mediated mast cell
angioedema) degranulation also underlies the pathogenesis of allergic contact urticaria
Types Subtypes Definition
in which direct contact with allergens on skin bind to the surface IgE on
mast cells causing release of histamine and other inflammatory mediators.
Spontaneous Acute spontaneous Spontaneous wheals and/or Autoantibodies against the IgE high-affinity receptor (FcεRI) or to IgE itself
urticaria urticaria angioedema < 6 weeks
are present in about 30% of patients with chronic urticaria, designated auto
Chronic spontaneous Spontaneous wheals and/or
urticaria angioedema > 6 weeks
immune urticaria, a type II hypersensitivity reaction.123,128–131 Patients with
physical urticaria or with connective tissue or autoimmune bullous disease
Physical Cold contact urticaria Eliciting factor: cold objects/ may also have anti-FcεRI. However, in the last group of patients, the autoan
urticaria air/fluids/wind
tibodies are nonfunctional (nonhistamine releasing), whereas in chronic urti
Delayed pressure Eliciting factor: vertical
caria, the antibodies are functional (histamine releasing).131,132 A type III
urticaria pressure (wheals arising with
a 3-12 h latency) hypersensitivity reaction, caused by circulating antigen–antibody immune
Heat contact urticaria Eliciting factor: localized heat complexes, underlies a form of urticaria associated with serum sickness.
Solar urticaria Eliciting factor: UV and/or A role for Helicobacter pylori in the causation of chronic urticaria has
visible light been suggested but other studies have challenged this theory.133–138
Urticaria factitia/ Eliciting factor: mechanical The pathogenesis of irritant contact urticaria is not well understood but
dermographic shearing forces (wheals evidence suggests that degranulation of mast cells due to direct, nonimmu
urticaria arising after 1-5 min) nologically mediated contact causes release of vasogenic mediators.53,124
Vibratory urticaria/ Eliciting factor: vibratory forces, Similarly, it is thought that the physical urticarias (heat, cold, pressure,
angioedema e.g. pneumatic hammer
vibration, water) also result from a direct effect on mast cells in susceptible
Other urticaria Aquagenic urticaria Eliciting factor: water individuals.127
types Cholinergic urticaria Elicitation by increase of body Some investigators have suggested that solar urticaria results from a type
core temperature due to I hypersensitivity reaction to a photoinduced antigen eliciting IgE-mediated
physical exercises, spicy food mast cell degranulation.9 An intriguing study has shown that most patients
Contact urticaria Elicitation by contact with
(77%) develop an urticarial reaction when challenged with autologous serum
urticariogenic substance
Exercise induced Eliciting factor: physical
that has been irradiated using the same spectrum of light that induces lesions
anaphylaxis/urticaria exercise in each particular patient.139 Furthermore, patients with ‘fixed’ urticaria
develop lesions at the same specific sites that are affected by light exposure
Table 2 from Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA2LEN/EDF/WAO
guideline: definition, classification and diagnosis of urticaria. Allergy 2009; following injection with irradiated plasma.14 Consistent with these observa
64:1417–1426. tions, some patients with severe solar urticaria may be effectively treated by
plasma exchange.140,141
A type III hypersensitivity reaction (caused by antibody–antigen com
plexes) appears to be the underlying etiology in some patients with urti
Pathogenesis and histological features carial vasculitis; however, no underlying cause is discovered in many
As has been stated above, urticaria is probably best viewed as a group of dis patients.64,67 More recently, urticarial vasculitis has been excluded from
orders sharing common clinical and histological features. The pathogenesis the formal urticaria group of disorders by some authors due to its variant
of some forms of urticaria (e.g., allergic contact urticaria) is well understood; pathogenic mechanism, but is still considered in this section for historical
however, the precise pathogenesis of many cases of urticaria is obscure.123 Mast purposes.2
cell degranulation with perhaps some involvement of basophils appears to be The biopsy findings in urticaria are non-specific. Dermal edema may be
a common denominator in the pathway of most types of urticaria.124,125 mild or severe and its presence is confirmed by separation of dermal retic
Release of histamine following a hypersensitivity reaction after exposure ular collagen fibers. An often sparse dermal perivascular and interstitial
to an allergen is the basis for allergic contact urticaria.56 In sensitized patients, mixed inflammatory infiltrate composed of variable numbers of lympho
an allergen binds to IgE on mast cells causing degranulation and the release of cytes, neutrophils, and eosinophils is present (Fig. 15.40). Of interest, mast
A B
Fig. 15.40
Urticaria: (A) at low-power examination, the features are easily overlooked. There is a light perivascular infiltrate and the collagen fibers appear separated; (B) at high power,
there is edema and a light perivascular infiltrate of lymphocytes with scattered eosinophils.
Eosinophilic cellulitis 649
cells – which play such an important role in the pathogenesis of urticaria –

do not appear to be increased in number except in chronic urticaria.130,142 Hypereosinophilic syndrome
Usually, more inflammatory cells are seen in lesions of chronic urticaria com
pared to those of acute urticaria.142 Clinical features
Urticarial vasculitis combines histological features of urticaria with super The hypereosinophilic syndrome is defined as an idiopathic condition
imposed vascular damage. The vasculitis affects the superficial vascular characterized by persistent eosinophilia (more than 1.5 × 109/L) for at least 6
plexus and shows features of a leukocytoclastic subtype; however, compared months and with involvement of one or more organs.1–4 The diagnosis should
with typical leukocytoclastic vasculitis, the histological findings tend to be be made only after other causes of eosinophilia, particularly parasitic infec
subtle and are easily overlooked. Mild or focal fibrinoid change apparent on tions, have been excluded. The heart, lungs, central and peripheral nervous
only a few sections associated with few neutrophils and sparse karyorrhexis system, liver, and skin are commonly affected. The disease, which may some
is typical. Some authors have shown that endothelial necrosis is unusual.64 times prove fatal, generally presents in adults.
Occasionally, impressive necrotizing vasculitis (features of typical leukocy Cutaneous lesions are seen in up to 53% of patients and usually consist
toclastic vasculitis) may be seen. In summary, urticarial vasculitis appears as of either pruritic papules and nodules or urticaria and angioedema.5 Rarely,
a continuum, ranging from urticaria with very mild vascular injury to frank skin lesions represent an initial manifestation and in this setting, annular ery
necrotizing vasculitis.143 thema and erythroderma have been reported.6–10 Oral and genital erosions
are quite characteristic and can be the first manifestation of the disease.11,12
Differential diagnosis Other rare cutaneous features include livedo reticularis, cutaneous infarction,
deep vein thrombosis, blisters, aquagenic pruritus, erythema gyratum repens,
The diagnosis requires careful clinical correlation. The biopsy findings are and Wells’ syndrome.13–19 Hypereosinophilic syndrome has been reported in
often very subtle: the dermal edema and sparse inflammatory infiltrate association with lymphomatoid papulosis, T-cell lymphoma, systemic mast
may be easily overlooked. A definitive diagnosis sometimes requires test cell disease, SLE, and HIV infection.20–25
ing for response to particular antigens. Other forms of hypersensitivity
reaction such as arthropod bite and drug eruption can show similar fea Pathogenesis and histological features
tures and require clinical correlation to distinguish them from urticaria.
The etiology is unknown. It has sometimes been categorized into:
Clinical correlation is necessary to distinguish urticarial vasculitis from
other forms of leukocytoclastic vasculitis. Although urticarial vasculi • idiopathic,
tis is often associated with subtle low-grade vascular injury, this pattern • clonal,
should not be relied upon in the distinction from other forms of vasculitis. • secondary types.26
Some forms of clonal eosinophilia (malignancy-associated) harbor activat
In short, the pathologist’s role in diagnosis is to confirm the presence of
ing mutations or rearrangements of fibroblast or platelet derived growth fac
vasculitis.
tor receptors (FGFR1, PDGFRA, PDGFRB) and are amenable to targeted
therapies.27,28 Secondary causes result from other causes such as an under
lying infection. Idiopathic is what remains when these first two categories
Papular urticaria are excluded. Elevated serum levels of IL-10 and soluble IL-2 receptor have
been documented.29 IL-2 stimulates release of eosinophilic cationic protein
Clinical features from eosinophils which contain IL-2 receptor (CD25) and this results in tis
Although papular urticaria (prurigo mitis) is often described as a variant sue damage.
of urticaria, and the histologic picture is that of an urticarial dermatitis, The histological findings vary according to the type of lesion biopsied.
the lesions are persistent and patients do not fulfill the criteria for the Urticarial and papular lesions show a superficial and deep perivascular
diagnosis of urticaria. In the latter, lesions are self-limited even in cases and interstitial mixed inflammatory cell infiltrate with variable numbers of
of chronic urticaria. The condition is generally regarded as a variant of eosinophils and scattered lymphocytes, histiocytes, and occasional plasma
an insect bite reaction.1–4 Papular urticaria has no sex predilection and cells. Rare flame figures may be present. Dermal edema is seen particularly
although the age range is wide, it tends to be more frequent in children. in urticarial lesions. Eosinophils are not always prominent and the findings
It presents as small, itchy, red papules that tend to appear in crops. Most can be entirely non-specific. Microthrombi are present in some cases and
lesions are no more than a few millimeters in diameter but larger lesions sometimes correlate with the severity of the disease.13,30
may be seen. They are more usually seen on exposed areas of the body and
tend to be more prevalent during the summer months. Changes secondary Eosinophilic cellulitis
to scratching including excoriations are frequent. There are no associations
with systemic disease. Clinical features
Eosinophilic cellulitis (Wells’ syndrome) is an uncommon disorder, character
Pathogenesis and histological features ized by recurrent erythematous and edematous plaques.1–6 It occurs with an
The pathogenesis is not entirely clear but it is generally believed that the equal sex ratio and there is a large age range, with a mean age of 37 years.7
condition is triggered by a hypersensitivity reaction to insect or arthropod It is sometimes also encountered in children and rare cases have been docu
bites.5,6 Many insects and arthropods have been implicated in the disease mented in neonates.7–11 It appears that cases occurring in childhood may be
including fleas, carpet beetles, lice, bedbugs, mosquitoes, and even caterpil particularly severe. Scalp involvement, with alopecia and scarring, is a feature
lars. This is further supported by the rash clearing after the patient returns in some patients.7,8
from holidays or after moving to a new house. A recent study found evidence The disease particularly affects the extremities and trunk. Although it pres
of IgG against bedbugs (Cimex lectularius) in affected patients suggesting a ents most commonly as well-defined (cellulitis-like) annular erythematous
role in the pathogenesis of the disease.6 plaques, which are edematous and firm, a wide variety of clinical appearances
The histological features are fairly non-specific. In intact lesions the epi have been described including blistering, nodular, papulovesicular eruptions,
dermis is unremarkable or slightly acanthotic. Changes of excoriation may be and itchy excoriated inflammatory papules (Figs 15.41–15.43).7,12–14 The
evident. In the dermis there is a mild to moderate, superficial and deep, often plaques, which cause pain and pruritus in some patients, typically heal with
wedge-shaped, mainly perivascular inflammatory cell infiltrate composed of out scarring.7 Eosinophilic cellulitis has been associated with urticaria.15
lymphocytes, histiocytes, and eosinophils.7 Neutrophils can be seen in some Dermatographism can be a feature.16 With progression, the lesions sometimes
cases.7 The presence of the latter is required for a histological diagnosis of adopt a greenish hue. Clinically, the lesion may occasionally be mistaken for
papular urticaria to be made. A few CD30-positive lymphocytes are some an infective process.17 The disease tends to be episodic, with remissions and
times present. relapses, which can last from months to years.
Large bullae are seen in rare patients.18 An unusual pattern of involvement

following Blaschko's lines has been reported and it has been proposed that
this form represents cutaneous mosaicism.19
Rarely, eosinophilic cellulitis is associated with a malignant neoplasm.
Cases accompanied by eosinophilic leukemia, colonic carcinoma, squamous
cell carcinoma of the lung, and non-Hodgkin’s lymphoma have been
described.20–23 Associations with HIV, hypereosinophilic syndrome, ulcerative
colitis, tetanus or thiomersal-containing vaccine and varicella infection have
occasionally been documented.24–30
Exceptional familial cases have been reported.31,32 In one family, the disease
showed an autosomal dominant pattern of inheritance and was associated
with mental retardation and dysmorphic body habitus.31 In another family,
the lesions were first noted during infancy.33

The pathogenesis is unknown and may simply represent an eosinophil-rich
inflammatory reaction to a variety of insults. The only consistent associa
tion appears to be a peripheral eosinophilia, manifested either as an elevated
total eosinophil count or as an increased percentage of eosinophils. Clinical
Fig. 15.41
Eosinophilic cellulitis: there is a large erythematous swollen plaque. The limbs are activity appears to correlate with increased eosinophil cation protein and
commonly affected. From the collection of the late N.P. Smith, MD, the Institute of IL-5 levels in the peripheral blood in addition to blood and bone marrow
Dermatology, London, UK. eosinophilia.31,32
An elevated ESR is occasionally present. It is possible that some patients
represent the benign end of the spectrum of the hypereosinophilic syndrome
discussed in the previous section.
Histologically, early lesions of eosinophilic cellulitis are characterized by
a diffuse and heavy dermal infiltrate of eosinophils: this occurs either in the
superficial dermis, as a bandlike infiltrate, or in the deep dermis with exten
sion into the underlying subcutaneous tissue, fascia, and muscle (Figs 15.44,
15.45).2,34 In addition, lymphocytes and plasma cells may be present. There
is sometimes edema of the papillary dermis to such an extent that subepi
dermal bullae develop (Fig. 15.46).35 The epidermis can be spongiotic and
occasionally intraepidermal vesicles are present.35 Over a period of 1–3 weeks
the eosinophils degranulate and degenerate, and eosinophilic material and
nuclear debris are deposited on collagen fibers to produce ‘flame figures’ (Fig.
15.47).35, 36 Sometimes these are surrounded by histiocytes and multinucleated
giant cells (Fig. 15.48). There is no evidence of primary collagen degenera
tion. It is likely that flame figures represent a non-specific eosinophil reaction
pattern to a variety of different provoking stimuli.36 Later, the lesion becomes
more granulomatous and giant cells are occasionally prominent.37 Vasculitis is
not usually a feature, although extravasation of red blood cells is sometimes
evident.35
Fig. 15.42 Indirect immunofluorescence studies have shown that flame figures con
Eosinophilic cellulitis: in this patient, there is striking symmetry. From the collection tain extracellular eosinophil granule major basic protein.36,38 Ultrastructural
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 15.43 Fig. 15.44

Eosinophilic cellulitis: bullous lesion with a hint of greenish discoloration in the adjacent Eosinophilic cellulitis: there is a light, deep dermal chronic inflammatory cell
skin. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK. infiltrate. A flame figure is present.
Eosinophilic pustular folliculitis 651
Fig. 15.45 Fig. 15.48

Eosinophilic cellulitis: the infiltrate is composed of lymphocytes and histiocytes Eosinophilic cellulitis: in this example, a flame figure is surrounded by an intense
with conspicuous eosinophils and extends into the subcutaneous fat. granulomatous infiltrate.
investigation confirms that the eosinophil granules invest the associated

collagen fibers.39 Direct immunofluorescence has demonstrated immu
noglobulins and/or complement in blood vessel walls in a minority of
cases.2,7,17,36
The histological features of eosinophilic infiltration with 'flame figures',
although characteristic of Wells’ syndrome, are not pathognomonic.40
Similar features may be seen in arthropod bite reactions, spider bites,
onchocerciasis, drug hypersensitivity reactions, diffuse erythema, tinea
infection, atopic eczema, allergic contact dermatitis, urticarial vasculi
tis, eosinophilic pustular folliculitis, bullous pemphigoid, herpes gestatio
nis, the hypereosinophilic syndrome, and cutaneous mastocytoma.2,36,41–47
Prominent flame figures are also seen in eosinophilic ulcer of the oral
mucosa.48–50 It should be emphasized that in regions where parasitic infec
tions are endemic, lesions with the histological appearance of eosinophilic
cellulitis have a high likelihood of representing parasitic infection such
as giardiasis, toxocariasis, and onchocerciasis.51–53 In eosinophilic fasciitis,
Fig. 15.46 diffuse fibrosis of the deep dermis with extension into the fibrous septa of
Eosinophilic cellulitis: subepidermal vesiculation as seen here is not uncommon. the subcutaneous fat and involvement of the fascia allow for easy distinc
The blister cavity may contain numerous eosinophils reminiscent of bullous
tion from Wells’ syndrome.
pemphigoid.
Eosinophilic pustular folliculitis

Clinical features
Eosinophilic pustular folliculitis (Ofuji’s disease) is a rare dermatosis seen
primarily in Japanese and Chinese, although occasional reports from Europe
and the USA are encountered.1–5 It is a disease which particularly affects
the seborrheic regions and, therefore, lesions are predominantly present on
the face and back.6 The extensor surfaces of the upper limbs are also fre
quently affected. Acral involvement is exceptional.7–9 Patients present with
crops of occasionally pruritic, sterile follicular papulopustules measuring
1–2 mm in diameter, grouped to form small plaques, which characteristi
cally spread centrifugally to produce an annular or serpiginous lesion.1,6 The
disease is typically recurrent and spontaneous resolution within months to
several years is characteristic.10,11 Healing is often associated with residual
postinflammatory hyperpigmentation.1 Males are predominantly affected
(5:1) and the peak incidence is in the third and fourth decades, although
children and infants can be affected.12,13 Sometimes there is a past or present
history of acne vulgaris.
Fig. 15.47 Extensive laboratory investigations reveal leukocytosis with hypereosino
Eosinophilic cellulitis: flame figures are typically present. philia.14 Serum IgE levels may be increased.5,15
Similar cases have been reported in Caucasians in association with HIV

infection.3,4,16–23 However, based on the clinical and histological findings,
many authors regard HIV-associated eosinophilic folliculitis as a separate
entity.20,22 Pruritus, which is always present in patients with HIV-associated
eosinophilic folliculitis, is seen only in occasional patients with Ofuji’s
disease.24
A small number of childhood cases of eosinophilic pustular folliculitis,
including several in neonates, have also been reported.15,25–31 Some authors
prefer to categorize these as a separate entity, others feel that this category
does not form a distinct condition.5,12,28,32 In children, the scalp is particularly
involved. There is less of a tendency to affect the seborrheic regions and poly
cyclic patterns are not evident.25
Eosinophilic pustular folliculitis has been described in association with
non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, polycythemia rubra
vera, myelodysplastic syndrome, bone marrow transplant for aplastic ane
mia, eosinophilic cellulitis, hepatitis C viral infection, and the nevoid basal
cell carcinoma syndrome.13,33–41 A few cases induced by allopurinol, time
pidium bromide, and chemotherapy for breast carcinoma has also been
documented.42–44

The etiology and pathogenesis of eosinophil pustular folliculitis are unknown. Fig. 15.49
(A, B) Eosinophilic
The possibility of an inherited or contagious cause for the disease has been
pustular folliculitis: there
raised by the observation of the disease in siblings.45 However, there is no firm
is spongiosis associated
evidence of an infective cause. A variety of immunological abnormalities have with an eosinophil-rich
A
been described including: abscess.
• raised IgE levels,
• low immunoglobulin levels,
• defects of neutrophil motility.6,28
A pemphigus-like antibody and an antibasal keratinocyte antibody have
also been recorded in patients with this disease.46,47
The seborrheic distribution raises a possible role for sebaceous glands in the
pathogenesis.10 A lipid-soluble eosinophil chemotactic factor has been iden
tified from epidermal surface lipids.48 The association of eosinophil pustular
folliculitis with AIDS (if indeed this is the same disease) raises the interesting
possibility of a diminished T-helper lymphocyte-mediated pathogenesis.
An increased number of mast cells has been described around hair follicles
and sebaceous glands, suggesting a role for these cells in the development of
the disease.49
In early lesions, spongiosis of the outer root sheath of the infundibulum
with an accompanying eosinophil and mononuclear cell infiltrate is char
acteristic.6 As the disease progresses, vesiculation and pustulation are seen
deep to the stratum corneum, often extending into the sebaceous gland (Fig.
15.49). The epithelium is infiltrated by large numbers of eosinophils with B
an admixture of neutrophils and mononuclear cells. In the superficial dermis
there is a perivascular mononuclear and eosinophil infiltrate. Follicular muci
nosis has been described.50–54
females is variable, manifestations being dependent on the effects of mosa
Differential diagnosis icism resulting from X-chromosome lyonization.5 It has occasionally been
As mentioned above, there is considerable overlap between eosinophilic folli described in identical twins.6 The disease is rarely transmitted from father
culitis associated with HIV infection and Ofuji’s disease. The latter condition to daughter.7
tends to form arcuate plaques. Histologically, well-developed large eosino Most males with incontinentia pigmenti die in utero and only very rare
philic pustules in the pilar canals are characteristic of Ofuji’s disease but are patients survive. As with females, it is associated with the same phenotypic
less common in HIV-associated eosinophilic folliculitis.55 mosaicism.8 In the majority of cases of male involvement it develops in asso
Identical histology may be seen in epidermal fungal infections and special ciation with Klinefelter’s syndrome.9,10,32 Half chromatid mutation, or more
stains are essential to exclude this possibility.49,56–59 recently an unstable pre-mutation, has been offered as explanations for
affected males with a normal karyotype.11,12
Typically, the condition has four stages: 13,14
Incontinentia pigmenti • Stage 1, comprising erythema and linear vesiculation on the trunk and
extremities, is apparent at birth or during the first 2 weeks of life
Clinical features (Fig. 15.50).15 Characteristically, the face is unaffected. Patients usually
Incontinentia pigmenti (Bloch-Sulzberger syndrome) is a rare systemic illness show associated leukocytosis and eosinophilia. On average, the blistering
with a striking female bias (in excess of 37:1), as affected males usually die stage completely resolves within 4 months.5
in utero.1–3 It has an X-linked dominant mode of inheritance.4 Cutaneous • Stage 2, which is uncommon and usually transitory, consists of
manifestations usually present at birth or during the first few weeks of life.1 hyperkeratotic verrucous papules and plaques most frequently found on
There may also be lesions affecting the hair, teeth, nails, eyes, skeleton and the extremities (Fig. 15.51). The verrucous lesions develop at sites of
the central nervous system in up to 80% of patients.1,4 The phenotype in previous blistering.15 They may resemble linear epidermal nevi.16 This
Incontinentia pigmenti 653
Fig. 15.52
Fig. 15.50 Incontinentia pigmenti: the whorl-like distribution of the pigment is characteristic.
Incontinentia pigmenti: the inflammatory stage is characterized by erythema, linear From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
clusters of intact vesicles, crusts, and scaling. By courtesy of J.C. Pascual, MD, London, UK.
Alicante, Spain.
Painful subungual digital verrucous nodules are occasional late features of

stage (when present) appears during the second to sixth weeks of life and incontinentia pigmenti.17,20 They are usually multiple, affect the hands more
usually resolves completely by 6 months.5 often than the feet and, in addition to nail destruction, they can also be asso
• Stage 3, which is pathognomonic of incontinentia pigmenti, presents ciated with scalloped resorption of the underlying phalanx.21 Spontaneous
as bizarre reticulated pigmentation, generally between the twelfth and regression is sometimes seen. Clinically, these nodules may be mistaken for a
twenty-sixth weeks after birth. It sometimes occurs de novo. The brown wart, subungual fibroma, keratoacanthoma or squamous cell carcinoma.22
to slate-gray pigmentation appears as splashes, streaks, and whorls Dermatoglyphic patterns presenting in patients and also in nonaffected
(sometimes referred to as ‘Chinese lettering’) on the torso and extremities family members have been described.23
(Fig. 15.52). The nipples are typically hyperpigmented and involvement Some patients develop episodes of late reactivation of the disease in hyperpig
of the groin and axillae is characteristic.5 The pigmentation appears to mented streaks and this appears to be related to a preceding infection.24 It sug
develop independently of the bullous lesions or verrucous plaques and gests that the mutated cells persist in the epidermis for a long period of time.
follows Blaschko's lines.15,16 Resolution of lesions is associated with There can be widespread systemic involvement (Table 15.4). Dental
atrophy and the pigmentation is usually imperceptible by adulthood. abnormalities include hypodontia, delayed eruption, impaction, and crown
• Stage 4, usually present in adulthood, shows only residual changes malformations such as conical forms and accessory cusps.5,16,25–27
that may be visible as occasional atrophic, hypopigmented, hairless, The most characteristic ocular changes are strabismus, microphthalmos,
reticulated patches and streaks best seen on the lower legs.1,5,17 cataract, and optic atrophy.28 Retinal detachment with a fibrovascular
Additional cutaneous lesions include mild nail dystrophy (40%), scalp alo retrolental membrane is the commonest intraocular abnormality.29–32
pecia at the vertex, and the woolly hair nevus.4,5 A whorled scarring alopecia Central nervous system involvement may result in encephalopathy,
following the lines of Blaschko has been documented.2 At this point, the skin seizures, mental retardation, microcephaly, cerebellar ataxia, and motor
lesions cease to be problematic and other issues such as ocular involvement effects including spastic quadriplegia, hemiplegia, slow motor develop
are the focus of concern.18,19 ment, and psychomotor retardation.1,33–35 There is some evidence to suggest
that incontinentia pigmenti can be associated with chromosomal instabil
ity and a slightly increased susceptibility to cancer; cutaneous squamous cell
carcinoma has been described in a 16-year-old.36,37 A unique case associated
with t wenty-nail dystrophy has been reported.38
Table 15.4
General manifestations of incontinentia pigmenti
System Abnormality
Scalp Scarring
Alopecia of variable severity
Nails Occasional dystrophy
Teeth Partial/complete absence
Conical (pegged)
Eyes Strabismus
Blindness
Cataracts
Atrophy of optic nerve
Central nervous system Spastic paralysis
Fig. 15.51 Mental retardation
Incontinentia pigmenti: verrucous lesions, seen in the second stage, predominantly Convulsions
affect the extremities. By courtesy of the Institute of Dermatology, London, UK.

Considerable new data have been published which sheds much light on the
pathogenesis of this disease:
• Linkage analysis has demonstrated two incontinentia pigmenti loci that
reside within the long arm of the X chromosome at Xq11 (IP1) and
Xq28 (IP2).5,39,40
• Mutations in the gene for the inhibitor of kappa light polypeptide gene
enhancer in B-cells, kinase gamma (IKBKG) also called nuclear factor
(NF)-κ,B gene modulator (NEMO), which plays a role in inhibiting
tumor necrosis factor (TNF)-induced apoptosis, has been shown to be
responsible for development of the disease.41–44
• A mouse model has been created by disruption of NEMO, which leads
to lethality in males and heterozygous females with skin and eye lesions
similar to incontinentia pigmenti.45,46 Biopsy of skin lesions of diseased
animals shows increased keratinocyte apoptosis, inflammation, and
pigment incontinence.45
• A relationship between incontinentia pigmenti and the osteopetrosis,
lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency
(OL-EDA-ID) syndrome has recently been suggested in a patient who Fig. 15.54
presented with the latter syndrome born to a mother with features of Incontinentia pigmenti: there is dyskeratosis and an upper dermal eosinophil-rich
incontinentia pigmenti.47 Both diseases are associated with mutations infiltrate.
in NEMO / IKBKG.48,49 Male patients with the disease often have
less deleterious mutations and present with ectodermal dysplasia and
immunodeficiency.10
• Eotaxin (an NF-kappaB-activated chemokine) is strongly expressed in the
suprabasal epidermis of involved skin in patients with the disease.50 This
expression is concomitant with the upper epidermal accumulation of
eosinophils, suggesting a pathogenetic role for this chemokine.
Histological examination of lesions in the vesicular stage (stage 1) shows
eosinophilic spongiosis (Fig. 15.53). Occasionally, aggregates of dyskeratotic
cells are evident (Fig. 15.54).4 A chronic inflammatory cell infiltrate with
conspicuous eosinophilia may be present within the dermis.
The verrucous lesions (stage 2) are characterized by hyperkeratosis, acan
thosis, papillomatosis, and focal dyskeratosis (Fig. 15.55).21 The dyskeratotic
cells are typically arranged in a whorled configuration.
Stage 3 lesions manifest marked pigmentary incontinence with numerous
melanophages in the dermis associated with epidermal basal cell degeneration.
End-stage lesions display epidermal atrophy and there may be loss of the
adnexae.45 Melanocytes appear to be present in reduced or normal num
bers and ultrastructurally have shown no significant lesion except for one
report in which small nondendritic forms with degenerate melanosomes were
described.6,51 Some authors have recommended biopsy of these late lesions in
adulthood as helpful for diagnosis.52
A
Fig. 15.53 Fig. 15.55

Incontinentia pigmenti: vesicular stage showing a subcorneal eosinophil pustule (A, B) Incontinentia pigmenti: verrucous stage showing massive hyperkeratosis,
and intraepidermal eosinophils. papillomatosis, acanthosis, and numerous dyskeratotic cells.
Molecular testing is available for confirmation of difficult cases and such

techniques can also be applied to prenatal testing.3,53–55
The subungual verrucous nodules show hyperkeratosis, hypergranulosis,
pseudoepitheliomatous hyperplasia, and striking dyskeratosis throughout the
epidermis.21,22
Clinically, incontinentia pigmenti may be confused with hypomelanosis of Ito
(incontinentia pigmenti achromians), and the central nervous system involve
ment in both diseases is similar.56 The latter condition, however, is character
ized by cutaneous pigmentary changes in the absence of either vesicular or
verrucous lesions.
Many conditions are associated with eosinophilic spongiosis, but with ade
quate clinical information none should pose diagnostic problems. Toxic erythema
of the neonate can be distinguished histologically from incontinentia pigmenti by
the absence of spongiosis in the former condition.
Fig. 15.56
Toxic erythema of the neonate Hidradenitis suppurativa:
early lesion presenting as
Clinical features an erythematous nodule
discharging clear fluid.
Toxic erythema of the neonate (erythema toxicum, erythema toxicum neonato The axilla is a commonly
rum) is a very common, self-limiting disorder that presents as an asymptomatic affected site. By courtesy
erythematous macular rash usually in the first few days of life. Very rarely, the of R.A. Marsden, MD,
eruption occurs a week or more after birth.1 It affects up to 50% of neonates. St George’s Hospital,
In survey studies from Japan, Australia, China, and India, toxic erythema was London, UK.
found in 40.8%, 34.8%, 33.7% and 20.6% of infants, respectively.2–5
It may be associated with papules, and occasionally pustule formation is
evident. It most often involves the forehead, face, chest, trunk, and extremi
ties.6 Lesions usually resolve in a few days.

The etiology of this condition is obscure, but some have suggested an immune
reaction to postnatal cutaneous comensural microbial colonization, perhaps
partially mediated by mast cells.7,8
Early erythematous lesions show a somewhat nondescript perivascular
inflammatory cell infiltrate with conspicuous eosinophils, which can be seen
penetrating the epidermis in close proximity to hair follicles. The pustules
are characteristically intrafollicular, sometimes subcorneal or intraepidermal,
and contain large numbers of eosinophils and occasional neutrophils.9
Toxic erythema of the neonate must be distinguished from incontinentia pig
menti. The latter, however, is characterized by eosinophilic spongiosis, a fea
ture not seen in toxic erythema. In miliaria rubra the vesicles are related to
sweat ducts rather than hair follicles and typically contain mononuclear cells Fig. 15.57
rather than eosinophils. Hidradenitis suppurativa:
in this very severe
example, there is marked
Hidradenitis suppurativa scarring and numerous
sinuses are present.
By courtesy of R.A.
Clinical features Marsden, MD, St George’s
Hidradenitis suppurativa (acne inversa, apocrine acne) is a common dis Hospital, London, UK.
ease.1–3 Studies from Denmark have found the prevalence to be around 4%,
while that in France is approximately 1%.4–6
It is a chronic relapsing suppurative inflammation of regions where apo Axillary lesions are more common in women and genitoinguinal lesions
crine glands occur, i.e., the axilla, inguinal folds, perineum, genitalia, and are more common in men. Changes may be confined to one region or occur
periareolar region (Fig. 15.56).7,8 It occurs postpubertally in both sexes, in both, but the axillary region is involved in over 70% of cases.15 Some
but is more common in women.5 Karl Marx was famously afflicted.9–11 The reports have attached etiological importance to axillary shaving and the
disease is seen most frequently in young adults, although its first presentation use of deodorants, but this is not generally accepted.15,16 In women, obesity
may be in older individuals and also before puberty.12,13 Initially, there is a appears to be a predisposing factor and smoking is closely associated, but it
firm painful nodule in the groin or axilla. The nodule can involute slowly or is not clear whether this is a cause or effect.6,17–19 In one study, nearly 90% of
else discharge pus through the skin; the discharge of pus is not copious, but German patients were smokers (expected prevalence rate 27%).12 Whether
is chronic and often malodorous. In the late stages a complex interconnecting cessation of smoking improves the course of the disease is unknown.20 Patients
system of sinuses extends deeply into the dermis and subcutaneous fat with with the hidradenitis suppurativa appear to be at increased risk of developing
extensive dense fibrosis (Fig. 15.57).14 nonmelanoma skin cancer.21
The lesions are clearly maintained by bacterial infection as various (Fig. 15.58).51 Other authors, however, believe that eccrine hidradenitis is
rganisms are often grown. Symptomatic improvement can be achieved with
o more commonly found than apocrine involvement and yet others think that
long-term antibiotics. Perineal lesions are often severe and complicated by the primary event is follicular obstruction.34,53 Some data suggest overacti
abscesses, fistulae, and draining sinus tracts.15 vation of the innate immune system, but a deeper underlying cause remains
Lesions are also rarely seen on the malar region of the face and even on the elusive.57,58
eyelids (glands of Moll), sites with modified apocrine glands. The provocation for the initial ‘apocrinitis’ is believed by some to be
Hidradenitis suppurativa can be present in association with conditions keratin occlusion of the corresponding hair follicle. Certainly, keratin plug
which are said to be pathologically similar, namely acne conglobata and dis ging of follicles and sinuses and inflammation in and around the hair fol
secting folliculitis of the scalp. These three conditions have been referred to licle are regularly seen.52 In one study, follicular occlusion was present in all
collectively as the ‘follicular occlusion triad’.22 Any one condition, however, of 118 specimens examined in patients with disease duration that ranged
may occur separately. Acne conglobata, an extremely severe nodulocystic from as little as 1 month to many years.54 The anatomic distribution of the
variant of acne, occurs extensively on the trunk, buttocks, and limbs with lesions also supports the concept of an underlying apocrine gland defect.
predilection for males.23 The disease has been described in association with The condition has some similarity to Fox-Fordyce disease, which is more
HIV and following pregnancy.24,25 Dissecting folliculitis (folliculitis capitis convincingly associated with an inflammatory process of the apocrine duct.
abscedens et suffodiens) is centered on the vertex of the scalp and is char Fox-Fordyce disease has the same sex predilection, age incidence, and ana
acterized by boggy tender lesions that tend to become confluent with for tomic distribution, and it too is alleviated by pregnancy. Interestingly, some
mation of draining sinuses and suppuration.26–29 The disease presents more cases of Fox-Fordyce disease have been reported to progress to hidradenitis
commonly in black males and it is very rarely familial.30 Radical surgery is suppurativa.
often the only satisfactory means of terminating the process. All the dis The other members of the follicular occlusion triad – acne conglobata and
eases in the follicular occlusion triad can occasionally be complicated by dissecting folliculitis – are both clearly associated with keratin plugging.
progression to cellulitis and septicemia. Squamous carcinoma (including the There is no doubt that the main symptoms and chronic disability are
verrucous variant) is a rare and late additional complication.31–38 As with related to the sinuses and fibrosis; these are largely due to the chronic second
Marjolin’s ulcer–cancer, the carcinomas are capable of aggressive invasion ary infection, since injection of sterile apocrine sweat into tissues does not
and metastasis (50%) and are generally associated with a poor prognosis.15 induce an inflammatory response.
Such tumors arise most frequently on the buttocks and are more often seen Organisms that may be found include Staphylococcus aureus, Streptococcus
in males.34 Hidradenitis has been shown to be rarely associated with sys viridans, Escherichia coli, Proteus mirabilis, Klebsiella spp, Pseudomonas
temic granulomatous lesions, in particular Crohn’s disease.17,39–41 An associa aeruginosa, Streptococcus milleri and anaerobic organisms. Coagulase-
tion with spondyloarthropathy, Dowling-Degos disease, and lithium therapy negative S. aureus is the most common bacterium isolated from the depth
has also been documented.42–44 of the lesions.59 Anaerobic organisms are responsible for the offensive smell,
Treatment of this disease is difficult due to its chronic relapsing nature. which can be a major problem for the patient. Generally, no immune defi
Surgery is often used to remove affected areas but the cure rate in some ciency is detectable, but there have been occasional reports of a functional
studies is very low.45 Nevertheless, occasional patients are satisfied with neutrophil deficiency.
the relief of symptoms, albeit temporary, afforded by surgery.45 Other In considering the pathogenesis of this condition it must also be noted
studies have shown a low recurrence rate following wide excision.46,47 that some cases clearly develop as an autosomal dominantly inherited ten
Early surgical treatment appears to increase the chance of success.48 dency.60,61 Others have no suggestion of familial incidence.
Recently, new-generation immunosuppressive agents have shown some The disease has been simulated in 3 of 12 normal volunteers by occlu
efficacy.49 Hormonal regulation has also been employed with more limited sion of axillary skin with atropine tape following depilation.62 The latter
success.50 in itself could be expected to produce some pathology, which is clearly
not seen in the normal individual. The absence of lesions in 75% of these
Pathogenesis and histological features volunteers shows at least that there is some variation in susceptibility to
The pathogenesis of hidradenitis suppurativa remains poorly understood.51–56 developing the disease. This experimental induction of the disease has not
It has generally been thought that the earliest lesion is an acute inflamma been repeated.
tory process involving the apocrine duct and gland, which extends into the In a study of 42 women with hidradenitis suppurativa, the authors
surrounding connective tissue with subsequent abscess and sinus formation noted premenstrual exacerbation of symptoms in two-thirds of patients
A B
Fig. 15.58
(A, B) Hidradenitis suppurativa: early lesion showing acute inflammation involving the apocrine gland.
and over one-third of patients reported menstrual irregularities.63 In this

same study, testosterone and free androgen index were higher compared
with control patients.63 In contrast, another study was not able to correlate
hyperandrogenism and development of hidradenitis in women.8,64 Pregnancy
may relieve the symptoms of the disease.
In summary, the precise pathogenesis of hidradenitis suppurativa is not
well understood. It seems likely, however, that while many patients have a
tendency to follicular occlusion with resultant acne-like lesions, some indi
viduals show an additional, occasionally inherited, tendency for follicular
obstruction to cause, or be associated with, inflammation of the apocrine
duct. With the additional occlusive effects of obesity and secondary infec
tion, often by mixed organisms, there is a resultant florid destructive fol
liculitis centered on, or also involving, the apocrine glands. The secondary
bacterial infection perpetuates the chronic inflammatory and scarring nature
of the process. A defect in the immune system would be expected to exac
erbate this vicious circle, but no consistent abnormality has yet been identi
fied.65,66 The changes with pregnancy and menstrual cycle can be attributed
to the hormonal effects on the apocrine gland and do not appear to be of
primary importance.
Biopsies of established hidradenitis suppurativa show sinus tracts with Fig. 15.59
Hidradenitis suppurativa: the sinuses are lined by stratified squamous epithelium
marked suppuration and frank abscess formation. The sinus tracts are lined
and surrounded by fibrosis and inflammation.
by a mixture of granulation tissue and squamous epithelium (Fig. 15.59).
The latter extends from the associated follicular epithelium. These inflam
matory sinus tracts usually contain desquamated keratin and sometimes hair experience, this is an uncommon finding in routine surgical specimens.
shafts, and are surrounded by dense fibrosis.54 The suppuration may extend Others have also found primary inflammation of apocrine glands in only a
into adjacent connective tissue where there can also be a chronic inflam minority of specimens.53,67
matory infiltrate frequently including histiocytes and giant cells that are
sometimes related to keratin fragments. At this stage apocrine glands are Differential diagnosis
conspicuously absent in the scarred and inflamed area, although adjacent The main differential diagnoses are primary infection, a response to a ruptured
apocrine glands often appear quite normal. Although some authors have epidermal inclusion cyst, or wounds. Clinical correlation and special stains
emphasized the presence of acute inflammation of apocrine glands, in our for microorganisms are necessary to establish the correct diagnosis.
Chapter
16 Vascular diseases See

for references and
additional material
Introduction 658 Thromboangiitis obliterans 688 Disseminated intravascular coagulation 701

Leukocytoclastic vasculitis 658 Temporal arteritis 689 Cryoglobulinemia 703
Henoch-Schönlein purpura 664 Juvenile temporal arteritis 692 Antiphospholipid antibody syndrome and
Sneddon's syndrome 705
Infantile acute hemorrhagic edema 665 Takayasu's arteritis 692
Thrombotic thrombocytopenic purpura and
Urticarial vasculitis 666 Infection-related vasculitis 694
hemolytic uremic syndrome 706
Polyarteritis nodosa and microscopic Paraneoplastic vasculitis 695
Immune thrombocytopenic purpura 707
polyangiitis 667
Vasculitis associated with palisaded
Factor V Leiden mutation 708
Wegener's granulomatosis 673 neutrophilic and granulomatous
dermatitis 696 Hypergammaglobulinemic purpura 708
Allergic granulomatosis with angiitis 677
Lymphocytic vasculitis 696 Hyperimmunoglobulinemia D
Mucocutaneous lymph node
syndrome 709
syndrome 679 Malignant atrophic papulosis 697
Superficial thrombophlebitis 709
Granuloma faciale 681 Atrophie blanche 699
Sclerosing lymphangitis 709
Erythema elevatum diutinum 684 Dermatological manifestations of cholesterol
crystal embolism and embolism from atrial Senile purpura 710
Behçet's disease 686
myxoma 700
of vascular disease may manifest as diverse histological patterns. For

Introduction example, connective tissue diseases may be associated with either a small-
vessel leukocytoclastic disease or a large vessel vasculitis. Likewise, different
Vasculitis and other forms of vascular damage are the subjects of this chapter. histological patterns may be seen in association with a given primary
Although minimal criteria for the diagnosis of vasculitis may differ among vasculitis. As an example, Wegener's granulomatosis may be linked with
experts, the presence of inflammation and some evidence of vascular damage either leukocytoclastic or granulomatous vasculitis.
in the form of vessel wall/endothelial cell necrosis or fibrinoid change fulfill The myriad schemata for the classification of the vasculitides are a reflection
most authorities' criteria for a diagnosis of vasculitis. Some, however, apply of the complexity of this controversial class of diseases. Over the last decade
the term less restrictively to vascular inflammation associated with non- or so, several new classifications have emerged that attempt to combine both
specific histological features such as extravasated red cells, endothelial histological and clinical information (Table 16.1).2 Undoubtedly, these will
swelling, or karyorrhexis but without fibrinoid change or necrosis. When continue to be refined as a more complete understanding of the pathogenesis
encountering such cases, we prefer to designate them as ‘low-grade vascular of these diseases is gained.
damage’ and include a comment that, although the findings may represent
very early vasculitis, they do not meet strict criteria for necrotizing vasculitis.
That inflammatory vascular disease is represented by a broad spectrum of Leukocytoclastic vasculitis
histological changes cannot be overemphasized.
The histological features of most forms of vasculitis are not specific for an Clinical features
entity per se. A specific diagnosis requires careful clinical, histological, and Leukocytoclastic vasculitis (allergic vasculitis, hypersensitivity vasculitis,
serological (i.e. presence of antineutrophil antibodies) correlation.1 The role leukocytoclastic angiitis) is the commonest form of vasculitis.1–6 It is not a
of the pathologist in evaluating a biopsy is to confirm or deny the presence disease entity but represents a vascular reaction pattern due to circulating
of vasculitis, and to describe the nature of the inflammatory infiltrate and immune complexes that may either be idiopathic or caused by a number
the type(s) and size(s) of the vessel(s) involved. A histological differential of underlying disorders. The antigens possibly involved are summarized
diagnosis is established to guide patient evaluation. Correct biopsy technique in Table 16.2.1–7 The most frequent associations are drugs in addition to
and timing are important to allow for adequate assessment for vasculitis. infections.8,9 In over 40% of cases, however, no underlying condition can be
Incisional biopsies to include sufficient subcutis and larger subcutaneous identified.10 Although the condition may be limited to the skin, it is important
vessels within the first 48 hours after development of the lesion yield the best to recognize that it can also be associated with systemic manifestations
results.1 involving the joints, kidneys, and gastrointestinal system in between 15%
A pathological diagnosis of vasculitis may indicate a primary or secondary and 50% of patients.5,10–12 The disease occurs equally in men and women, and
disease (i.e. in the setting of connective tissue disease). Secondary forms may present in any age group.
Leukocytoclastic vasculitis 659
Table 16.1
Types and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis*
Type of vasculitis Essential components/nonessential components

Large vessel vasculitis
Giant cell (temporal) arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial
branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than
50 and often is associated with polymyalgia rheumatic.
Takayasu arteritis Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger
than 50.
Medium-sized vessel vasculitis
Polyarteritis nodosa† (classic Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in
polyarteritis nodosa) arterioles, capillaries, or venules.
Kawasaki disease Arteritis involving large, medium-sized and small arteries, and associated with mucocutaneous lymph
node syndrome. Coronary arteries are often involved; aorta and veins may be involved. Usually occurs in
children.
Small vessel vasculitis
Cutaneous leukocytoclastic angiitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis.
Henoch–Schönlein purpura Vasculitis, with IgA-dominant immune deposits, affecting small vessels (i.e. capillaries, venules or
arterioles). Typically involves skin, gut, and glomeruli, and is associated with arthralgias
or arthritis.
Microscopic polyangiitis† Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e. capillaries, venules or
(microscopic polyarteritis)‡ arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing
glomerulonephritis is very common. Pulmonary capillaritis often occurs.
Wegener's granulomatosis‡ Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to
medium-sized vessels (e.g. capillaries, venules, arterioles and arteries). Necrotizing glomerulonephritis is
common.
Churg-Strauss syndrome‡ Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis
affecting small to medium-sized vessels, and associated with asthma and eosinophilia.
Essential cryoglobulinemic vasculitis Vasculitis, with cryoglobulin immune deposits, affecting small vessels (i.e. capillaries, venules or arterioles),
and associated with cryoglobulins in serum. Skin and glomeruli are often involved.
Reproduced with permission from Jennette, J.C., et al. 1994 Seminars in Diagnostic Pathology, 18, 3–13.
* Large vessel refers to the aorta and the largest branches directed toward major body regions (e.g. to the extremities and the head and neck); medium-sized vessel refers to the
main visceral arteries (e.g. renal, hepatic, coronary, and mesenteric arteries); small vessel refers to venules, capillaries, arterioles, and the intraparenchymal distal arterial radicals that
connect with arterioles. Some small and large vessel vasculitides may involve medium-sized arteries, but large and medium-sized vessel vasculitides do not involve vessels smaller
than arteries. Essential components are represented by normal type; italicized type represents usual, but not essential, components.
† Preferred term.
‡ Strongly associated with antineutrophil cytoplasmic autoantibodies.
Skin lesions are typically polymorphic, but palpable purpura (nonblanching In one study, drug therapy, often following an upper respiratory tract
erythematous papules) is the commonest manifestation (Fig. 16.1). Urticarial, infection, was the inciting event in 45% of patients.20 Numerous drugs
bullous or vesicular, ulceroinfarctive, nodular, pustular, livedoid, and annular have been implicated as a trigger including non-steroidal anti-inflammatory
lesions may also be encountered (Figs 16.2–16.8).13–17 The lesions measure drugs (aspirin, ibuprofen, naproxen, phenylbutazone), phenytoin, quinidine,
from 1 mm to several centimeters in diameter. Occasionally, annular erythema amiodarone, potassium iodide, allopurinol, sulfonamides, griseofulvin,
multiforme-like lesions occur (Fig. 16.9). The lower legs are affected most penicillin, erythromycin, clindamycin, oxacillin, vancomycin, ofloxacin, clarithro
often, but lesions can present at a wide variety of sites, including the buttocks, mycin, furosemide (frusemide), thiazides, cimetidine, omeprazole, gabapentin,
arms, feet, ankles, trunk, and face, particularly in more seriously affected orlistat, zidovudine, indinavir, efavirenz, lisinopril, sotalol, insulin, retinoids,
patients (Figs 16.10, 16.11). Lesions may be noted in the skin of dependent propylthiouracil, thiouracil, mefloquine, methotrexate, azathioprine,
areas of bedridden patients, such as the back and buttocks. A frequent sirolimus, granulocyte colony-stimulating factor, haloperidol, cytarabine, erlo
accompaniment is edema of the lower legs or ankles (Fig. 16.12). Patients tinib, rituximab, cinacalcet, famciclovir, rifampin, pyrazinamide, insulin
either experience a single occurrence or develop frequent recurrences over aspart, metformin, gold and disulfiram.2,21–63 Levamisole has been described
months or years. The eruption often occurs in episodes at irregular intervals, as producing a vasculitis localized to the ears in children.64, 65 Localized
each lasting 1–4 weeks. Lesions usually heal completely, although on occasions leukocytoclastic vasculitis may occur at the site of interferon alpha injection.66,
atrophic scars and hyperpigmentation may occur. Rarely, leukocytoclastic 67
vasculitis shows an erythema gyratum repens gross morphology.18 Collagen vascular disease (most often rheumatoid arthritis and lupus
Although occasional cases are asymptomatic, patients not uncommonly erythematosus) is commonly associated with leukocytoclastic vasculitis,
complain of pruritus or burning; less frequently, pain is a feature. Additional 2,68 and in one study it was found in 21% of patients.2 The presence of
features, which are sometimes present, include abdominal pain and leukocytoclastic vasculitis in a patient with dermatomyositis raises the
gastrointestinal bleeding, joint pains with associated erythema and swelling, possibility of associated malignancy.69
and evidence of renal involvement.19 In severe cases, the features resemble Infection is also commonly associated with leukocytoclastic vasculitis, with
acute glomerulonephritis and the nephrotic syndrome may even supervene. bacterial, fungal, and viral infection all being implicated.70 Associated bacterial
Rarely, patients have respiratory involvement (nodular or diffuse infiltrative infections include streptococci, Klebsiella pneumoniae, Mycobacterium
lesions on X-ray examination), and very exceptionally the central or peripheral tuberculosis, and Mycoplasma pneumoniae.71–73 Systemic cat scratch disease
nervous system is affected, causing symptoms such as headache, diplopia, and presenting as leukocytoclastic vasculitis has been documented.74 Hepatitis
dysphagia. C infection is a particularly frequent association. It should be noted that
660 Vascular diseases
Table 16.2
Possible causes of allergic vasculitis
• Infection
– bacterial: Streptococcus
– mycobacterial: Mycobacterium tuberculosis
– viral: hepatitis, influenza
– cytomegalovirus
– HIV infection
– leprosy
• Drugs
– aspirin, phenacetin, sulfonamides, penicillin, iodides, phenothiazines
• Chemicals
– insecticides, weed killers, petroleum products
• Foreign proteins
– serum sickness
– hyposensitization antigens
• Associated diseases
– autoimmune diseases: systemic lupus erythematosus, inflammatory
bowel disease Fig. 16.2
– hemolytic anemia Leukocytoclastic vasculitis: close-up view showing small erythematous lesions. By
– Hodgkin's lymphoma, carcinoma courtesy of the Institute of Dermatology, London, UK.
– rheumatoid arthritis
– mixed connective tissue disease
– dermatomyositis
– relapsing polychondritis
– Sjögren's syndrome
– Henoch-Schönlein purpura
– cryoglobulinemia
– polyarteritis nodosa
– Wegener's granulomatosis
– Churg-Strauss disease
– granuloma faciale
– erythema elevatum diutinum
– Waldenström's hypergammaglobulinemia
– sarcoidosis
Fig. 16.3
Leukocytoclastic vasculitis: in this patient an extensive purpuric eruption showing
central necrosis is evident. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
Fig. 16.1
Leukocytoclastic vasculitis: typical erythematous maculopapular lesions are present
on the medial aspect of the ankle. By courtesy of R.A. Marsden, MD, St George's
hepatitis C is also often associated with cryoglobulins (see section on

cryoglobulinemia).75–77
Inflammatory bowel disease, both ulcerative colitis and Crohn's disease,
may be coupled with leukocytoclastic vasculitis.78,79 Further rare associations Fig. 16.4
include sarcoidosis, α1-antitrypsin deficiency, cystic fibrosis, and the Wiskott- Leukocytoclastic vasculitis: here confluent purpura with ulceration is present.
Aldrich syndrome.15,80,81 By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 16.5
Leukocytoclastic
vasculitis: this patient
presented with bullous Fig. 16.7
lesions which developed Leukocytoclastic vasculitis: in this patient, there are extensive ulceroinfarctive
as a consequence lesions. By courtesy of the Institute of Dermatology, London, UK.
of thrombosis with
epidermal infarction. By
UK.
Fig. 16.8
Leukocytoclastic vasculitis: close-up view of a hemorrhagic blister. By courtesy of
include the use of a nicotine patch, drug additives, sodium benzoate, protein
Fig. 16.6 A column pheresis, interleukin-12 receptor beta-1 deficiency, prolonged
Leukocytoclastic vasculitis: Nodular lesions. By courtesy of the Institute of exercise, and as a complication of an infected hip prosthesis.90–96
Dermatology, London, UK. Laboratory investigation may reveal an elevated erythrocyte sedimentation
rate (ESR), proteinuria or hematuria. In some idiopathic cases and in those
associated with systemic disease (e.g. rheumatoid arthritis, systemic lupus
Physical exercise has also been related to the development of leukocytoclastic erythematosus (SLE), and Sjögren's syndrome), hypocomplementemia
vasculitis. Outdoor activities in hot weather such as walking, running, and is sometimes evident.5 Urinalysis may reveal proteinuria or hematuria.
golfing (Golfer's vasculitis) have especially been implicated and middle-aged Cryoglobulins have been found in up to 25% of patients.2 Perinuclear staining
to elderly individuals are more frequently affected.82–84 Leukocytoclastic antineutrophil antibodies are present in about 20% of patients.2,97
vasculitis rarely represents a paraneoplastic manifestation of an underlying The outcome of leukocytoclastic vasculitis is variable, ranging from
malignancy, especially leukemia and lymphoma.85 Hairy cell leukemia is a mild, self-limiting illness through to a serious, potentially fatal disorder
particularly often associated with leukocytoclastic vasculitis but other due particularly to renal involvement.19 About 1.9% of patients die of
forms of vasculitis may also be seen. In one study of 42 patients with hairy systemic disease.2 Most patients have a benign outcome. An acute clinical
cell leukemia and vasculitis, 21 had leukocytoclastic vasculitis and 17 had course is seen in approximately 50% of patients.2,10 A chronic course or one
polyarteritis nodosa.86 In addition, four patients had direct infiltration of characterized by relapses and remissions is seen in some patients.2 In one
vessel walls by leukemic cells (see also section on paraneoplastic vasculitis). study of patients with hypersensitivity vasculitis, 54 did not require therapy,
Although uncommon, leukocytoclastic vasculitis may also be seen in patients 26 were treated with non-steroidal anti-inflammatory medications, and 14
with a variety of solid tumors including non-small cell carcinoma of lung, and required immunosuppressive agents, most often corticosteroids.20
adenocarcinoma of breast, colon, prostate, and kidney.87, 88 Specific syndromes associated with leukocytoclastic vasculitis, such as
Leukocytoclastic vasculitis can be a manifestation of human immuno urticarial vasculitis and Henoch-Schönlein purpura, are discussed under
deficiency virus (HIV) infection.89 Unusual associations of this condition separate headings in this chapter.
Fig. 16.9 Fig. 16.10 Fig. 16.11

Leukocytoclastic vasculitis: these urticarial lesions Leukocytoclastic vasculitis: lesions may be widely Leukocytoclastic vasculitis: this patient
on the back of the arm resemble those of erythema disseminated in severely affected patients. By has serological evidence of systemic lupus
multiforme. By courtesy of R.A. Marsden, MD, St courtesy of R.A. Marsden, MD, St George's Hospital, erythematosus.
George's Hospital, London, UK. London, UK.
lysosomal enzymes, including elastases and collagenases, resulting in blood

vessel wall damage, fibrin deposition, and the release of red blood cells
(purpura) into the perivenular connective tissue. Thrombosis may ensue and,
in particularly severe examples, epidermal ischemic damage results. Lesions
are particularly seen on the lower legs because of hydrostasis and blood vessel
flow sludging.5
Evidence for an immune complex-mediated pathogenesis is convincing.1
Patients have been clinically proven to have high levels of circulating
immune complexes, and these are shown to correlate with vasculitic
lesions. Immunoglobulin and complement can be identified in vitro, by
immunofluorescence or immunoperoxidase techniques, and in biopsies from
blood vessel wall lesions less than 24 hours old (Fig. 16.13).99 Immune
complexes can be identified ultrastructurally as clumps of electron-dense
material, usually within the basement membrane between endothelial
cells and pericytes of postcapillary venules. Examination of apparently
uninvolved skin from patients with leukocytoclastic vasculitis sometimes
shows immunoglobulin and complement within the walls of dermal blood
vessels. If histamine is injected into uninvolved skin 3–4 hours previously,
Fig. 16.12 all the features of leukocytoclastic vasculitis are evident at biopsy, including
Leukocytoclastic neutrophil degeneration; this suggests that the immunoreactants are a cause
vasculitis: in addition to rather than a consequence of the vasculitis.1
the typical maculopapular The findings of immunofluorescence studies vary according to the age of
eruption there is marked
the lesion. Immunoglobulins have been described in up to 81% of patients.8
swelling of the legs. By
In early lesions, C3 and IgM predominate, in fully developed lesions there is
MD, St George's Hospital, predominance of fibrinogen and IgG, and in late lesions fibrinogen and C3
London, UK. are detected.8
Some authors, noting that early lesions may contain abundant CD3+, CD4+
and CD1a+ cells, have suggested that cell-mediated immune mechanisms may
Pathogenesis and histological features also play a role in the pathogenesis of leukocytoclastic vasculitis.8 Consistent
Leukocytoclastic vasculitis is an immune complex-mediated disorder with this hypothesis is the demonstration of Langerhans cells in the late phase
similar to the classic Arthus reaction.98 Immune complexes are deposited in of vasculitis.100 Expression of 72 kD heat shock protein and the presence of
the walls of small blood vessels.5 This is associated with activation of the gamma/delta T cells in patients with vasculitis associated with infection have
complement cascade and the production of C5a (a neutrophil polymorph led one group of authors to postulate that the cell-mediated immune response
chemotactant). The resultant polymorph influx is associated with release of plays an important role in that subset.101
Fig. 16.13 Fig. 16.15

Leukocytoclastic vasculitis: IgM is present in the blood vessel walls (direct Leukocytoclastic vasculitis: high-power view showing complete vessel wall destruction.
immunofluorescence). By courtesy of B. Bhogal, FIMLS, Institute of Dermatology,
London, UK.
In leukocytoclastic vasculitis, it is the postcapillary venule and the capillary

loops (and not the arteriole) which are primarily affected, usually within the
superficial dermis (Figs. 16.14, 16.15). In severe cases, particularly those
associated with malignancy or connective tissue disease, the inflammatory
changes extend into the vasculature of the deep reticular dermis or even the
subcutaneous fat.9 The histological features are similar irrespective of the
underlying etiology.
The histological features of leukocytoclastic vasculitis are those of fibrinoid
necrosis associated with endothelial cell swelling and infiltration of the blood
vessel walls by neutrophils and conspicuous nuclear dust (Fig. 16.16).2,102,103
Variable numbers of mononuclear cells and eosinophils may be seen. In early
lesions, nuclear dust is associated with a perivascular neutrophilic infiltrate
but multiple tissue sections may be needed to identify fibrinoid vascular
changes. The former features, even without unequivocal fibrinoid change,
are suggestive of an evolving leukocytoclastic vasculitis.
Intravascular thrombi and ischemic necrosis of the overlying epidermis
(often with bullae formation) may sometimes be seen (Figs 16.17–16.19).
Occasionally, one may encounter intradermal or subepidermal pustules. Fig. 16.16
In patients with associated hypocomplementemia, neutrophils are predom Leukocytoclastic vasculitis: high-power view showing fibrinoid necrosis and a mixed
inant with far fewer lymphocytes; patients who are normocomplementemic inflammatory cell infiltrate composed of neutrophils, eosinophils, and lymphocytes.
There is marked leukocytoclasis (karyorrhexis, nuclear dust).
Fig. 16.14 Fig. 16.17

Leukocytoclastic vasculitis: the blood vessels show florid fibrinoid necrosis and Leukocytoclastic vasculitis: vascular thrombosis as seen in this field is not uncommon.
intense inflammation.
Fig. 16.18 Fig. 16.20

Leukocytoclastic vasculitis: in this example, there is incipient subepidermal Leukocytoclastic vasculitis: note the marked red cell extravasation.
vesiculation.
vasculitis. An inadequate biopsy that does not include deep dermis and
subcutaneous tissue containing large vessels can produce misleading results.
The presence of leukocytoclastic vasculitis in a superficial biopsy does
not exclude an associated large-vessel vasculitis; therefore the report of a
superficial biopsy from a patient suspected of having large-vessel vasculitis
should comment on the lack of larger vessels for evaluation.
Sweet's syndrome may resemble leukocytoclastic vasculitis; however, the
presence of a diffuse (rather than predominantly perivascular) neutrophilic infiltrate
without fibrinoid vascular change or necrosis favors the former condition.
Henoch-Schönlein purpura
Clinical features
Henoch-Schönlein purpura is a syndrome characterized by abdominal
pain, joint symptoms, and palpable purpura secondary to leukocytoclastic
vasculitis, and caused by circulating IgA immune complexes. The disease
typically involves children (males more often than females), although adults
may also be affected.1–4 Occurrence during pregnancy has only rarely been
Fig. 16.19 documented.5 In a large study of children with Henoch-Schönlein purpura,
Leukocytoclastic 92% of patients were less than 10 years of age.6
vasculitis: vascular It often complicates an upper respiratory tract infection and is characterized
thrombosis is by a seasonal incidence with a peak in winter.1 Clustering of cases has
accompanied by
been described, leading one group of authors to postulate that person-to-
epidermal infarction.
Note the cytoplasmic
person spread of an infectious agent plays a role in the pathogenesis of
eosinophilia and loss of this syndrome.7 Although it may follow a streptococcal throat infection, it
nuclei. sometimes develops after a wide variety of other infective conditions including
amebiasis, chickenpox, hepatitis, HIV, yersiniosis, and infection by Toxocara
canis, Helicobacter pylori, Pseudomonas aeruginosa, Staphylococcus aureus,
may show lymphocyte predominance. In the surrounding connective tissue, red Escherichia coli, and erythrovirus (formerly parvovirus) B19.8–13 Additional
cell extravasation, edema, and an inflammatory neutrophil infiltrate associated causes include adverse reactions to drugs such as ampicillin, penicillin,
with karyorrhexis (leukocytoclasis) are typically present (Fig. 16.20). erythromycin, and clarithromycin.14,15 An association with cocaine inhalation
The severity of the histopathological changes in the cutaneous lesions of has also been described.16 In one study, drug therapy may have been a
leukocytoclastic vasculitis does not predict extracutaneous involvement.104 precipitating cause in 26% of patients.17
As noted above, classic Henoch-Schönlein purpura is characterized by
Differential diagnosis a triad of purpura, abdominal pain, and arthralgia. The cutaneous clinical
The diagnosis is relatively straightforward. It is critical to understand that findings are those of leukocytoclastic vasculitis. Cutaneous lesions are
leukocytoclastic vasculitis is not a disease sui generis. Rather, it represents most frequently the presenting symptom and comprise palpable purpura
a reaction pattern due to circulating immune complexes that may be caused predominantly affecting the lower limbs, thighs, and buttocks (Fig. 16.21).1,18–20
by myriad underlying disorders. Furthermore, leukocytoclastic vasculitis is Targetoid lesions are often present.21 Hemorrhagic bullae are rare.22–24
frequently encountered in association with other forms of vasculitis. For Subcutaneous nodules have also been documented.25 A prodrome of itchy
example, it is much more commonly encountered in patients with Wegener's urticaria is sometimes described.2 Children often have edema, particularly of
granulomatosis than granulomatous vasculitis. Therefore, a biopsy showing the feet and lower legs, although it may be more widespread.
leukocytoclastic vasculitis does not exclude diseases that may be associated In one large study, arthritis was seen in 82% of patients and was the
with other forms of vasculitis. Sometimes it coexists with a large-vessel presenting feature in 24%.6 Joint involvement consists of migratory arthralgia
Infantile acute hemorrhagic edema 665
Low serum C3, leukopenia, and thrombocytopenia are rare findings.33

Henoch-Schönlein purpura in children is generally associated with a good
prognosis, with less than 2% suffering long-term morbidity.34,35 However,
patients do occasionally die from renal failure, gastrointestinal infarction or
respiratory involvement. In contrast to pediatric patients, adults are thought
to have a worse prognosis. However, one study found that, although older
patients had more severe symptoms including frequent renal involvement,
prognosis was equally good in young and older patients.36 In another study,
complete recovery was seen in 67% of adults after a median follow-up period
of 36 months.10 In a further series, a third of patients suffered at least one
recurrence of symptoms, usually within a few months of initial presentation.6
Recurrences were also found to be more frequent in patients > 8 years of age
and in those with nephritis.18
Solid tumors including breast cancer and hematological malignancy have
been associated with Henoch-Schönlein purpura.37–41 One study found that
nearly a third of adults with Henoch-Schönlein purpura had an associated
tumor.37 For this reason, the authors concluded that physicians should suspect
A an underlying malignancy in older patients (especially males of 40 years or
more) with Henoch-Schönlein purpura.38
Pulmonary hemorrhage is a rare complication that may prove fatal.42,43

An incomplete picture of the pathogenesis of Henoch-Schönlein purpura
has emerged. As noted above, it seems a wide variety of infective agents
may trigger this disease. Henoch-Schönlein purpura is associated with IgA
deposition in blood vessel walls, both in the dermis and in the renal glomerulus
(mesangium). IgA1 is the major IgA subclass found in the cutaneous blood
vessels.44 Fibrinogen and C3 are also usually present. Raised levels of serum
IgA and IgE are present in some, but not all, patients.6 IgA antineutrophil
cytoplasmic antibodies (ANCA) and IgA anticardiolipin antibodies have
also been documented.45,46 There is evidence that patients have an increased
number of IgA-type B cells.47 More recently, IgA-binding regions from
streptococcal M proteins have been identified in a significant subset of skin
and renal biopsies from patients with Henoch-Schönlein purpura.48
The finding of IgA deposition by immunofluorescence is not equivalent
B to a diagnosis of Henoch-Schönlein purpura. A vasculitis with the presence
of IgA deposition in patients lacking other typical features of Henoch-
Fig. 16.21 Schönlein purpura has been described in association with cancer, Wegener's
(A, B) Henoch-Schönlein purpura: palpable purpura in the classical distribution on
granulomatosis, and inflammatory bowel disease.49
the buttocks and thighs. From the collection of the late N.P. Smith, MD, the Institute
The observation of an association between DRB1*01 and DRB1*11
and Henoch-Schönlein purpura suggests a genetic susceptibility in some
patients.50,51 Other authors have suggested that DQA1*0301 and C4 deletion
may also represent risk factors for IgA nephropathy as well as Henoch-
predominantly affecting the large joints of the lower limbs. In one study, 37% Schönlein nephritis.52
also had involvement of the upper extremities, with the hand and wrist being Biopsies of cutaneous lesions show features of typical leukocytoclastic
more often affected than the elbow.6 vasculitis (Fig. 16.22).
Intestinal involvement with resultant red cell extravasation or hemorrhage
leads to abdominal pain and gastrointestinal bleeding. Abdominal pain was Differential diagnosis
noted in 63% of patients in one study of 100 consecutive children presenting The histological differential diagnosis includes other forms of leukocytoclastic
with the condition.6 Gastrointestinal disease develops as a consequence of acute vasculitis. Since IgA deposition can be seen in the blood vessel walls of patients
vasculitis. Bleeding may be either occult or in the form of bloody or melanotic with leukocytoclastic vasculitis but without evidence of Henoch-Schönlein
stools.6 Intussusception is an occasional complication.26,27 Abdominal pain purpura, this finding is not diagnostic in isolation.53 In one study, only 24%
was the presenting complaint in 19% of patients in one study.6 Endoscopy of patients with vascular IgA deposition had Henoch-Schönlein purpura.53
may reveal hemorrhage, ulceration, and erosions.28 IgA is often noted in Careful clinical correlation is necessary to establish the diagnosis.
capillaries of the gastrointestinal tract but frank necrotizing vasculitis was
not seen in any patients in two series.28,29 Rarely, gastrointestinal involvement
with minimal skin lesions is encountered.30
Renal symptoms are variable and include microscopic hematuria, acute Infantile acute hemorrhagic edema
nephritic syndrome, nephrotic syndrome, and acute or chronic renal failure.
The pathological features seen on renal biopsy range from mild focal glomerulo Clinical features
nephritis to necrotizing or proliferative glomerulonephritis.1,6 In a consecutive Infantile hemorrhagic edema is a form of leukocytoclastic vasculitis that
series of 100 pediatric patients, a single patient required transplantation.6 is mostly seen in newborns but has also been described in the first 3 years
Patients older than 7 years are at increased risk of renal involvement.31 of life and occasionally in older children.1–11 The disease is usually limited
Orchitis is a recognized complication of Henoch-Schönlein purpura, to the skin but mucosal involvement may be an additional feature.10
affecting 14% of male patients.6,18 Transient renal involvement with microscopic hematuria and proteinemia,
Neurological involvement may be manifested by headaches, seizures, mental hypocomplementemia, abdominal pain, and elevated transaminases are
status changes and, less frequently, ataxia and peripheral neuropathy.32 exceptional additional findings.12,13 It frequently follows vaccination or
Fig. 16.22 Fig. 16.23

Henoch-Schönlein purpura: this small venule shows striking fibrinoid change. There Urticarial vasculitis: this very large lesion has developed a bizarre outline due to
is considerable red cell extravasation. central clearing. By courtesy of the Institute of Dermatology, London, UK.
infection including otitis, upper respiratory tract infection or conjunctivitis.1,10,11

An association with cytomegalovirus, herpes simplex virus-1 or rotavirus
infection has been documented.14–16 Since many children had received
antibiotics for infection prior to development of lesions, a subset of cases
may represent reaction to medication.1 This disease has a peak incidence in
the winter months.
Skin lesions are widely distributed, and often involve the head and neck, and
limbs. They present as purpuric lesions that often have a rosette or targetoid
configuration.2,3 The cheeks and ears seem to be sites of predilection.3,11
Resolution within a few weeks is typical and recurrences are not reported.1,11,17
An elevated ESR and leukocytosis are usually present.

The pathogenesis of infantile hemorrhagic edema is unknown; however,
it is likely that the disease is immune mediated. Biopsy shows features of
leukocytoclastic vasculitis with variable fibrinoid necrosis.3
Some authors consider infantile hemorrhagic edema to be a variant of Fig. 16.24
Henoch-Schönlein purpura. Others do not agree, arguing that the absence Urticarial vasculitis: close-up view. By courtesy of the Institute of Dermatology,
of perivascular IgA on immunofluorescence staining, absence of systemic London, UK.
involvement in most patients, and the benign clinical course do not support
this view.3,18 However, a very interesting hypothesis possibly linking the two with nonblanchable purpura (Figs 16.23, 16.24). However, in contrast to
diseases has been postulated.19 Goraya and Kaur note that, since the IgA uncomplicated urticaria, cutaneous lesions of urticarial vasculitis often last
immune system in infants is immature, if acute hemorrhagic edema were related 24–72 hours.9 Patients commonly complain of pruritus, burning or pain. The
to Henoch-Schönlein purpura, the patient would be incapable of mounting frequency of cutaneous symptoms varies considerably, from daily to monthly.
an IgA-mediated immune response and this would explain the lack of IgA Joint pain, stiffness, and swelling, particularly of the hands, elbows, feet,
on immunofluorescence studies in the majority of patients.19 Clearly, further ankles, and knees, are seen; however, frank arthritis is extremely rare.10
study of this disorder is necessary to elucidate its pathogenesis and to clarify its Hypocomplementemia, which correlates with systemic involvement, is a
nosological position in the classification of leukocytoclastic vasculitis. feature in many patients.4,7,8,11,12 Proteinuria and hematuria may also be noted.
Rarely, patients develop focal or diffuse proliferative glomerulonephritis.
Crescentic glomerulonephritis, mesangial glomerulonephritis, and
Urticarial vasculitis membranous nephropathy have also been documented.8,13–16 Gastrointestinal
symptoms can include abdominal pain, nausea, vomiting and diarrhea, and
Clinical features an associated peripheral neuropathy has been reported.17
Urticarial vasculitis is an uncommon condition characterized clinically by The ESR is raised in many patients with hypocomplementemia. There
urticaria and histologically by leukocytoclastic venulitis.1–5 In addition to may also be depression of the early classic pathway components C1q, C4
urticarial skin lesions, patients may also experience angioedema, arthralgia, and C2. Patients with hypocomplementemic urticarial vasculitis have a high
gastrointestinal symptoms, and evidence of renal involvement.6,7 The term prevalence of autoantibodies to endothelial cells.18,19
encompasses a spectrum of illness, with some patients experiencing only mild Schnitzler's syndrome is a term that has been applied to patients with urticarial
symptoms while others develop serious systemic involvement.7,8 vasculitis and monoclonal IgM gammopathy.20–25 Hepatosplenomegaly,
Urticarial vasculitis is most often seen in the third to fifth decades and elevated ESR, and white blood cell count, fever and joint pain are characteristic
shows a female predominance.7 The cutaneous lesions are urticarial in features.21–23 An associated monoclonal IgA gammopathy has been reported and
appearance, consisting of edematous, raised, erythematous plaques associated an underlying lymphoproliferative disorder is present in some patients.20,26,27
Polyarteritis nodosa and microscopic polyangiitis 667
Importantly, urticarial vasculitis (especially the hypocomplementemic

variant) is often associated with, or heralds the onset of, a variety of systemic Polyarteritis nodosa and microscopic
diseases, including SLE, arthritis, interstitial lung disease, pericarditis, polyangiitis
mixed connective tissue disease, systemic sclerosis, relapsing polychondritis,
hepatitis, inflammatory bowel disease, serum sickness, polyarteritis Classic polyarteritis nodosa (Kussmaul-Maier disease) is a rare systemic
nodosa and Wegener's granulomatosis, viral infection, Sjögren's syndrome, vasculitis involving medium-sized and small arteries.1 Some view the disorder
cryoglobulinemia, polycythemia rubra vera, reaction to drugs (including not as a disease sui generis but, less restrictively, as a syndrome with many
cocaine and diltiazem), and as a response to sunlight.8,13,28–38 The condition triggering causes and disease associations. Classic polyarteritis nodosa
may be exacerbated by methotrexate.39 In one study, more than 50% of overlaps both clinically and histologically with microscopic polyangiitis
patients had uveitis, scleritis, conjunctivitis or episcleritis.8 It appears that (microscopic polyarteritis nodosa, microscopic polyarteritis). Distinction
patients with hypocomplementemia have more severe disease.28 Some authors between these entities may be difficult and criteria for their distinction are
have postulated that hypocomplementemic urticarial vasculitis represents a controversial. Nevertheless, they seem to represent distinctive syndromes that
subset of SLE. Others, however, have failed to confirm this observation.8,40 warrant separate classification to facilitate appropriate treatment.2 In order
Urticarial vasculitis has been documented in association with malignancy.8,41 to maintain a usable working classification, we – while admitting they are
Given the rarity of this association, this may well be coincidental. Nevertheless, a separate diseases – prefer to describe them in the same section to facilitate
diagnosis of urticarial vasculitis should always initiate an evaluation for possible comparisons between them.
underlying disease. Urticarial vasculitis usually has a benign outcome.8
Clinical features
Pathogenesis and histological features Classical polyarteritis nodosa
In many patients, no underlying cause is discovered. In others, antibody–
Classic polyarteritis nodosa is a multisystem disease with protean clinical
antigen complexes (a type III hypersensitivity reaction) is implicated.4,5
manifestations (Table 16.3).1,3–5 It should be noted that the 1990 criteria
The vasculitis affects the superficial vascular plexus and is characterized
from the American College of Rheumatology do not distinguish polyarteritis
by a leukocytoclastic pattern (Fig. 16.25). Extravasation of red blood cells is
nodosa from microscopic polyarteritis. However, in the more recent Chapel
evidence of vascular damage. A background of dermal edema may be seen.
Often, the histological features are subtle and are easily overlooked, with only
focal fibrinoid vascular change, few neutrophils, and sparse karyorrhexis. In Table 16.3
our experience, the vasculitis is usually low grade or subtle in nature; however, 1990 criteria for the classification of polyarteritis nodosa (traditional format)*
more impressive necrotizing vasculitis is seen in some patients. Others have
shown that endothelial necrosis is unusual.5 Criterion Definition
In summary, urticarial vasculitis may show a spectrum of histological
Weight loss ≥ 4 kg Loss of 4 kg or more of body weight
changes ranging from urticaria with very mild vascular injury to frank
since illness began not due to dieting or
necrotizing vasculitis.42 other factors
Differential diagnosis Livedo reticularis Mottled reticular pattern over the skin of
portions of the extremities or torso
Clinical correlation is necessary to distinguish urticarial vasculitis from other
forms of leukocytoclastic vasculitis. Although urticarial vasculitis is often Testicular pain or Pain or tenderness of the testicles not
tenderness due to infection, trauma or other causes
associated with subtle low-grade vascular injury, this feature should not be
relied upon in its distinction from other forms of vasculitis. In short, the Myalgias, weakness, or leg Diffuse myalgias (excluding shoulder
pathologist's role in diagnosis is to confirm the presence of vasculitis. tenderness and hip girdle) or weakness of muscles
or tenderness of leg muscles
Mononeuropathy or Development of mononeuropathy,
polyneuropathy multiple mononeuropathies or
polyneuropathy
Diastolic BP > 9 mmHg Development of hypertension with the
diastolic BP higher than 90 mmHg
Elevated BUN or creatinine Elevation of BUN > 40 mg/dL or
creatinine > 1.5 mg/dL not due to
dehydration or obstruction
Hepatitis B virus Presence of hepatitis B surface antigen
or antibody in serum
Arteriographic abnormality Arteriogram showing aneurysms or
occlusions of the vesical arteries not
due to arteriosclerosis, fibromuscular
dysplasia, or other non-inflammatory
causes
Biopsy of small or medium- Histological changes showing the
sized artery presence of granylocytes or granulocytes
and mononuclear leukocytes containing
PMN in the artery wall
*For classification purposes, a patient shall be said to have polyarteritis nodosa if at

least three of these 10 criteria are present.
The presence of any three or more criteria yields a sensitivity of 82.2% and a
specificity of 86.6%.
Fig. 16.25 BP, blood pressure; BUN, blood urea nitrogen; PMN, polymorphonuclear neutrophils.
Urticarial vasculitis: the Reproduced with permission from Lightfoot, D.W. (1991) Current Opinion in
changes are unusually Rheumatology, 3, 3–7.
florid in this example.
Hill nomenclature this discrimination is made (see Table 16.1). Polyarteritis is also a common cutaneous manifestation (Fig. 16.29). Cutaneous nodules
nodosa is associated with significant morbidity and mortality even when may also be seen. A maculopapular rash, vesiculation, and pustular lesions
treated with corticosteroids. With therapy, survival is in the range of 75–80%.1 are occasional features (Figs 16.30–16.33).
Although a wide age group may be affected, patients are most often in their Joint involvement (arthralgias and arthritis) is often present; arthritis is
fifth or sixth decade.6 There is a male predilection (4:1). Patients commonly usually asymmetrical and particularly affects the lower limbs. Non-specific
present with constitutional symptoms including weight loss, pyrexia, and muscle pain and weakness are additional features. Muscle wasting is
anorexia.1 commonly found.
Cutaneous lesions are common and are present in over 40% of patients.6–10 Both peripheral and central nervous system involvement are often
Palpable purpuric lesions and foci of ulceration, particularly involving the encountered. The former presents as sensory neuropathies (numbness
lower limbs, are most often found (Figs 16.26–16.28).10 Livedo reticularis or paresthesias), motor neuropathies (wrist or foot drop) and combined
A B
Fig. 16.26 Fig. 16.27

Polyarteritis nodosa: (A) a sharply defined ulcer with an indurated purplish border on the shin; (B) multiple Polyarteritis nodosa: this patient presented with large
ulcers, nodules, and foci of livedo reticularis. By courtesy of R.A. Marsden, MD, St George's Hospital, hemorrhagic lesions on the legs. By courtesy of the
London, UK. Institute of Dermatology, London, UK.
Fig. 16.28 Fig. 16.29

Polyarteritis nodosa: epidermal infarction has resulted in these digital ulcers. Polyarteritis nodosa: this patient shows florid livedo reticularis. By courtesy of the
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. Institute of Dermatology, London, UK.
Fig. 16.30 Fig. 16.33

Polyarteritis nodosa: erythematous macules are occasionally seen. By courtesy of Polyarteritis nodosa: in some patients, an intense neutrophil infiltrate results in
the Institute of Dermatology, London, UK. pustular lesions as seen in this patient. By courtesy of the Institute of Dermatology,
London, UK.
sensorimotor lesions (mononeuritis multiplex and polyneuropathy). Central

nervous system involvement may present as confusion, disorientation
or delirium. Eye involvement is a rare feature of polyarteritis nodosa.11
Complications include choroidal infarction, ischemic optic neuropathy,
retinal artery occlusion, episcleritis, ulcerative keratitis, uveitis, and orbital
pseudotumor.11–13
Involvement of the kidney is very common and is of major importance
because its sequelae – renal failure and hypertension – are among the
commonest causes of death in this disease. Patients on occasion have episodes
of loin pain due to renal infarction. Hypertension is often present in patients
with classical polyarteritis nodosa and in some patients it may enter the
malignant phase. Urinalysis for proteinuria, hematuria and red cell casts, and
serum creatinine estimations are therefore mandatory early investigations.
Gastrointestinal involvement is also an important cause of morbidity
and mortality.14,15 Symptoms include nausea, vomiting, and abdominal pain.
Serious complications include gastrointestinal hemorrhage, perforation, and
infarction, the last being a not uncommon cause of death. Involvement of the
hepatobiliary tract may also be seen.16,17 Involvement of the gallbladder and
Fig. 16.31
Polyarteritis nodosa: erythematous papules are present around this patient's pancreas has also been reported and can represent an incidental finding or
ankles. By courtesy of the Institute of Dermatology, London, UK. patients may present with symptoms of acute cholecystitis.18,19
Cardiac manifestations include pericarditis, arrhythmias, and myocardial
infarction due to coronary artery involvement (Fig. 16.34). Although it is
often stated that polyarteritis nodosa does not involve the lung, in exceptional
cases pulmonary involvement is seen and patients occasionally complain of
asthma, hemoptysis, and effusions. Although clinical involvement of the lungs
is rare, autopsy evaluation has shown that arteritis affecting the bronchial
arteries is not uncommon, being seen in 70% in one small series.20
Orchitis, usually unilateral, is a characteristic feature of polyarteritis
nodosa.21–23 Affected patients present with symptoms of acute orchitis or
features that suggest a testicular neoplasm.21,23
Laboratory investigations often reveal anemia, leukocytosis, and a raised
ESR. Low-titer rheumatoid factor and antinuclear antibody are sometimes
features and, in occasional patients, a cryoglobulin is identified. Diminished
serum complement levels may also be detected. ANCAs are uncommonly
seen in patients with classic polyarteritis nodosa. One group with extensive
experience estimates that less than 5% of patients with the classic form of
the disease have ANCAs.24 Others have found a somewhat higher frequency.
Nevertheless, this is in contrast to microscopic polyangiitis, a form of vasculitis
that is usually associated with ANCAs (see below).
Polyarteritis nodosa in children may present in two forms: the infantile
Fig. 16.32 variant, which may be related to Kawasaki syndrome, and a childhood form,
Polyarteritis nodosa: this patient presented with acral erythematous lesions. By which is similar to adult polyarteritis nodosa (see also section on Kawasaki
courtesy of the Institute of Dermatology, London, UK. syndrome).25
Fig. 16.34
Polyarteritis nodosa:
coronary arteries showing Fig. 16.35
conspicuous aneurysmal Microscopic polyarteritis: p-ANCA. By courtesy of G. Swana, MD, St Thomas'
dilatation are now very Hospital, London, UK.
rarely seen (museum
specimen). By courtesy
of the Department of with either disease have neither pulmonary nor renal involvement, precise
Pathology, St Thomas' classification can be difficult.24 Microscopic polyangiitis is a diagnosis of
Hospital, London, UK. exclusion; other conditions that may manifest similar renal features include
Wegener's granulomatosis, rapidly progressive glomerulonephritis, Churg-
Strauss syndrome, SLE, classic polyarteritis nodosa, and Henoch-Schönlein
Cutaneous polyarteritis nodosa purpura.18
Microscopic polyangiitis is usually associated with positive neutrophil
In addition to classic polyarteritis nodosa, ‘localized (cutaneous) polyarteritis
cytoplasmic antibodies, typically of the antimyeloperoxidase (perinuclear-
nodosa’ has also been described.26–32 This is a relatively benign variant in
antineutrophil cytoplasmic antibody, p-ANCA) subtype (Fig. 16.35).40 Since
which patients develop cutaneous lesions, often over very prolonged periods,
most (but not all) patients with classic polyarteritis nodosa do not have
but serious visceral involvement is, by definition, never a feature. In one study,
ANCAs, this is useful in distinguishing these conditions.
none of 79 patients with cutaneous polyarteritis nodosa who were followed
This disease is of particular importance due to its high morbidity and
for an average of 6.9 years developed systemic vasculitis.26 It may occur at
mortality, with a 5-year survival of approximately only 65%.38 As a result
any age, including childhood, and shows no sex predilection. The disease has
of improved medical treatment outcome has significantly improved over the
occasionally been associated with minocycline treatment.33–35
past few decades, with a quoted 5-year survival of 81%.41 Severe renal disease
Patients have recurrent episodes during which tender, painful nodules
and disease relapse are the best indicators for poor prognosis.41
develop, particularly on the lower legs, although these may sometimes be
Patients often present with non-specific constitutional symptoms including
quite widespread. Individual lesions vary from 2 mm to 2 cm in diameter. In
malaise, fever, and myalgia. There may be a past history of sore throat
the early stages they are pink or red, while more established nodules may have
or a flulike illness, which obviously raises the possibility of an iatrogenic
a purplish coloration. Patients sometimes also manifest livedo reticularis,
pathogenesis for the subsequent vasculitic process.38 Renal involvement
usually on the lower legs and often related to groups of nodules. Other
may manifest as microscopic hematuria, proteinuria or acute renal failure.
complications include ulceration and, rarely, gangrene. Very occasionally,
Hypertension is present in a large proportion of patients. Pulmonary lesions
patients develop lesions reminiscent of atrophie blanche.30
present as hemoptysis, pulmonary fibrosis, and intrapulmonary hemorrhage,
Other features include fever, malaise, arthralgias, and myalgias, and
which can prove fatal.42,43
peripheral nerves may be affected, but there is never any evidence of more
Dermatological signs, which are found in approximately 40% of patients,
widespread visceral involvement.28,32
include purpura, erythema, splinter hemorrhages, and leg ulceration.10,39,44
Immunofluorescence often reveals IgM and/or complement in the walls
Bullous presentation or urticaria are occasionally encountered but cutaneous
of cutaneous arteries, suggesting a possible immune complex pathogenesis.36
nodules and livedo are rare features of this disease due to absence of involvement
Rare reports of infants of mothers with cutaneous polyarteritis developing the
of larger vessels.10,44–46 Other manifestations such as nervous system lesions,
disease and experiencing subsequent resolution are suggestive of a pathogenic
gastrointestinal bleeding with pain, and diarrhea, are sometimes evident.47–50
circulating factor.37
Laboratory findings in microscopic polyarteritis include a raised
ESR, normochromic normocytic anemia, leukocytosis with neutrophilia
Microscopic polyangiitis
and thrombocytosis, raised C-reactive protein, and raised α-1 and α-2
Microscopic polyangiitis (microscopic polyarteritis) is a more recently described globulins. Rheumatoid factor and immune complexes are present in less
entity, which involves the skin in a significant proportion of patients.2,38–40 than 50% of patients.38 Anti-DNA antibodies are not a feature. Cutaneous
Its definition and relationship to classic polyarteritis nodosa are somewhat immunofluorescence is usually negative.
controversial. The disease essentially consists of small vessel vasculitis in
association with glomerulonephritis. In contrast, renal involvement in classic Pathogenesis and histological features
polyarteritis is a vascular nephropathy. Lung capillaritis is sometimes seen
in patients with microscopic polyangiitis. By way of distinction, classic Polyarteritis nodosa
polyarteritis nodosa is very rarely associated with clinical manifestations of The pathogenesis of polyarteritis nodosa is poorly understood. Classic
pulmonary involvement (although pathological involvement of large vessels polyarteritis nodosa has been suggested to be immune-complex mediated, on
may be more common than suspected: see above) and this, clinical difference the basis of serum immune-complex levels, immunofluorescence investigations
is helpful in distinguishing these entities.24 However, since many patients and ultrastructural studies. However, in many patients immune complexes
cannot be demonstrated and their role in the development of this disease infarction (Fig. 16.37). Although the whole circumference and thickness of
is controversial. Important suspect antigens include hepatitis B virus (HBV) the vessel wall is often affected, sometimes the changes are focal. Typically in
surface antigens and cryoglobulins.51–54 It has been shown that a significant polyarteritis nodosa, the vascular changes are discontinuous, with uninvolved
number of patients with polyarteritis nodosa have circulating HBV antigen.9,54 skip lesions between affected segments (Fig. 16.38).
Furthermore, circulating immune complexes containing HBV antigen and The acute changes, those of fibrinoid necrosis, involve the muscle coat and
immunoglobulin have been characterized in occasional patients.9 HBV surface often destroy the internal elastic lamina; this is often best appreciated by the
antigen has also been identified within affected vessels in a small number of use of a stain for elastic tissue (Fig. 16.39). Associated with the necrosis is
patients.9 A decrease in HBV-associated cases of polyarteritis nodosa in France an inflammatory cell infiltrate of neutrophils, eosinophils, and mononuclear
has been reported and it has been suggested that this phenomenon is the cells. Leukocytoclasis is sometimes an additional feature. Thrombosis
result of vaccination programs.55 Rarely, however, polyarteritis nodosa may is common and may be complicated by ischemic necrosis of the surface
also develop following hepatitis B vaccination.56 Human immunodeficiency epithelium. Healing lesions are associated with fibroblastic proliferation and
viral infection has also been reported in cases of polyarteritis nodosa or a eventual fibrous scarring. Endarteritis is often evident and any disruption
polyarteritis nodosa-like syndrome.57–63 of the internal elastic lamina is permanent. A characteristic feature often
Evidence of hepatitis C viral infection has been documented in some present in wedge biopsies that contain multiple vessels is the presence of
patients. In one study, 20% of patients had antibodies against hepatitis lesions at varying stages of evolution. Deep, surgical incisional biopsies are
C virus.62,64 Erythrovirus (parvovirus) infection has been associated with essential for the diagnosis of cutaneous involvement in polyarteritis nodosa.
polyarteritis nodosa in occasional cases.65,66 A punch biopsy will often not sample larger vessels that are typically affected.
In childhood polyarteritis nodosa, there appears to be a striking association Furthermore, the diagnosis is subject to sampling error due to the multifocal
with group A streptococci.67 nature of the disease. Aneurysm formation may sometimes be appreciated
Although there is some evidence to suggest a role for immune complexes microscopically.1
generated during infection, such a relationship cannot be demonstrated in
many cases. Therefore, the pathogenesis of classic polyarteritis nodosa is
unclear in many patients.
As with other ANCA-associated vasculitides, the presence of ANCAs
(usually p-ANCAs) in most patients with microscopic polyangiitis suggests
that these antibodies may play a pathogenic role. In contrast, ANCAs are
not usually seen in patients with classic polyarteritis nodosa. Additionally,
again in contrast to classic polyarteritis nodosa, immune complexes are
not thought to play a role in the pathogenesis of microscopic polyarteritis
nodosa. The presence of ANCAs suggests a shared pathogenic relationship
with other ANCA-associated vasculitides (i.e. Wegener's granulomatosis,
Churg-Strauss syndrome) and there is recent evidence to suggest that
different but overlapping epitopes of myeloperoxidase (MPO) are
recognized by ANCAs in Wegener's granulomatosis and microscopic
polyangiitis.68 HIV infection has been documented in patients with
microscopic polyangiitis.58
The histological features of the cutaneous lesions in both the classic
and localized variants of polyarteritis nodosa are similar and changes are
variable.38,69,70 In some instances, the changes are indistinguishable from
leukocytoclastic vasculitis involving the superficial dermal vessels (Fig.
16.36). More characteristic, however, is the finding of necrotizing vasculitis
involving the muscular arteries of the deep dermis or subcutaneous fat; these Fig. 16.37
are the changes that are also seen in the internal viscera, often associated with Polyarteritis nodosa: high-power view showing fibrinoid necrosis.
Fig. 16.36 Fig. 16.38

Polyarteritis nodosa: in this case the features are those of a superficial Polyarteritis nodosa: while fibrinoid necrosis involves both lateral extremities of this
leukocytoclastic vasculitis. It is important to remember that this histological lesion vascular segment, the middle portion is relatively unaffected.
may represent a serious systemic disease.
Fig. 16.40
Polyarteritis nodosa: in this kidney section an arcuate artery shows necrotizing
vasculitis and fibrointimal thickening. The inflammatory cell infiltrate contains
conspicuous eosinophils.
Fig. 16.39
Polyarteritis nodosa: (A) there is marked red cell extravasation; (B) elastic–van
Gieson staining shows disruption of the internal elastic lamina.
Internal visceral involvement is based upon the effects of necrotizing

arteritis. Interestingly, nodular swellings (aneurysms) are much more obvious. Fig. 16.41
Polyarteritis nodosa: segmental necrotizing glomerulonephritis.
The effects depend upon the relative interplay of infarction and hemorrhage.
Renal involvement in classical polyarteritis nodosa is predominantly due to
large-vessel vasculitis, with resultant thrombosis and infarction, coupled
with the effects of hypertension (Fig. 16.40).71 Patients may also manifest
focal, segmental proliferative or necrotizing glomerulonephritis similar to
that seen in patients with microscopic polyarteritis nodosa (Fig. 16.41).
Microscopic polyangiitis
Microscopic polyangiitis (microscopic polyarteritis) is characterized by small-
vessel vasculitis, which may predominantly affect the muscular arteriole,
capillaries, and venules (Fig. 16.42).2,40,72 Given the spectrum of vessel types
involved and the absence of arteriolar involvement in some patients, the term
‘microscopic polyangiitis’ is preferred by some authors.2,73 The absence of
involvement of capillaries and venules in classic polyarteritis nodosa is a major
point of distinction from microscopic polyarteritis nodosa. Necrotizing vasculitis
with fibrinoid necrosis and variable numbers of neutrophils and monocytes is
seen. In early lesions, neutrophils associated with karyorrhexis predominate,
while lymphocytes and histiocytes dominate the infiltrate in older lesions. In some
patients, acute lesions are indistinguishable from leukocytoclastic vasculitis.
Renal lesions include focal segmental necrotizing glomerulonephritis (often
with crescents), vasculitis, interstitial inflammation, and tubular atrophy. Fig. 16.42
Large-vessel disease, visceral infarction, and granulomatous inflammation Microscopic polyarteritis nodosa: acute necrotizing vasculitis of a small muscular
are not features. arteriole is evident. Numerous eosinophils are present.
Wegener's granulomatosis 673
Differential diagnosis Table 16.4

1990 criteria for the classification of Wegener's granulomatosis (traditional
Since other vasculitides may show similar histological features, particularly format)*
cases with only small-vessel involvement (leukocytoclastic vasculitis pattern),
the biopsy findings must never be used in isolation to determine the diagnosis.
Criterion Definition
Only after careful clinical, serological, and histological correlation should a
definitive diagnosis be rendered. Criteria are admittedly definitional and as Nasal or oral Development of painful or painless
inflammation oral ulcers or purulent or bloody nasal
we learn more about this disease (or group of diseases), criteria are likely to
discharge
change. Careful clinical investigation is required to evaluate for underlying
causes/disease associations. Abnormal chest Chest radiograph showing the presence of
As noted above, distinction between classic polyarteritis nodosa and radiograph nodules, fixed infiltrates or cavities
polyangiitis is based on the size of vessels involved, spectrum and type Urinary sediment Microhematuria (> 5 red blood cells per
of organ involvement, and presence of ANCAs. Microscopic polyangiitis high power field) or red cell casts in urine
may also be confused with Wegener's granulomatosis and Churg-Strauss sediment
syndrome. The presence of granulomatous inflammation in the lung favors Granulomatous Histological changes showing
the first of the last two conditions. The presence of blood eosinophilia and inflammation on biopsy granulomatous inflammation within the
asthma favors a diagnosis of Churg-Strauss syndrome. As can be seen, wall of an artery or in the perivascular or
microscopic polyangiitis is a diagnosis of exclusion. In fact, with clinical extravascular area (artery or arteriole)
follow-up, the diagnosis may be revised. For example, patients who
* For purposes of classification, a patient shall be said to have Wegener's
appear to fit criteria for microscopic polyangiitis may eventually develop granulomatosis if at least two of these four criteria are present. The presence of any
manifestations that allow for classification as Wegener's granulomatosis.2 two or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%
Diagnostic criteria are likely to change as we understand more about these Reproduced with permission from Leavitt, R.Y. (1990) Arthritis and Rheumatism, 33,
disorders. 1101–1107.
Wegener's granulomatosis not uncommon and occur either as a consequence of direct extension through
the base of the skull from sinus involvement or as a result of meningeal or
Clinical features intracerebral necrotizing granulomata. Patients may experience myelopathy
or neuropathy.12 Vasculitis involving intracerebral vessels can also result in
Wegener's granulomatosis is a multisystem vascular disease associated
cerebral lesions. Patients develop cranioneuropathy, cerebrovascular accidents
with high morbidity and mortality.1,2 Before the introduction of
or seizures.11 Involvement of the vasa nervora may give rise to mononeuritis
cyclophosphamide therapy it was associated with a dismal prognosis.
multiplex.
Mean survival was of the order of 5 months following diagnosis and
Ocular lesions result in a variety of complications including conjunctivitis,
approximately 80% of patients died within 1 year, most as a consequence
granulomatous keratitis, sclerouveitis, and orbital pseudotumor. Proptosis
of renal involvement.
is sometimes a feature.13 Involvement of the temporal artery results in
Although it may present in a wide variety of age groups, from infancy to
features (i.e. vision loss, jaw claudication) similar to those seen in temporal
the elderly, it is the middle-aged that are predominantly affected, with a peak
arteritis.14
incidence in the fourth decade.1–4 There is a slight predilection for males (3:2).
Cutaneous manifestations are common, occurring in about 14–50%
In one large study, 97% of patients were Caucasians.5
of patients.15–18 Several different types of skin lesion may be encountered,
Wegener's granulomatosis comprises a triad of characteristics:
including vasculitic lesions with purpura, bruising, and nodule formation
• necrotizing, destructive, granulomatous lesions in the upper respiratory (Figs 16.43–16.45). Pyoderma gangrenosum-like lesions with necrosis
tract (nose, nasal sinuses, nasopharynx, and larynx) and/or in the lower
and ulceration that have a predilection for the lower limbs are sometimes
respiratory tract (trachea, bronchi or lungs); frequently, both are present.
encountered. The presence of skin lesions appears to correlate with disease
Similar lesions may also be found in virtually any organ in the body,
activity. Oral ulceration is common.18,19
• a generalized focal vasculitis occurring in a wide variety of sites, but
particularly affecting the lungs,
• glomerulonephritis.6,7
Early in the disease, when patients may not have developed the full clinical
triad, definitive diagnosis can be difficult or impossible (see Table 16.4).
The most common presenting symptoms relate to involvement of the nose
and nasal sinuses, and include severe and often purulent nasal discharge
or evidence of sinusitis with pain and discharge. Clinical examination may
reveal mucosal ulceration, perforated septum, paranasal sinusitis or a saddle-
nose deformity. Serous or purulent otitis media is occasionally a presenting
feature. Middle and inner ear involvement is also a common manifestation
of disease.8–10
Pulmonary lesions are invariably present and patients may have cough,
chest pain or hemoptysis. Radiological examination frequently reveals solitary
or more commonly multiple nodular opacities, which are often bilateral, may
be diffuse or sharply delineated, and are typically transient. Cavitation is
frequently a feature. Lesions may present as large nodules that are clinically
and radiologically suspicious for malignancy.
Renal involvement is common and urinalysis typically reveals hematuria
(often microscopic), proteinuria, and red cell casts.
Joint involvement may present as arthralgia or, less commonly, frank
arthritis. Fig. 16.43
In one large series, 34% of patients developed neurological involvement.11 Wegener's granulomatosis: multiple purpuric macules and papules. By courtesy of
Peripheral neuropathy was seen in 16%.11 Central nervous system lesions are D. McGibbon, MD, St Thomas' Hospital, London, UK.
Fig. 16.44 Fig. 16.46

Wegener's granulomatosis: cutaneous nodules as seen in this patient are a not Pathergic granulomatosis: gross necrosis and ulceration have resulted in very
uncommon manifestation. By courtesy of the Institute of Dermatology, London, UK. disfiguring tissue damage.
Fig. 16.45 Fig. 16.47

Wegener's granulomatosis: this patient has ulcerating plaques and nodules. By Wegener's granulomatosis: c-ANCA. By courtesy of G. Swana, MD, St Thomas'
courtesy of the Institute of Dermatology, London, UK. Hospital, London, UK.
In addition to the organ-specific features noted above, patients also often orbit or lung) in association with a positive serum cytoplasmic-antineutrophil
have a variety of constitutional symptoms, including anorexia, weight loss, cytoplasmic antibody (c-ANCA) represents the earliest stage in the evolution
fever, and general malaise. of Wegener's granulomatosis.23 Such a concept, if proven viable, should result
Two limited forms of Wegener's granulomatosis are recognized: pathergic in diagnosis at a stage before the development of more serious multisystem
granulomatosis and limited pulmonary granulomatosis.20–22 disease and, hence, earlier treatment.
• Pathergic granulomatosis is of particular importance because mucosal and The vast majority of patients with Wegener's granulomatosis have ANCA
cutaneous lesions may predominate and persist for very long periods of detected in their sera; rising titers have been shown to correlate with disease
time before intractable renal failure develops. In the absence of evidence activity and are a valuable method of predicting relapse.2,24 Typically, the
of pulmonary and renal involvement, there may be a delay in establishing indirect immunofluorescence shows a cytoplasmic pattern of staining
the diagnosis and administration of appropriate chemotherapy, with (c-ANCA) (Fig. 16.47).1 In the majority (70–80%) of patients with active
resultant increased morbidity and mortality. Patients with this variant are disease ANCAs are directed against proteinase 3 (PR3) while ANCAs against
at particular risk of facial mutilation; sites especially involved include the myeloperoxidase (MPO) are detected in approximately 10% of patients.25,26
nose, nasopharynx, sinuses, and middle ears (Fig. 16.46). ANCAs have also been detected in patients with Takayasu's arteritis, Churg-
• In limited pulmonary granulomatosis patients have respiratory symptoms Strauss syndrome, Kawasaki's arteritis, microscopic polyangiitis, and
with associated fever and weight loss. Radiologically, multiple bilateral idiopathic crescentic glomerulonephritis.24,27,28
discrete nodular infiltrates and thin-walled cavitating lesions are seen,
usually in the lower lobes. No evidence for renal involvement is present.
Patients with this variant appear to have a somewhat better prognosis Pathogenesis and histological features
than those with classic (generalized) Wegener's granulomatosis. This rare disease is thought to represent a hypersensitivity reaction to an as yet
A further development is the proposed purely granulomatous Wegener's unidentified allergen. Response to immunosuppressive therapy is consistent
granulomatosis (PGWG), in which it has been suggested that the presence with this hypothesis. The presence of ANCAs against PR3 and to a lesser amount
of extravascular granulomata (particularly affecting the ears, nose, throat, MPO in most patients with Wegener's granulomatosis and the correlation
Wegener's granulomatosis 675
of circulating levels of ANCAs with disease activity suggest a role in the of the necrotic focus (Fig. 16.49). In addition, the features of an active
pathogenesis of this disease. Additionally, although immune complexes have angiitis are present; this may involve both arteries and veins and frequently
not been demonstrated, disease activity is ameliorated with plasma exchange. has a granulomatous component (Fig. 16.50). The adjacent parenchyma is
Thus, there is compelling anecdotal evidence suggesting ANCAs are central to chronically inflamed and often shows severe, diffuse, interstitial fibrosis.
pathogenesis, most likely through activation of neutrophils, lymphocytes, and Early renal lesions are characterized by focal segmental glomerulonephritis.
macrophages.29 In particular, abnormal numbers and function in regulatory T In more advanced cases the glomerulitis becomes generalized, with fibrinoid
cells (Treg) have been demonstrated in patients with Wegener's granulomatosis necrosis and widespread epithelial crescent formation.43 The renal interstitial
and appear to also correlate with disease activity.30–32 However, the precise tissue may contain necrotizing granulomata, and vasculitis is sometimes
mechanism action of ANCAs is not yet fully understood.29 a feature. Immunofluorescence occasionally reveals granular deposits of
It is postulated that exposure to an antigen (or antigens) may trigger immunoglobulin and complement along the glomerular capillary walls.
ANCAs that have pathophysiological effects leading to tissue destruction.33 This is taken as evidence for possible immune complex involvement. Similar
Infectious agents have received some attention as potentially playing a role granulomata and evidence of vasculitis have been described in all organ
in the pathogenesis of Wegener's granulomatosis. It is interesting to note that systems of the body, but are particularly often seen in the spleen.
relapses of the disease may follow infection.29 In some patients, a complete Cutaneous lesions reveal a variety of features including necrotizing
or partial remission is achieved with antibiotic treatment combined with vasculitis, in which small or medium-sized dermal vessels display fibrinoid
immunosuppressive agents.29,34 Trimethoprim-sulfamethoxazole has also necrosis, a neutrophil polymorphonuclear infiltrate, and nuclear dust (Figs
been used to reduce the frequency of relapses in Wegener's patients.35 Patients 16.51, 16.52). In one series, 80% of biopsies from patients with cutaneous
who are chronic nasal carriers of Staphylococcus aureus seem to have a lesions (of 244 patients in this series, 14% had cutaneous lesions) showed
higher relapse rate compared with noncarriers.36 Furthermore, antibodies leukocytoclastic vasculitis.17 In another study, nearly a third showed
against hepatitis C virus, Epstein-Barr virus, and Helicobacter pylori as leukocytoclastic vasculitis and another third showed non-specific chronic
well as IgG antibodies against Toxoplasma gondii and IgM antibodies
against cytomegalovirus are significantly more common in patients with
Wegener's granulomatosis than in unaffected individuals.37 Gastrointestinal
and renal manifestation correlate well with the presence of IgG antibodies to
cytomegalovirus while otolaryngeal manifestation is more common in patients
with IgG antibodies to the EBV early antigen.37 Despite considerable research
to establish a possible relationship between Wegener's granulomatosis and
infection, a categoric role in the disease is elusive.38
In addition to that for infectious agents, a search for putative roles for
physical agents in the environment has also been undertaken. Perhaps most
attention has focused on silicon compounds.39–41 One case-control study
showed that exposure to silicon-containing compounds conferred a sevenfold
risk for the development of Wegener's granulomatosis.40 It has been postulated
that silica-induced apoptosis of inflammatory cells may release lysosomal
enzymes that stimulate ANCAs.29,39
Pulmonary lesions are characterized by necrotizing granulomatous
inflammation that may bear more than a superficial resemblance to the
caseation of pulmonary tuberculosis (Fig. 16.48).42 The similarity is increased
by the presence of large numbers of Langhans giant cells at the periphery
Fig. 16.49
Wegener's granulomatosis: this lung section shows extensive necrosis associated
with a granulomatous infiltrate containing Langhans giant cells. These appearances
resemble pulmonary tuberculosis.
Fig. 16.48
Wegener's
granulomatosis: this
postmortem lung
specimen shows
consolidation and
numerous abscesses.
By courtesy of B. Corrin, Fig. 16.50
MD, Brompton Hospital, Wegener's granulomatosis: a branch of the pulmonary artery shows necrotizing
London, UK. arteritis with fibrointimal thickening.
Fig. 16.51 Fig. 16.53

Wegener's granulomatosis: leukocytoclastic vasculitis as shown in this field is the Wegener's granulomatosis: low-power view of a necrotizing dermal granuloma.
most frequently encountered cutaneous lesion.
Fig. 16.52 Fig. 16.54

Wegener's granulomatosis: large vessel showing intense chronic inflammation, Wegener's granulomatosis: high-power view of an ill-defined granuloma.
thrombosis, and intimal fibrosis.
inflammation.44 In this study, nearly 50% of patients had entirely non-specific diagnosis including sarcoidosis and infections, particularly mycobacterial
findings. Extravasated red blood cells are invariably present.15,16 In severe and fungal. Granulomatous vasculitis may also be seen in association with
cases, the epidermis may show ischemic necrosis. Bone fide granulomatous lymphoproliferative diseases including lymphoma, angioimmunoblastic
vasculitis of skin appears to be a very rare feature. In fact, one study failed lymphadenopathy, and leukemia.45
to demonstrate granulomatous vasculitis in 75 skin biopsies from 46 Microscopic polyangiitis can be confused with Wegener's granulomatosis.
patients.44 In other patients, there may be granulomatous infiltration of the The presence of granulomatous inflammation in the lung would favor the
dermis, which may be related to foci of collagen necrosis and sometimes latter. Microscopic polyangiitis is approached as a diagnosis of exclusion.
resembles the Churg-Strauss granuloma (Figs 16.53, 16.54). In some cases, In fact, a diagnosis may be revised as the pattern of clinical involvement
extensive geographic zones of necrosis are present, associated with a mixed changes. For example, patients that appear to fit criteria for microscopic
inflammatory cell infiltrate including variable numbers of histiocytes, giant polyangiitis may eventually develop manifestation allowing for classification
cells, lymphocytes, eosinophils, and plasma cells. Erythema nodosum and as Wegener's granulomatosis.46
granuloma annulare-like lesions may also be encountered.44 When granulomata and/or allergic vasculitis are the only features, it
may not be possible to histologically distinguish Wegener's granulomatosis
Differential diagnosis from the Churg-Strauss syndrome. A high eosinophil content, however, is
As mentioned above, early in the course of the disease, when patients may somewhat suggestive of the latter condition but certainly not diagnostic, as
not have developed the full clinical triad, definitive diagnosis is sometimes this finding may sometimes be seen in Wegener's granulomatosis.44 Therefore,
impossible. distinction of Wegener's granulomatosis from other forms of granulomatous
In those instances where a granulomatous dermal infiltrate occurs inflammation and leukocytoclastic and granulomatous vasculitis requires
in the absence of vasculitis, a host of conditions enters the differential careful clinicopathological and serological correlation.
Allergic granulomatosis with angiitis 677
On CT scan, pulmonary infiltrates may take the form of opacification, nodules,

Allergic granulomatosis with angiitis or bronchial wall and interlobular septal thickening.17 Bronchoalveolar
lavage reveals alveolar eosinophilia.1 Certain patients develop an eosinophil-
Clinical features rich pleural effusion.1
Allergic granulomatosis with angiitis (Churg-Strauss syndrome) is a very In addition to pulmonary lesions, systemic involvement most commonly
rare disease that combines the features of asthma, fever, multisystem affects the heart, nervous system, gut, and kidneys.6 Cardiac lesions may
necrotizing vasculitis, extravascular granulomata, and hypereosinophilia.1,2 be a cause of dysrhythmia or sudden death. Cardiac manifestations also
Although there is clinical overlap, it can be distinguished from polyarteritis include valvulopathy, ventricular insufficiency, global cardiac insufficiency,
nodosa and Wegener's granulomatosis (Table 16.5). The criteria published and endomyocarditis.1,18–20 Pericardial effusion was seen in 23% of patients
by the Chapel Hill Consensus conference differ somewhat.3 In this scheme, in one study.1 Complications relating to cardiac involvement are the most
Churg-Strauss syndrome is defined as ‘eosinophil-rich and granulomatous common cause of death in patients with Churg-Strauss syndrome. Nearly
inflammation involving the respiratory tract, and necrotizing vasculitis 40% of deaths are due to cardiac involvement.1
affecting small to medium-sized arteries, and associated with asthma and Neurological manifestations are frequent, particularly mononeuritis
eosinophilia’.3 Given differences in classification criteria, it comes as no multiplex and symmetric polyneuropathy.21,22 In one large study, 72% of
surprise that inconsistencies between these classification schemes exist.4,5 patients developed mononeuritis multiplex.1,23 Intracerebral hemorrhage
One study found good concordance between classification schemes for the or infarction sometimes develops.21 Ischemic optic and bilateral trigeminal
diagnosis of Wegener's granulomatosis but not Churg-Strauss syndrome.4 neuropathy are rare complications.22 Myalgia, epilepsy, hydrocephalus,
As we gain further understanding of this disease, refinement of diagnostic chorea, and vertigo are further occasional features.24
criteria is likely. Evidence of gastrointestinal involvement, such as nausea, bleeding,
Churg-Strauss syndrome may present in a wide range of age groups, vomiting, and abdominal pain, is often found. In one study, one-third of
but most patients are adults, those in the third and fourth decades being patients experienced gastrointestinal symptoms, usually abdominal pain.1
most commonly affected. The disease has a slight male predominance.6–9 Diffuse bowel ischemia is an uncommon but serious complication.1
Presentation in children is very rare.10–12 Renal disease in Churg-Strauss syndrome is usually manifest as
Asthma and necrotizing vasculitis are invariably present. Asthma glomerulonephritis, most often a focal segmental glomerulonephritis.1,25
often precedes the onset of vasculitis, sometimes by many years, or these Patients with renal involvement show hematuria, proteinuria, and increased
features develop simultaneously. In one large study, asthma preceded creatinine.1 Renal infarction appears to be a rare complication.1
definitive diagnosis in 94% of patients.1 Asthma may be associated with Rheumatological involvement in the form of polyarthralgia and consti
transient pulmonary infiltrates (Loeffler's syndrome) or there can be full- tutional symptoms, including fever, anemia, and weight loss, is common.1
blown chronic eosinophilic pneumonitis.6 There is some evidence to Amyloidosis is a rare complication.26,27 Exceptionally, Churg-Strauss
suggest that patients in whom vasculitis occurs rapidly after presentation syndrome may present with temporal nongiant cell arteritis.28 Involvement of
of asthma have a particularly poor prognosis. It has been suggested that, the breast occurs exceptionally as eosinophilic mastitis.29 A limited form of
in some cases, treatment for allergic rhinitis with steroids suppresses the the disease has been described.30,31
full-blown syndrome.13,14 Recently, an association between treatment of Cutaneous lesions are seen in 40–70% of patients and include petechiae,
asthma with antileukotrienes and development of Churg-Strauss syndrome purpura, papules, vesicles, facial erythema, urticaria, and ulceration.32–37
has been suggested.2,15 The association is controversial and what role, if any, Cutaneous infarction and bullae are less common manifestations.35,38 Livedo
antileukotrienes play in development of disease in these patients is unclear. reticularis involving the lower limbs is occasionally a feature. Patients may
However, it has also been proposed that it is the withdrawal of the steroids also develop tender nodules, which particularly affect the extensor aspects of
and not the administration of antileukotrienes that leads to disease.2 Further the arms, legs, hands, and feet (Fig. 16.55). The sacrum, buttocks, and scalp
investigation is required to resolve this controversy. Churg-Strauss syndrome can also be involved. The cutaneous lesions tend to appear in crops with
has also been described following treatment with anti-IgE antibodies spontaneous relapses and remissions.
(omalizumab) for asthma and may represent unmasking of the disease while Churg-Strauss syndrome has been seen in association with HIV infection,
reducing steroid treatment.16 hepatitis B, Wells' syndrome, and bronchopulmonary candidiasis.39–42 The
Common manifestations of upper respiratory tract involvement include disease has also been described in association with drugs including fluticasone
allergic rhinitis (which is sometimes associated with polyp formation and and cocaine.43,44
sinusitis) and hay fever. A family history of atopy and allergic reactions to Laboratory investigation usually reveals leukocytosis and a raised ESR in
inhaled antigens and drugs is often present. association with peripheral blood eosinophilia.35 Blood eosinophilia often
Chest radiography frequently confirms the presence of pulmonary decreases with treatment but some authors stress that such a response should
involvement, which takes a variety of forms including transient patchy not be taken as evidence that disease activity is under control.45 ANCAs are
infiltrates, discrete noncavitating nodular masses, or diffuse interstitial disease. demonstrated in many patients (see below).
Table 16.5
1990 criteria for the classification of Churg–Strauss syndrome (traditional format)*
Criterion No. of CSS patients (n = 20) Sensitivity (%) No. of control patients (n = 787) Specificity (%)
Asthma 19 100 782 96.3
Eosinophilia > 10% 20 95 708 96.6
Neuropathy (mono or poly) 20 75 781 79.8
Pulmonary infiltrates, non-fixed 20 40 736 92.4
Paranasal sinus abnormality 14 85.7 366 79.3
Extravascular eosinophils 16 81.3 385 84.4
* For classification purposes, a patient shall be said to have Churg-Strauss syndrome (CSS) if at least four of these six criteria are positive. The presence of any four or more of the
six criteria yields a sensitivity of 85% and a specificity of 99.7%.
Reproduced with permission from Masi, A.T. (1990) Arthritis and Rheumatism, 33, 1094–1100.
Fig. 16.55
Churg-Strauss syndrome: this patient presented with painful nodules on the limbs. Fig. 16.56
By courtesy of the Institute of Dermatology, London, UK. Churg-Strauss syndrome:
this early lesion shows
a swollen collagen fiber
Pathogenesis and histological features in the superficial dermis.
Note the surrounding
The etiology and pathogenesis of Churg-Strauss syndrome is poorly multinucleate giant cells.
understood. The presence of perinuclear-antineutrophil cytoplasmic
antibodies (p-ANCA) in many patients is of considerable interest.46–49
ANCAs are detected in approximately 40% of patients.50–52 The ANCAs
seen in these patients usually target myeloperoxidase.52 However, the various
types of ANCA are non-specific, being present in a spectrum of disease.53
Their presence is associated with higher risk of developing renal disease and
peripheral neuropathy, while absence of ANCAs is linked to heart disease
and fever.51,52,54 ANCAs may activate neutrophils, causing degranulation and
vascular injury.55 T lymphocytes can also be stimulated, leading to endothelial
cell injury.55 As with other ANCA-associated vasculitides, it is suspected that
they play a role in the pathogenesis of Churg-Strauss syndrome; however,
the precise mechanism, particularly triggering factors, is not yet known.
Persistence of ANCAs with therapy may be of limited value in making
treatment decisions.56 One group has found that, although there is poor
correlation between ANCA titer and disease activity, disappearance of ANCA
can reflect absent disease activity.57
Pulmonary lesions comprise variably sized (up to 1.5 cm) nodules, ranging
from only a few lesions to hundreds which may coalesce. Histologically,
they are composed of granulomata with central necrosis and surrounding
epithelioid histiocytes with occasional giant cells. Large numbers of
eosinophils with an admixture of lymphocytes, neutrophils, plasma cells, and Fig. 16.57
Churg-Strauss syndrome: medium-power view showing swelling of the dermal
histiocytes infiltrate the adjacent lung parenchyma. Vasculitis involving small
collagen fibers and a perivascular chronic inflammatory cell infiltrate.
arteries and sometimes veins is also present.
Cutaneous lesions are variable. A common feature is the so-called ‘Churg-
Strauss (extravascular) granuloma’. Early lesions are characterized by focal Differential diagnosis
collagen degeneration in association with a varying and mixed inflammatory The histological features encountered in skin biopsies of patients with
cell infiltrate comprising neutrophils, lymphocytes, and histiocytes (Figs Churg-Strauss syndrome are not diagnostic. Careful clinicopathological and
16.56, 16.57). Eosinophils may be sparse or numerous. Leukocytoclasis is serological evaluation is necessary to establish a definitive diagnosis. Although
often a feature. In more advanced examples the granuloma is more mature Churg-Strauss syndrome, polyarteritis nodosa, and Wegener's granulomatosis
in appearance, consisting of a central zone of collagen necrosis surrounded show both clinical and histological overlap, research over the last several
by a peripheral palisade of epithelioid and giant cells (Figs. 16.58,16.59). decades leaves no doubt that they represent distinctive entities. Nonetheless,
In some examples, the features are those of a rather diffuse and ill-defined they form a spectrum of disease with similar pathogenesis, although there are
granulomatous inflammatory process without obvious collagen degeneration. sufficient differences to justify their separate classification:
Commonly, features of necrotizing vasculitis are evident: fibrinoid necrosis • Asthma may be seen in both polyarteritis nodosa and Churg-Strauss
accompanied by an eosinophilic and neutrophilic infiltrate with leukocytoclasis syndrome, but characteristically polyarteritis affects medium-sized and
involving the more superficial small blood vessels (Fig. 16.60). There may small arteries, while Churg-Strauss syndrome typically affects small
be epidermal ischemic necrosis. In one study, 16 of 37 biopsies (taken from arteries and veins.
29 patients) showed leukocytoclastic vasculitis.34 Occasionally, the arteries • The neutrophil dominates the inflammatory cell infiltrate in polyarteritis
in the dermis and subcutaneous fat show changes similar to those seen in nodosa, whereas in Churg-Strauss syndrome it is the eosinophil.
polyarteritis nodosa.35 Additionally, acute and chronic panniculitis with • Necrotizing extravascular granulomata are not a feature of polyarteritis
eosinophils has been described.35 nodosa.
Mucocutaneous lymph node syndrome 679
Fig. 16.58
Churg-Strauss syndrome: in this field there is a more obvious granulomatous infiltrate.
Fig. 16.60
Churg-Strauss syndrome:
the features of small-
vessel leukocytoclastic
vasculitis are evident.
by both endemic and epidemic variants.4 The incidence among Japanese

children is 16–150/100 000/ year whereas in white children the incidence is
6–10/100 000/year.4,6 The incidence of reported disease in the United States
is rising but has been attributed to increased physician awareness.7,8 The
syndrome shows a male predominance and occurs most frequently in children
aged 6–18 months.9 Adults are only rarely affected.10–12 Kawasaki syndrome
is thought to have an infectious etiology on the basis of symptoms of fever
and exanthem, age distribution, seasonality (peaks in winter and spring), and
occurrence of community-wide epidemics.13
Clinical features
The diagnostic features of Kawasaki syndrome are summarized in Table 16.6
and include:
Fig. 16.59
Churg-Strauss syndrome: this florid example shows a granulomatous infiltrate
• a spiking fever unresponsive to antibiotic therapy,
containing prominent giant cells. By courtesy of E. Wilson Jones, MD, Institute of
• an erythematous polymorphic cutaneous eruption (Fig. 16.61),
Dermatology, London, UK. • erythema, edema, and induration of the extremities followed by
cutaneous desquamation of the tips of the fingers and toes (Fig. 16.62),
• Patients with Wegener's granulomatosis present with ulceroproliferative

lesions of the upper respiratory tract, chest pain, and hemoptysis rather
Table 16.6
than asthma.
Kawasaki syndrome: diagnostic guidelines
• Marked eosinophilia is uncommon in Wegener's granulomatosis.
Churg-Strauss granulomata may be seen in Wegener's granulomatosis; • Fever lasting ≥ 5 days plus
however, the necrosis is more often of the tuberculocoagulative type. • Polymorphous rash
Granulomatous vasculitis is not a feature of Churg-Strauss syndrome. • Bilaterial conjunctival injection
It must be stressed that Churg-Straus granulomata should not be taken as • At least one of the following changes of the mucosal membranes:
pathognomonic for Churg-Strauss syndrome. Churg-Strauss granulomata, or – erythema or fissuring of the lips
– strawberry tongue
nearly identical lesions, have been described in the setting of other systemic
– diffuse injection of oral and pharyngeal mucosa
diseases including rheumatoid arthritis, lupus erythematosus, other forms
of vasculitis (Wegener's granulomatosis, polyarteritis nodosa, Takayasu's • Acute non-purulent cervical lymphadenopathy (at least one node
arteritis), lymphoproliferative disorders, Crohn's disease and ulcerative ≥ 1.5 cm)
colitis, bacterial endocarditis, and hepatitis.35,58–62 • At least one of the following changes of the peripheral extremities:
– erythema of palms and soles
– indurative edema of hands and feet
Mucocutaneous lymph node syndrome – membranous desquamation from fingertips
Mucocutaneous lymph node syndrome (Kawasaki syndrome) is a multisystem Fever plus four of the above criteria must be present for a secure diagnosis; other
illness that can present with similar clinical findings must be excluded.
disease that predominantly affects infants and young children.1–5 Although it
Reproduced with permission from Wortman, D.W. (1992) Seminars in Dermatology, 11,
was first described, and shows a marked preponderance, in Japan, it has been 37–47.
diagnosed worldwide and in all races. Kawasaki syndrome is characterized
Fig. 16.61 Fig. 16.63

Kawasaki syndrome: erythematous macular eruption. By courtesy of W.G. Phillips, Kawasaki syndrome: the lips are erythematous and swollen. Angular cheilitis is
MD, Institute of Dermatology, London, UK. evident. By courtesy of J. Ross, MD, Lewisham Hospital, London, UK.
Fig. 16.62 Fig. 16.64

Kawasaki syndrome: the tongue shows intense erythema. By courtesy of J. Ross,
Kawasaki syndrome:
MD, Lewisham Hospital, London, UK.
desquamation of the
skin of the toes is a
characteristic finding.
By courtesy of J. Ross, Cervical lymphadenopathy affects 50–75% of patients and may be
MD, Lewisham Hospital, unilateral or bilateral and involves one or a group of nodes.
London, UK. Cardiovascular involvement is characteristic and is the most important
cause of morbidity and mortality.2 Some 50% of patients show evidence of
myocarditis, which may progress to congestive cardiac failure. Pericardial
• oropharyngeal mucosal changes including edema, erythema, and fissuring effusion (subclinical) is not uncommon. Of particular significance is the
of the lips, erythema of the cheeks, and a strawberry (scarletiform) development of coronary artery ectasia or aneurysm, a feature that develops
tongue (Figs 16.63, 16.64), in 15–25% of patients, which may be complicated by coronary artery
• bilateral, nonexudative conjunctivitis, ischemia, thrombosis, and infarction. In 2% of patients, it proves fatal.12
• nonsuppurative cervical lymphadenopathy. In a very large follow-up study of 594 patients, the incidence of coronary
In an appropriate clinical context, children are judged to have Kawasaki artery aneurysm was 25%.17 Angiographic evidence of regression was seen
syndrome if they show a high fever plus four of the signs described above.4,14 in 55% of patients.17 There is an inverse relationship between the size of
More recently, this has been amended to include coronary artery aneurysm the aneurysm and the likelihood of resolution: large aneurysms, especially
plus three of the above features.4 giant aneurysms (defined as greater than 8.0 mm), tend to persist, or become
The cutaneous findings are variable and include erythematous, macular, obstructed or stenotic.18
maculopapular (morbilliform), urticarial, pustular, erythema multiforme- Gastrointestinal involvement presents as abdominal pain, vomiting,
like (targetoid), and erythema marginatum-like lesions.2,15 A vesiculopustular and diarrhea. Liver lesions may result in abnormal liver function tests and,
eruption has also been reported.16 The skin lesions show a propensity for the less often, jaundice. Pancreatitis and hydrops of the gallbladder are seen in
trunk and extremities, but may be more generalized. A diffuse, erythematous approximately 10% of patients.2
macular or plaquelike eruption involving the perineum is said to be Neurological symptoms develop in about 30% of patients and include
characteristic.5 This can be pruritic or painful and typically desquamates. features of aseptic meningitis, seizures, and transient paralyses.2 Arthralgias
Granuloma faciale 681
Fig. 16.65
Kawasaki syndrome:
disease in an adult is Fig. 16.66
very rare. In this patient, Kawasaki syndrome: in this example, the features of severe, acute leukocytoclastic
the erythema particularly vasculitis are present in the superficial dermis. This is an uncommon finding. By
affects the buttocks courtesy of W.G. Phillips, MD, Institute of Dermatology, London, UK.
and thighs. By courtesy
of W.G. Phillips, MD,
The histopathological features of cutaneous lesions in Kawasaki disease
London, UK.
are often non-specific and comprise severe edema of the papillary dermis
accompanied by vascular dilatation, endothelial cell swelling and degeneration
associated with a superficial perivascular mononuclear infiltrate.5 Immuno
and arthritis are present in up to 30–40%, although chronicity is not a pathological studies have shown the infiltrate is usually composed of CD4+
feature. Renal involvement manifests as sterile pyuria, hematuria, and T lymphocytes and macrophages.30 Occasionally, however, the features of a
infarction. leukocytoclastic vasculitis are evident (Fig. 16.66). The epidermis may show
The features of adult Kawasaki syndrome are essentially those described mild basal cell degeneration.5 Vesiculopustular lesions develop on the basis of
above and are illustrated in Figure 16.65. Coronary artery aneurysm, subcorneal spongiform pustulation.9
however, appears to be a less common complication.10 It is important to Systemic lesions are characterized by necrotizing vasculitis.19,31,32 Aneurysm
differentiate this condition from staphylococcal toxic shock syndrome.19 with mural thrombus formation may be evident in advanced lesions.
Occasionally, patients develop a relapse, which may occur years after Lymph node involvement includes vasculitis, focal necrosis, and
initial disease and resolution.20 infarction.
Pathogenesis and histological features Differential diagnosis

The etiology of this disease is unknown. Recent evidence points to an The mucocutaneous manifestations of Kawasaki disease show considerable
immunoregulatory defect of T cells stimulated by superantigen-producing overlap with those seen in the toxic shock syndrome, which is not surprising,
strains of Streptococcus pyogenes and Staphylococcus aureus.19,21,22 given that they appear to share a similar pathogenesis. Palmoplantar
Superantigens are a class of microbial antigens that are thought to be capable erythema, cutaneous desquamation, conjunctivitis, and pharyngitis are
of stimulating a large number of naive T cells in a non-specific manner by therefore common to both.33 The toxic shock syndrome (which is due to a
binding to histocompatibility antigens on antigen-presenting cells leading to staphylococcal exotoxin complicating constant tampon use in menstruating
T-cell activation. Superantigens have been postulated to play a role in the females) is, however, not associated with systemic vascular involvement.
pathogenesis of a number of skin diseases in addition to Kawasaki syndrome, Histologically, it is characterized by a mild, superficial, perivascular
such as atopic dermatitis, psoriasis and toxic shock syndrome. However, in lymphocytic infiltrate associated with edema of the papillary dermis and no
one study, superantigen-producing bacteria were found in 56% of cultures evidence of vasculitis.34
(taken from throat, rectum, and groin) from patients with Kawasaki syndrome
compared with 35% of controls with positive culture.23 These differences did
not achieve statistical significance. Another study found strains of streptococci Granuloma faciale
and staphylococci in the jejunum of patients with Kawasaki syndrome but
not in controls.24 These same authors, in a follow-up study, found V beta Clinical features
2+ T cells selectively increased in small bowel mucosa of Kawasaki patients Granuloma faciale is a localized form of leukocytoclastic vasculitis of
compared with control subjects.25 Clearly, further research is necessary to uncertain pathogenesis. Although children may be affected, most cases occur
elucidate the precise pathogenesis of Kawasaki disease. in people who are middle aged or older. There is predilections for males.1
Other infectious agents that have been implicated in the pathogenesis Lesions occur most commonly on the face and are single or more often
of Kawasaki disease include retroviruses, rickettsiae, spirochetes and multiple, erythematous or brownish red, soft discrete papules, plaques or
Propionibacterium acnes.5,26 Additionally favored hypotheses include nodules up to several centimeters in diameter (Fig. 16.67).2–4 The surface
exposure to house mites and recently cleaned or shampooed carpet, living in often shows dilated follicles and fine telangiectasia (Fig. 16.68). Common
close proximity to open water or complicating a recent respiratory illness.13 It sites include the nose, malar prominence, forehead, and ear (Fig. 16.69).
is possible that Kawasaki syndrome represents a vasculitic disorder developing A case simulating rhinophyma has been documented.5 Extrafacial lesions may
as a consequence of multiple infectious agents. occur on the extremities, neck, chest, and scalp (Fig. 16.70).1,6–13 Although
Of interest, there is a growing body of literature reporting Kawasaki often asymptomatic, patients sometimes report symptoms of mild pruritus or
disease, or a Kawasaki-like syndrome, in patients infected with the human stinging. There is no evidence of associated systemic involvement. Granuloma
immunodeficiency virus.27–29 faciale tends to chronicity and is typified by periods of relapse and partial
Fig. 16.67
Granuloma faciale: multiple brown nodules. From the collection of the late N.P. Fig. 16.69
Smith, MD, the Institute of Dermatology, London, UK. Granuloma faciale: the
lesions are frequently
multiple. By courtesy of K.
Liddell, MD, Eastbourne
District Hospital, East
Sussex, UK.
Fig. 16.68
Granuloma faciale: the
face is a commonly
affected site. From the
of Dermatology, London, Fig. 16.70
UK. Granuloma faciale: there are multiple lesions on this patient's neck. By courtesy of
remissions. Treatment is very difficult and recurrences manifest after surgical
excision, even at the site of full-thickness grafting.14 non-specific. Immunohistochemistry shows the presence of abundant
A histologically similar lesion affecting the mucosa of the upper respiratory eosinophilic cationic protein.22 T-helper lymphocytes represent the main
tract has been designated ‘eosinophilic angiocentric fibrosis’. Concurrent nonmyelocytic cell in the infiltrate and it has been suggested that they play a
cases of granuloma faciale and eosinophilic angiocentric fibrosis have been role in the pathogenesis of the disease, being attracted to the site by gamma-
described.15–17 This suggests that the two diseases represent part of the same interferon.23
spectrum. Histologically, granuloma faciale is characterized by a dense cellular
Granuloma faciale has been documented in a patient with prostate infiltrate, which often has a nodular outline (Fig. 16.71).24 This infiltrate
carcinoma.18 Any relationship with tumors is likely to be coincidental. usually occupies the mid dermis, although the deep dermis and the subcutaneous
fat may be involved; it typically spares the immediate subepidermis and hair
Pathogenesis and histological features follicles, forming a ‘grenz zone’ (Fig. 16.72). The infiltrate is polymorphic,
Examination of lesional biopsies by immunofluorescence reveals granular being composed of large numbers of eosinophils, neutrophils (often displaying
IgG and complement along the epidermal–dermal junction, outlining the leukocytoclasis), and an admixture of plasma cells, mast cells, and lymphocytes
hair follicles, and also within the walls of blood vessels; less often IgA (Fig. 16.73).25 Red cell extravasation is often present. Blood vessels, which
and IgM are present, and there is abundant fibrin.19–21 Granuloma faciale often appear increased in number, are dilated and may show infiltration of
is, therefore, a chronic vasculitis and may be immune complex mediated. their walls by eosinophils with fibrin deposition (Fig 16.74). Diagnostic
However, some authors consider the above immunofluorescence findings features of vasculitis, namely inflammation of vessel walls associated with
Granuloma faciale 683
Fig. 16.71 Fig. 16.74

Granuloma faciale: a dense inflammatory cell infiltrate is present in the dermis. Granuloma faciale: this dilated blood vessel shows marked endothelial swelling,
Note the conspicuously spared grenz zone. fibrin deposition, and disruption of its wall.
Fig. 16.72 Fig. 16.75

Granuloma faciale: close-up view of grenz zone. Granuloma faciale: there is a well-developed storiform pattern.
fibrinoid change, may be difficult to identify in some lesions. In other cases,

fibrin is widely distributed in the dermis. Older lesions may show fibrosis and
hemosiderin deposition.1 The microscopic picture in late stages overlaps with
that seen in erythema elevatum diutinum (Fig 16.75).1
An ultrastructural study of a case of granuloma faciale has shown that the
cytoplasmic granules in the eosinophils display alterations and Langerhans
cells are absent.26
The morphological features of granuloma faciale are distinctive. The presence
of a mixed infiltrate with a grenz zone distinguishes it from neutrophilic
dermatoses and leukocytoclastic vasculitis. Erythema elevatum diutinum,
another form of localized vasculitis, tends to be located on the extensor
surfaces of the extremities and shows more sclerosis, more neutrophils,
and fewer eosinophils. The presence of large numbers of eosinophils may
raise the possibility of a Langerhans cell proliferative disorder; however, the
presence of only scattered Langerhans cells and a grenz zone (Langerhans cell
proliferative disorders tend to be epidermotropic) with significant numbers of
neutrophils favors granuloma faciale. The grenz zone also helps to distinguish
Fig. 16.73 granuloma faciale from hypersensitivity reactions such as to an arthropod
Granuloma faciale: the infiltrate contains large numbers of eosinophils as well as bite. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma)
lymphocytes, histiocytes, and occasional polymorphs and plasma cells. is distinguished by the presence of highly unusual thick-walled blood vessels
with prominent endothelial cells. An exceptional case of infection by

Trichophyton rubrum with histology mimicking that of granuloma faciale
has been documented.27
Histological features identical to those of granuloma faciale may be seen
in patients presenting with a solitary lesion (papule, nodule or plaque) that
does not have the clinical appearance or location typical of the disease. The
histological picture in these cases has been described as chronic fibrosing
vasculitis. As there is also histological overlap with erythema elevatum
diutinum, it has been suggested that the microscopic appearances represent
a non-specific inflammatory reaction pattern.28 Therefore, establishing the
diagnosis requires close clinicopathological correlation.
Erythema elevatum diutinum

Clinical features
This uncommon disease represents a localized variant of leukocytoclastic
vasculitis.1–3 Although it can occur in any age group, patients are usually in
their third to fifth decade.4 Incidence is equal in men and women. Patients
present with papules and nodules measuring up to about 1 cm in diameter; Fig. 16.77
Erythema elevatum diutinum: the extensor surfaces are commonly affected. From
they may also develop round or oval, indurated, elevated plaques 5–6 cm in
diameter. Lesions are red or purple, although some have a yellowish tinge,
which may be confused with a xanthomatous process. Bullous lesions are
occasionally present and an annular distribution has been reported.1,5,6 The An association with paraproteinemia is frequently present, often of the
disease is characteristically persistent and the distribution of the lesions often IgA subtype.1,13,14 Hyperimmunoglobulinemia D syndrome is a further rare
symmetrical. Large nodules resembling keloids or tumor are sometimes association.15 An underlying myelodysplastic syndrome or a hematological
found.7,8 malignancy (e.g. multiple myeloma, B cell lymphoma, and chronic
Lesions are located particularly in relation to the extensor surfaces of the lymphocytic leukemia) has been found in some patients.1,16–19 Often, the skin
joints and are, therefore, seen on the backs of the hands and fingers, wrists, lesions precede development of the hematological disorder.1 In one study, an
elbows, knees, ankles, and toes (Figs 16.76, 16.77). The buttocks may also average of 7.8 years separated onset of skin lesions and development of a
be affected, but the trunk is usually spared.9 We have observed a case with myeloproliferative disorder.1,20
oral involvement. Although lesions are often asymptomatic, some patients Erythema elevatum diutinum has rarely also been associated with other
complain of itching and pain, and symptoms are frequently made worse in a malignancies such as pulmonary lymphoepithelioma-like carcinoma and
cold environment. Patients sometimes also have arthralgia. Eye involvement breast carcinoma.21,22
includes keratolysis and ulcerative keratitis with positive rheumatoid Inflammatory bowel disease – both Crohn's disease and ulcerative colitis –
factor.10,11 Although the disease is chronic and progressive, resolution usually has also been associated with erythema elevatum diutinum.23–25 Interestingly,
occurs by 5–10 years. The disease characteristically responds to dapsone. in one patient with Crohn's disease, skin lesions seemed to appear during
Systemic involvement does not usually occur but pulmonary infiltrates exacerbation of bowel symptoms.23 In another patient with ulcerative colitis,
have exceptionally been documented.12 onset of erythema elevatum diutinum lesions coincided with presentation of
bowel disease, and skin lesions resolved following colectomy.24 Erythema
elevatum diutinum has also been reported in association with celiac
disease.26–28 In one patient with celiac disease, skin lesions resolved with the
introduction of a gluten-free diet.27
Rheumatoid arthritis has been described in conjunction with erythema
elevatum diutinum.29–31 Other reported associations include Wegener's
granulomatosis, relapsing polychondritis and pyoderma gangrenosum,
cutaneous lupus erythematosus, nodular scleritis and panuveitis, Hashimoto's
thyroiditis, juvenile idiopathic arthritis, and Sjögren's syndrome.32–40 Erythema
elevatum diutinum is also seen in patients with HIV infection.41–46 In HIV-
infected patients, lesions may mimic Kaposi's sarcoma.41 Extensive acro-
osteolysis has been described in a single case.47 The exceptional association
with pityriasis rubra pilaris and mosquito bites is probably coincidental.48
A condition described as ‘neutrophilic dermatosis of the dorsal hands’ is
likely to be part of the spectrum of erythema elevatum diutinum.49

Erythema elevatum diutinum is possibly immune complex mediated. Both
a streptococcal antigen and Escherichia coli have been implicated.2,50 As
mentioned above, the disease has also been recorded in association with
cryoglobulin IgA, monoclonal or biclonal gammopathy, multiple myeloma,
Fig. 16.76 hairy cell leukemia, and polycythemia rubra vera.1,51–53 In addition, IgA
Erythema elevatum
antineutrophil cytoplasmic antibodies (ANCA) and less frequently IgG ANCA
diutinum: tuberose
nodules present on the
have been identified in patient's serum.54 In early lesions, there is increased
elbow. From the collection expression of the beta (2)-integrins CR3 and LFA-1 and this diminishes in
of the late N.P. Smith, older lesions.55 Peripheral blood neutrophils show increased migration in
MD, the Institute of response to interleukin-8 (IL-8) and decreased responsiveness to the bacterial
Dermatology, London, UK. peptide analogue N-formyl-methionyl-leucyl-phenylalanine. These findings
Erythema elevatum diutinum 685
Fig. 16.79
Fig. 16.78 Erythema elevatum diutinum: older lesion showing scar tissue with a vaguely
Erythema elevatum storiform growth pattern.
diutinum: early lesion
showing leukocytoclastic
vasculitis in a background be found after examination of multiple sections (Fig. 16.79). In ‘burnt out’
of a Sweet's syndrome- lesions, vasculitis may not be present. Granulation tissue and dense scarring
like neutrophil infiltrate. mark the site of the previous acute inflammatory process. In older lesions
the scarring often shows a storiform pattern (Fig. 16.80). Interstitial lipid
suggest that in erythema elevatum diutinum the recruitment of neutrophils deposition described in the past as extracellular cholesterolosis is uncommon.
occurs as a result of activation of cytokines such as IL-8.55 Immune complexes In ocular lesions, leukocytoclastic vasculitis with focal granulomatous
and bacterial peptides sustain the persistent local inflammatory response.55 inflammation has been described.11
Biopsy of early lesions reveals typical features of leukocytoclastic vasculitis Rare histopathological features described include palisaded necrotizing
(Fig. 16.78).1,56 The epidermis may show acanthosis and parakeratosis. granuloma and pyogenic granuloma-like features.48
Fibrinoid necrosis and infiltration of the superficial vessels by neutrophil
polymorphs are present. The perivenular connective tissue contains abundant Differential diagnosis
fibrin and a dense inflammatory cell infiltrate of neutrophils, histiocytes, Erythema elevatum diutinum typically involves the dermis and must,
lymphocytes, and eosinophils. Leukocytoclasis is usually evident. therefore, be distinguished from granuloma faciale. Granuloma faciale
Older lesions are characterized by the development of granulation tissue usually shows an eosinophil predominance whereas in erythema elevatum
and fibrous scarring, although even then, foci of neutrophilic vasculitis may diutinum neutrophils are much more numerous. However, the histological
Fig. 16.80
(A, B) Erythema elevatum diutinum: this example was clinically thought to
represent a keloid. There is a circumscribed dermal nodule composed of spindle
A cells in a hyalinized stroma. Focally perivascular nuclear debris is evident and
there are scattered eosinophils.
features of late lesions in both entities often overlap and similar appearances Table 16.8
are found in chronic fibrosing vasculitis. The latter represents a non-specific Behçet's disease: diagnostic criteria*
reaction pattern that is occasionally seen in solitary lesions from patients who
have no clinical features of either granuloma faciale or erythema elevatum Criterion Definition
diutinum.57 Distinction from Sweet's syndrome is afforded by the presence of Recurrent oral Minor aphthous, major aphthous, or
neutrophilic vasculitis. Older sclerotic lesions, particularly when they present ulceration herpetiform ulceration observed by physician
as mass lesions, may be mistaken for a neoplastic process or dermatofibroma.8 or patient, and recurrent at least three times
The presence of a leukocytoclastic vasculitis and neutrophilic infiltrate with in one 12-month period
karyorrhexis favors erythema elevatum diutinum. Plus two of:
Recurrent genital Aphthous ulceration or scarring, observed by
Behçet's disease ulceration physician or patient
Eye lesions Anterior uveitis, posterior uveitis or cells in
Clinical features vitreous on slit lamp examination
This rare disease was originally described as a combination of recurrent oral or
Retinal vasculitis observed by
and genital ulceration associated with uveitis. However, it is now known
ophthalmologist
to represent a systemic illness with lesions involving the joints and central
nervous, vascular, respiratory, gastrointestinal, and urogenital systems, in Skin lesions Erythema nodosum observed by physician or
addition to mucous membranes and integument (Table 16.7).1–7 Although it patient, pseudofolliculitis or papulopustular
lesions; or acneiform nodules observed
is seen worldwide, it has a high incidence in Japan, Southeast Asia, the Middle
by physician, patient not on corticosteroid
East, Turkey, and some countries bordering the Mediterranean. Behçet's treatment
disease shows a male predominance and most commonly presents in young
adults with a peak incidence of onset in the third decade.8 Children may Positive pathergy test Read by physician at 24–48 hours
also be affected with an approximately equal sex incidence.9 One study has * Findings applicable only in the absence of other clinical explanations.
suggested that the disease is less aggressive in children.10 Some data appear to Reprinted with permission from Elsevier (International Study Group for Behçet's
indicate that males have a higher mortality rate.11 Disease (1990) Lancet, 335, 1078–1080).
The International Study Group established diagnostic criteria for Behçet's
disease in 1990 and these are summarized in Table 16.8.4 It should be kept
in mind that these criteria are somewhat controversial.12 More research is
necessary before we can fully understand this complex disease.
Recurrent oral ulceration is an invariable feature. Some patients have a
long history of oral ulceration before developing other features that allow
for a definitive diagnosis of Behçet's disease. Ulcers typically measure up to
1 cm across but may be larger. They develop anywhere in the oral cavity,
in the pharynx, and even in the larynx (Fig. 16.81).13 They are exquisitely
painful, and usually regress spontaneously within 14 days although they can
persist for much longer. A yellow, necrotic crust covers the ulcer floor. Some
patients develop ulcerations in a herpetiform configuration.14 Patients with
larger ulcers tend to have greater severity of oral disease with more frequent
relapses.14
Cutaneous lesions are common, recurrent, and comprise a wide variety of
manifestations including erythema nodosum-like lesions, usually on the lower
extremities.15,16 Patients may also develop acneiform papules and pustules,
furuncles, pyoderma, and thrombophlebitis (Fig. 16.82). In one very large
study, papulopustular lesions (followed by erythema nodosum-like nodules)
were the most commonly encountered skin manifestation.7 Patients have also
been described with Sweet's syndrome-like features.17
Fig. 16.81
Behçet's disease: superficial ulcers are present on the inner aspect of both lips. By
Table 16.7 courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Behçet's disease: frequency of organ involvement
Typical of Behçet's disease, and an important diagnostic clue, is

Sign or symptom Incidence (%) development of sterile pustules at sites of mild skin trauma such as injection
Oral ulcers 90–100 sites (pathergic response) (Fig. 16.83).18,19 Paradoxically, some authors have
Genital ulcers 64–88 found that wound healing after 4 mm punch biopsy does not seem to differ
compared with control subjects.20
Ocular lesions 27–90
Genital lesions, similar in appearance to those of the oral mucosa, occur
Cutaneous lesions 48–88 on the scrotum, penis, vagina, and vulva (Figs 16.84, 16.85).7
Joint manifestations 18–64 Ocular involvement is important because, if left untreated, it may
Neurological features 10–29
progress to cataracts and blindness. Both eyes are affected in the majority of
patients. Almost any part of the eye is affected and bilateral inflammation
Intestinal manifestations 0–59 of the anterior segment (anterior uveitis), posterior uveitis with hypopyon
Thrombophlebitis 10–37 and vitritis are said to be pathognomonic.21,22 Uveitis is more common and
is associated with a more severe clinical course in males potentially leading
Reproduced with permission from Arbesfield, S.J. and Kurban, A.K. (1988) Journal
to loss of vision.22 Conjunctivitis, corneal ulceration, choroiditis, and retinal
of the American Academy of Dermatology, 19, 767–779. Copyright © The American
Academy of Dermatology, Inc. vessel involvement (arterial and venous vasculitis) are sometimes additional
features.
Behçet's disease 687
Fig. 16.82
Behçet's disease: typical pustules on the lower leg. By courtesy of R.A. Marsden, Fig. 16.84
MD, St George's Hospital, London, UK. Behçet's disease: there
is a typical scrotal ulcer
with central slough. By
courtesy of D.A.H. Yates,
London, UK.
Fig. 16.83
Behçet's disease: this ruptured pustule developed at the site of a previous
venipuncture. Such a positive provocation test is virtually pathognomonic for Behçet's
disease. By courtesy of D.A.H. Yates, MD, St Thomas' Hospital, London, UK.
Joint involvement is not uncommon and usually affects the knees, ankles,
elbows, and wrists.23 A mono- or oligoarticular pattern is typical. The affected Fig. 16.85
joints are swollen, red, tender, and painful. It is of interest that despite many Behçet's disease: multiple
years of arthritic symptoms, joint deformities do not develop. superficial vulval ulcers
Vascular disease in Behçet's disease takes the form of both thrombo- are present. By courtesy
occlusive disease and frank vasculitis. Vascular involvement is an important of R.A. Marsden, MD,
cause of both morbidity and mortality and is seen in approximately one-third St George's Hospital,
of patients.24,25 Males appear to be at an increased risk.25 Thrombophlebitis is London, UK.
common and can affect both superficial and deep veins of the limbs. Superior
and inferior vena caval obstruction are not uncommon complications. A
particularly perilous form of vascular involvement is hepatic vein occlusion Intestinal involvement particularly affects the ileocecal region; ulcers may
(Budd-Chiari syndrome), which is associated with a high mortality.26 be complicated by perforation, presenting as an intra-abdominal emergency
Pulmonary artery aneurysm occurs in approximately 1% of patients and is necessitating surgical intervention.30 The esophagus is uncommonly affected
associated with a 50% mortality rate.27,28 by ulcers and erosion, stenosis or esophagitis.31
The inflammation may affect virtually any artery and the development of Involvement of the nervous system, which is associated with a poor
an aneurysm with subsequent rupture is an important cause of death. prognosis, occurs in up to 25% of patients.24 Lesions develop anywhere in the
Respiratory involvement presents as dyspnea, cough, pleuritic chest central and peripheral components and, therefore, virtually any neurological
pain, and hemoptysis.29 The last, due to pulmonary artery–bronchial fistula sign or symptom may be seen, including sensory losses, strokes, and spinal
formation, is an important cause of death. Lung involvement occurs in up to cord, cranial and peripheral nerve lesions. Dural sinus thrombosis is a well-
5% of patients.29 recognized complication.32
The kidney is affected in up to 55% of patients and manifestations include

amyloidosis, glomerulonephritis, interstitial nephritis, and vasculitis.33
A study of relative organ system involvement has led to a subclassification
of a spectrum of Behçet's disease.34,35 The mortality of Behçet's disease is,
however, surprisingly low, of the order of 2–4%.

The precise etiology and pathogenesis are unknown. Recent interest has
focused on the possibility of an altered immune response in patients with
Behçet's disease. It has been suggested that heat shock proteins may play an
important role in its pathogenesis.36,37 They have been found to be elevated
in serum together with increased levels of vascular endothelial growth factor
(VEGF) and antiphospholipid antibodies independent of disease activity.38
Heat shock proteins reactive in Behçet's patients induce uveitis in rats.37
Increased VEGF levels correlate significantly with the presence of vascular
or ocular disease.38 Oligoclonal expansion of T cells in some patients with
Behçet's disease has been documented.39 In one study, serum IL-12 and
peripheral Th1 lymphocyte levels correlated with disease activity.40
Complement components C3 and C9 have been identified in blood vessel
Fig. 16.87
walls in oral biopsies.35 Increased interleukin levels associated with increased Behçet's disease: there is florid suppurative acute folliculitis.
B-cell activity have also been described.41 Of possible importance in the
pathogenesis is the frequent presence of high levels of circulating immune
complexes and the common detection of immunoglobulins (particularly
IgM) and complement in blood vessel walls.42–44 Behçet's disease is associated lesions, acute folliculitis, and acneiform folliculocentric pustular changes (Fig.
with human leukocyte antigen (HLA)-B5, -B12, -B27, and particularly with 16.87).12,49,50 Biopsy after needle trauma in one study showed a neutrophilic
HLA-BW51.24 Anticardiolipin antibodies have been described.24 infiltrate with intraepidermal pustules. Vasculitis was not seen in pathergic
Despite the accumulation of considerable immunological and genetic data, lesions in this study.51 Other authors have found that the pathergic lesions may
the underlying antigen or other stimulus that drives these changes, and is show leukocytoclastic vasculitis or Sweet's syndrome-like features.18
ultimately responsible for the disease, remains elusive. The erythema nodosum-like lesions correspond to necrotizing vasculitis
The histological features are in themselves largely non-specific.35,41,45,46 of the subcutaneous vessels, usually associated with thrombosis. Septal and
The diagnosis of Behçet's disease is essentially clinical. The pathological lobular panniculitis have also been described.13 Superficial thrombophlebitis
features that may be detected include both lymphocytic and necrotizing is present in up to 30% of patients (Fig. 16.88).34 Oral lesions and genital
vasculitis affecting the superficial postcapillary venules with associated ulcers show non-specific ulceration, accompanied in some instances by
fibrinoid necrosis (Fig. 16.86).45 In one study, nearly 50% of patients had leukocytoclastic or lymphocytic vasculitis.
evidence of vasculitis.47 Often, however, such vasculitic changes appear to be Pulmonary involvement is characterized by pulmonary artery vasculitis,
a consequence, rather than a cause, of the dermal or mucosal inflammatory sometimes also affecting the veins and capillaries.29 Thrombosis, infarction,
changes.46 Endothelial swelling may be a feature and there is often an hemorrhage, and the development of aneurysm are important sequelae. The
associated lymphocytic perivascular infiltrate although sometimes neutrophils inflammation is usually transmural and may be associated with damage to the
are abundant.48 Venulitis and phlebitis were the most common forms of associated elastic tissue. Older destructive vascular lesions are characterized
vasculitis seen in one series of patients.12 In this study, phlebitis/venulitis was by fibrous scarring.
seen in 48% of patients while leukocytoclastic vasculitis and lymphocytic Cerebral lesions in the early stage are characterized by a perivenular
vasculitis were seen in 17% and 31% of patients, respectively.47 lymphocytic infiltrate. In the more advanced lesions there is extensive
Non-specific features include a diffuse neutrophil polymorph dermal demyelination resembling multiple sclerosis.24
infiltrate with or without abscess formation, corresponding clinically to pustular
Given the myriad non-specific histological manifestations that Behçet's
disease may produce, it comes as no surprise that the histological differential
diagnosis is usually broad. The authors of one large study stated that clinical
data are most important in establishing a diagnosis and suggested that the
role of biopsy is to confirm the clinical impression.7 Others propose that
biopsy is critical to evaluate for vessel-based pathology as clinical distinction
from pustular (non-vascular) lesions may be important.12 It is likely that the
criteria for diagnosis of Behçet's disease will continue to be refined.
The differential diagnosis includes other causes of folliculitis, infection,
erythema nodosum, connective tissue disease, neutrophilic and lymphocytic
vasculitis, and neutrophilic dermatoses. There are no pathognomonic
histological changes. Both clinical and pathological data must be considered
before arriving at a final diagnosis.7
Thromboangiitis obliterans
Clinical features
Thromboangiitis obliterans (Buerger's disease) is most often seen in young
adults and is much more common in males than in females.1 However, the
Fig. 16.86 ratio of men to women is shifting, with the disease becoming more common
Behçet's disease: this field shows a superficial vulval ulcer with an intense in women.2,3 In one large study, 23% of patients were female.2 In addition,
neutrophilic infiltrate and changes of acute vasculitis. the disease is seen more frequently in older patients.2 Buerger's disease occurs
Temporal arteritis 689
Fig. 16.89
Buerger's disease: digital gangrene is present in this amputation specimen.
products are toxic to endothelial cells or elicit immune reactions that

damage vessels. Of interest, the disease has been described in patients who
use smokeless tobacco.20 Antiendothelial antibodies are elevated in a subset
of patients with Buerger's disease.21 Furthermore, disease activity correlates
with antiendothelial cell antibody titers.21 Response to acetylcholine, an
endothelium-dependent vasodilator, is diminished in ‘nondiseased’ extremities
of Buerger's patients compared with control subjects.22 IgG, IgM, and IgA are
present along the internal elastic lamina.23
Lesions are characterized by thrombosis of small or medium-sized
arteries and, less commonly, veins associated with a variable inflammatory
infiltrate composed of a mixture of neutrophils, lymphocytes, eosinophils,
B histiocytes, and giant cells.19,24 Immunohistochemical studies have confirmed
the heterogeneous nature of the infiltrate. T cells, B cells, macrophages, and
Fig. 16.88 dendritic cells may all be present.23 CD4-positive T cells outnumber CD8-
(A, B) Behçet's disease: this section shows thrombophlebitis involving a vein in the positive cells and T cell-mediated inflammation appears to be of significance
subcutaneous fat. The vessel is infiltrated by large numbers of lymphocytes. in the development of the disease.25 A characteristic finding is the presence of
a microabscess associated with an intraluminal thrombus. Inflammatory cells
may be seen in all layers of the vessel wall (Fig. 16.90). Preservation of the
almost exclusively in smokers. Although most patients are considered ‘heavy’ internal elastic lamina is a typical feature.19
smokers, some smoke less than a pack of cigarettes a day.4 In fact, some As lesions age, thrombi become organized and are replaced by fibrosis, and
authors view a history of smoking a necessary criterion for diagnosis. In eventually the vessel is recanalized (Fig. 16.91). A definitive diagnosis based
one study from Japan, nonsmokers with Buerger's disease were more likely on biopsy findings is not possible during the later stages of organization.
to be women.5 In Bangladesh, smoking bidis (a hand-rolled, additive-free,
unprocessed form of tobacco) is particularly associated with this disease.6 Differential diagnosis
The worldwide incidence of Buerger's disease differs dramatically from The histopathological features are probably not specific for Buerger's disease,
region to region. For example, the incidence is 50-fold greater in Nepal and differential diagnosis includes other thrombotic vasculopathies. Clinical
compared with North America.7 This disease has its highest prevalence in correlation is advised before rendering a definitive diagnosis. Preservation
Eastern Europe, the Middle East, and Asia. Patients most often present with of the internal elastic lamina is a characteristic feature and is said to help in
painful cyanotic lesions of the extremities, especially the fingers or toes, which distinction from other vasculitides.19,26
may ulcerate and become gangrenous (Fig. 16.89). Sensitivity to cold is a
common complaint.
Resolution of disease usually follows cessation of smoking.8,9 Patients who Temporal arteritis
continue to smoke suffer autoamputation of digits and distal extremities.
In one study, only 2% of patients who quit smoking had amputations. In Clinical features
contrast, 42% of those that continued to smoke required amputation.2 Temporal arteritis (giant cell arteritis) is a disease of the elderly that shows
In most patients, the disease is limited to the extremities; however, some a marked female predominance (3:1).1,2 It is a generalized vasculitis that
patients develop visceral involvement,10–13 and this can prove fatal.10 The predominantly affects large and medium-sized arteries.3 It is mainly seen in
vessels of the brain, intestine, heart, kidney, and lung may therefore be Caucasians and its etiology is unknown.2,3
affected.14–17 Occasional patients have involvement of multiple organs.18 Five of the American College of Rheumatology 1990 criteria are outlined
in Table 16.9.1 Classically, the temporal arteries are primarily affected,
Pathogenesis and histological features but giant cell arteritis may also affect the occipital or facial arteries and,
The pathogenesis of Buerger's disease is poorly understood. Clearly, the in fact, has the potential to involve virtually any medium-sized or large
strong association with smoking suggests that this habit plays an important vessel, including the aorta and its branches.3 Patients with giant cell arteritis
role in eliciting thrombosis and resultant ischemia.19 It is unclear if tobacco present with pyrexia, severe headache, and throbbing scalp pain. Clinical
A A
B B
Fig. 16.90 (A, B) Buerger's disease: this acute lesion shows pan-mural Fig. 16.91 (A, B) Buerger's disease: old lesion showing luminal obliteration and
inflammation with abscess formation and thrombosis. recanalization. Note the intact elastic lamina.
The vast majority of patients have an elevated ESR.16 C-reactive protein

examination may reveal scalp tenderness and the skin overlying the affected
is also typically elevated.16 Elevated levels of anticardiolipin antibodies are
vessel may be erythematous, edematous or appear bruised.4 Palpation
frequently present.17–20 Some studies suggest that the presence of anticardiolipin
often reveals a cordlike and nodular vessel. Pulsation can be diminished or
antibodies correlates with more severe vascular damage.19,20 In most patients,
absent.
anticardiolipin antibody titers return to normal range with steroid therapy.18
Visual disturbance due to involvement of the ophthalmic or retinal vessels
is an important complication which sometimes results in blindness. Lesions
of the central nervous system may result in stroke, subarachnoid hemorrhage
Table 16.9
or mental confusion, and aural involvement can cause deafness. In one large
1990 criteria for the classification of giant cell (temporal) arteritis (traditional
study, neurological problems were present in nearly one-third of patients.5
format)*
Peripheral neuropathic syndromes are evident in 14% of patients.4 Often the
associated lymph nodes are enlarged and tender. Symptoms of polymyalgia
rheumatica (i.e. stiffness, weakness, aching and pain in the muscles of the
Age at disease Development of symptoms or findings beginning at
neck, limb girdles, and upper limbs) are extremely common, occurring in up
onset ≥ 50 years age 50 or older
to 75% of patients.6 Laboratory investigations typically reveal mild anemia,
neutrophilia, and a very high ESR. Elevated levels of von Willebrand factor are New headache New onset of or new type of localized pain in the head
characteristic.7 Temporal artery Temporal artery tenderness to palpation or decreased
Cutaneous lesions other than those mentioned above are uncommon, abnormality pulsation, unrelated to arteriosclerosis of cervical arteries
presumably reflecting the vast collateral circulation of the integument.8,9 Elevated ESR ESR ≥ 50 mm/hour by the Westergren method
Patients may occasionally manifest ulcers (sometimes quite widespread),
Abnormal Biopsy specimen with artery showing vasculitis
massive necrosis, bullae, and gangrene (Fig. 16.92).10,11 Involvement of the
artery biopsy characterized by a predominance of mononuclear cell
lingual artery can cause glossitis or gangrene of the tongue.12,13 Masticatory
infiltration or granulomatous inflammation, usually
claudication is an additional feature. with multinucleated giant cells
Rare patients with disseminated visceral arteritis with giant cell arteritis-
like histological features have been described.14 The heart, lungs, kidneys, *For purposes of classification, a patient shall be said to have giant cell (temporal)
stomach, pancreas, and liver may be involved.14 It is debatable what arteritis if at least three of these five criteria are present. The presence of any three or
more criteria yields a sensitivity of 93.5% and a specificity of 91.2%.
terminology should be applied to such rare and unusual cases.
Reproduced with permission from Hunder, G.G. (1990) Arthritis and Rheumatism, 33,
Life expectancy does not seem to be adversely affected by having temporal 1122–1128.
arteritis.15
Temporal arteritis 691
Fig. 16.92
Giant cell arteritis: severe ischemic necrosis with ulceration has destroyed most
of this patient's scalp. By courtesy of D. McGibbon, MD, St Thomas' Hospital,
London, UK.

The pathogenesis of temporal arteritis is poorly understood. Although an
immunological mechanism has been suggested, it has not been proven. Evidence
of familial aggregation and an increased incidence of the HLA-DR4 antigen have
raised the possibility of a genetic influence.3 However, consistent reproducible
HLA associations have not been demonstrated in all populations.
It has been suggested that giant cell arteritis is an autoimmune disease
perhaps directed, at least in part, against the vascular elastic lamina.3
T cells in the infiltrate are predominantly of the helper subclass and B
expression of HLA-DR has been recorded, thereby suggesting that they
are activated.3 The lymphocytes have been shown to respond to antibodies Fig. 16.93
against transferrin and IL-2 receptors.21 Proliferation of mononuclear cells (A, B) Giant cell arteritis: this scalp biopsy showed multiple affected vessels.
following incubation in cultures containing elastin-derived peptides is By courtesy of P.A. Burton, MD, Southmead Hospital, Bristol, UK.
increased compared with control subjects.22 This finding suggests elastin-
derived peptides are the targets of T cells in giant cell arteritis.22 Disease
activity has been shown to correlate with plasma concentrations of IL-6.23
The demonstration by some authors of a fluctuating cyclical pattern of
incidence has raised the possibility of an infectious agent or other triggering
factor playing a significant pathogenetic role.24–26 A study from the Mayo Clinic
showed a variation in incidence with peak periods occurring approximately
every 7 years.24 Similarly, a study from Denmark demonstrated marked
variation in the incidence of temporal arteritis with five peak periods.26 Of
these, there appeared to be association with two epidemics of Mycoplasma
pneumoniae infection, two possibly related to erythrovirus (parvovirus)
B19 epidemics and one peak that may have been related to an epidemic
of Chlamydia pneumoniae.26 Another study showed a threefold increased
likelihood of infection in patients with temporal arteritis compared with
control subjects.27 An association between temporal arteritis and antibodies
to parainfluenza type 1 has been demonstrated.28,29 A different hypothesis
implicated altered endogenous material due to age- or sun damage-related
changes.30–32 Despite these observations, the precise triggering factors and the
pathogenesis of temporal arteritis remain unclear.
The lesions of giant cell arteritis are typically focal in distribution; therefore,
the vessel should be carefully palpated to find an obviously affected segment
before a biopsy is undertaken. Even then, false negatives are not uncommon
(see below). The lesion is granulomatous in nature and may affect only part
or the whole circumference of the vessel wall (Fig. 16.93).33 The infiltrate,
which particularly affects the intima and media, is composed of lymphocytes, Fig. 16.94
plasma cells, histiocytes, and variable numbers of giant cells of both foreign Giant cell arteritis: the intima and media are infiltrated by a dense chronic inflammatory
body and Langhans type (Fig. 16.94). Giant cells are sometimes relatively cell infiltrate containing conspicuous Langhans giant cells. By courtesy of P.A. Burton,
sparse and multiple levels have to be examined before they are identified. MD, Southmead Hospital, Bristol, UK.
On occasion, they are absent. Typical of giant cell arteritis is damage to the
internal elastic lamina, which appears swollen and fragmented, and portions Juvenile temporal arteritis
may be identified within the cytoplasm of giant cells (Fig. 16.95).4
A second, less common form consists of a panarteritis composed of lymphocytes, Clinical features
macrophages, neutrophils, and eosinophils but giant cells are absent. Varying Juvenile temporal arteritis is a rare and poorly defined entity first reported
degrees of vessel wall necrosis are evident and the vessel is often thrombosed. in 1975.1 Thus far, only approximately 20 cases have been reported in the
In the late stages of the disease, fibrous scarring takes place and a literature.2–10 The disease is unrelated to classic temporal arteritis and is not
reconstituted, often multilayered, internal elastic lamina may be identified. In associated with abnormal erythrocyte sedimentation rate or signs of systemic
cases of doubt, an elastic tissue stain can prove invaluable. The thrombus is involvement. It occurs in patients under the age of 40, most commonly
on occasions recanalized. manifesting as a unilateral painless nodule or swelling of a few centimeters
Initiation of corticosteroid treatment before biopsy influences the histological in the temporal area.1–10 Painful presentation and bilateral involvement are
appearances.34 Giant cells are rare or entirely absent, there are large circumferential rare features.2–4 The disease may be accompanied by blood eosinophilia and
defects in the elastic lamina, and there is a mantle of lymphocytes and epithelioid it may be related to or associated with Kimura's disease.4,5,7,9,10
histiocytes between the outer muscular layer and the adventitia.34 These changes
can be noted as early as 1 week following steroid treatment.34 Histological features
It is crucial to note that patients with classic symptoms of temporal arteritis
Juvenile temporal arteritis is characterized by intimal proliferation and
may have a negative biopsy, most likely due to the multifocal nature of the
disruption of the media of the temporal artery associated with a heavy
arteritis and sampling bias. In one study, 44% of patients who were regarded
chronic inflammatory infiltrate composed predominantly of lymphocytes and
as having clinical manifestations of temporal arteritis, which improved with
eosinophils. Endothelial proliferation is an additional finding and formation
steroid treatment, had negative biopsies.35 Therefore, a negative biopsy does
of lymphoid follicles and germinal centers may be present. Giant cells as seen
not necessarily exclude this disease. Given the consequences of delayed or no
in classical temporal arteritis are not a feature.
treatment, it is often necessary to treat selected patients even without definitive
biopsy diagnosis. One study found that patients with temporal arteritis who have
constitutional symptoms or an abnormal temporal artery detected by physical
examination are more likely to have a positive biopsy.36 Doppler flow studies Takayasu's arteritis
may be used to improve the sensitivity of biopsy.37 Given the multifocal nature of
giant cell arteritis, the diagnostic yield, not surprisingly, is likely improved with Clinical features
longer artery length biopsied and increased number of sections examined.38 Takayasu's arteritis (pulseless disease, giant cell arteritis) is a rare
granulomatous disease that predominantly affects the aorta and its major
Differential diagnosis branches and results in vascular stenoses with bruits and diminished or
The histological findings are identical to those seen in some patients with absent pulses (hence the term ‘pulseless disease’).1,2 Aneurysm formation
Takayasu's disease, another form of giant cell arteritis. Careful clinical may be an additional feature. It predominantly affects females (7:1), most
correlation is required to distinguish these conditions and, since overlap often involves the upper limbs, and usually presents in the second or third
exists, many cases are not easily subclassified. Some authors consider these decade. Although most patients are young adults, the disease is also seen in
diseases part of a continuum of giant cell vasculitis, with patient age being children.3,4 It is rare in Europe and the United States, occurring more often
an important discriminator: patients under age 40 are more likely to have in Japan, China, Korea, Southeast Asia, India, and Mexico.2 It appears to
Takayasu's arteritis; those over 50 are more likely to have temporal arteritis. have two stages:
It should be noted that fragmentation of the internal elastic lamina may • an acute systemic illness characterized by fever, malaise, arthralgias,
result from either age-related changes or atherosclerosis and these conditions myalgias, and ocular lesions including uveitis and episcleritis,
may be difficult to distinguish from healed arteritis. The presence of medial • a chronic stage of large-vessel involvement.5
scarring is suggestive of temporal arteritis. The extent of destruction, Current diagnostic criteria are shown in Table 16.10. In addition to the
particularly confluent loss of the internal elastic lamina, is said to correlate obligatory criterion, the presence of two major criteria, one major plus two
with probability of healed arteritis.6 or more minor, or four or more minor criteria, is associated with a high
probability of Takayasu's arteritis.6
Table 16.10
Takayasu's arteritis: diagnostic criteria
• Obligatory criterion
– age < 40 years
• Major criteria
– left mid subclavian artery lesion
– right mid subclavian artery lesion
• Minor criteria
– high ESR
– carotid artery tenderness
– hypertension
– aortic regurgitation or annuloaortic ectasia
– pulmonary artery lesion
– left mid common carotid lesion
– distal brachiocephalic trunk lesion
– descending thoracic aorta lesion
– abdominal aorta lesion
Fig. 16.95 Reproduced with permission from Bentsson, B.A. and Anderson, T. (1991) Current
Giant cell arteritis: there is fragmentation of the internal elastic lamina. By courtesy Opinion in Rheumatology, 3, 15–22.
of P.A. Burton, MD, Southmead Hospital, Bristol, UK.
Takayasu's arteritis 693
Fig. 16.96
Takayasu's arteritis: (A) this patient presented with
multiple lesions as seen here on the lower legs; (B) a large
ulcerated inflammatory nodule is present on the left thigh.
A B By courtesy of P. Godeau, MD, and C. Francès, MD, Groupe
Hospitalier, Pitié-Salpêtrière, Paris, France.
Cutaneous manifestations have been described in up to 50% of patients

and include Raynaud's syndrome (due to large-vessel involvement), acute
inflammatory nodules and erythema nodosum-like features (particularly in
Europe and North America), pyoderma gangrenosum-like lesions (especially
in the Japanese), pseudoerythema induratum, superficial phlebitis, tuberculid
eruptions, and purpura (Figure 16.96).5,7,8 Patients may present with
cutaneous necrotizing vasculitis.8
Cases have been reported describing an overlap between Takayasu's
arteritis and polyarteritis nodosa.6 Rare patients with a lupus-like malar flush
and an urticarial reaction with livedo reticularis have been documented.7
Renal artery involvement with stenosis causes severe hypertension secondary
to renin secretion. Stroke due to severe hypertension is a serious complication
in some patients. Patients with Takayasu's arteritis also have an increased
incidence of associated Crohn's disease.9
Pathogenesis and histological features A

The etiology and pathogenesis of Takayasu's arteritis is poorly understood.
Occasionally, other diseases are seen in association with Takayasu's arteritis
including tuberculosis, inflammatory bowel disease, polymyositis, sarcoidosis,
and rheumatoid arthritis.1,5,10–12 Coexpression with polyarteritis nodosa raises
the possibility of an autoimmune phenomenon.13
The diagnosis is usually made by clinical and radiological
correlation; however, in some cases tissue is sent to the pathologist. The
histological features are variable and include granulomatous vasculitis
indistinguishable from giant cell arteritis, leukocytoclastic vasculitis,
lymphocytic vasculitis, and polyarteritis nodosa-like features ( Figs
16.97, 16.98).5–7,13,14
Septal and lobular panniculitis with granulomatous vasculitis may be the
underlying histology of erythematous nodules and erythema nodosum-like
lesions.7 Features of Churg-Strauss granulomata have also been reported.5
As can be seen from the above discussion, several different patterns of vasculitis B
may be encountered in Takayasu's arteritis. Furthermore, the histological findings
seen in this disease may be identical to other forms of vasculitis. Therefore, Fig. 16.97
careful clinical and radiological correlation is necessary to establish the correct (A, B) Takayasu's arteritis: this occluded artery was present with a thickened
diagnosis. septum of the subcutaneous fat from the thigh of a young woman.
Table 16.11
Infections known to be associated with clinically defined vasculitis
Vasculitic syndrome Infective agent

Leukocytoclastic vasculitis Bacterial
(including Henoch-Schönlein Streptococcus
purpura) Staphylococcus
Salmonella
Yersinia
Mycobacterium
Viral
varicella-zoster
hepatitis B
cytomegalovirus
influenza
Polyarteritis nodosa Bacterial
Streptococcus
Viral
hepatitis A, B, C
Fig. 16.98
human immunodeficiency virus
Takayasu's arteritis: high-power view showing granulomatous inflammation.
cytomegalovirus
The features are indistinguishable from giant cell arteritis.
human T-cell leukemia
erythrovirus
Isolated granulomatous vasculitis Treponema pallidum
Infection-related vasculitis of the central nervous system Mycobacterium tuberculosis
Fungal
Infection must be considered in the evaluation of many forms of vasculitis, Coccidioides
particularly leukocytoclastic vasculitis. Infective vasculitis is caused by a wide Actinomyces
variety of agents including bacteria, fungi, protozoa, viruses, spirochetes, Cryptococcus
and rickettsiae (Table 16.11). The relationship between particular Histoplasma
microorganisms and vascular lesions is covered under the specific infection in Nocardia
Chapter 18. In general terms, vessel wall damage may occur as a consequence
Aspergillus
Borrelia burgorferi (Lyme)
of direct microbial toxic damage or else develop as a complication of an Varicella-zoster
immunologically mediated injury (Table 16.12).1
Kawasaki disease Bacterial
Bacterial arteritis can develop as a result of embolization from valvular
lesions in patients with infective endocarditis. Although many different
Streptococcus
Salmonella
organisms are of etiological importance in the latter condition, staphylococcal Yersinia
and streptococcal infections remain the most important.2 It may also occur by Mycoplasma
direct spread from an adjacent septic focus, by lymphatic spread, or represent Viral
a manifestation of underlying bacteremia or septicemia. There also appears parainfluenza
to be a significant relationship between group A streptococci and childhood rotavirus
polyarteritis nodosa, both cutaneous and generalized.3 In addition, Kawasaki
Reproduced with permission from Mader, R. and Keystone, E.C. (1992) Current
syndrome has been reported in association with group A streptococci, Opinion in Rheumatology, 4, 35–38.
possibly as a result of superantigen stimulation.4 Gonococcal bacteremia due
to Neisseria gonorrhea is another important cause of vasculitis. Neisseria
meningitis infection may result in vasculitis associated with considerable
morbidity and mortality. Table 16.12
The histological features of small-vessel involvement are variable and depend Mechanisms for infection-associated vasculitis
to some extent on the nature of the causative organism. Suppurative features
are most likely to be due to staphylococcal, streptococcal, Pseudomonas or • Direct microbial toxicity
Klebsiella infection.2 A Gram stain is advisable in all suspected cases. – direct endothelial infection
– effect of microbial toxins
Obviously, in the context of immunosuppressed patients, the range of
bacteria and fungi that can be implicated is very broad. In cases of suspected • Immune mediated
cutaneous infective vasculitis, especially in immunosuppressed patients, a – humoral: soluble immune complexes; in situ complex formation
detailed clinical history is essential and the judicious use of special stains is – cellular: cytotoxic cell reaction (T cell, NK cell, other); polyclonal T- or
B-cell response; monoclonal T- or B-cell response
highly advisable.
Candidiasis, aspergillosis, cryptococcosis, and mucormycosis are of NK, natural killer. Reproduced with permission from Calabrese, L.H. (1991) Rheumatic
special importance. Mycobacterium tuberculosis is also sometimes a cause of Disease Clinics of North America, 17, 131–147.
vascular damage. It tends to affect veins rather than arteries.2 The features are
usually those of a granulomatous thrombophlebitis, usually in the absence
of caseation necrosis, although sometimes this is a feature. Occasionally,
however, arteries are primarily affected (Fig. 16.99). fever.2,5 The histological features include endothelial swelling and a mixed
Lepra bacilli are very commonly seen in endothelial and vascular smooth inflammatory cell infiltrate of T lymphocytes, macrophages, and occasionally
muscle cells in lepromatous leprosy. Vasculitis in the setting of leprosy neutrophils.2 Thrombosis is sometimes present.
(erythema nodosum leprosum) is a common cause of vasculitis in regions of Small-vessel vasculitis may be seen in all three stages of syphilis. The features
the world where this disease is endemic. vary from a non-specific lymphocytic inflammation through to necrotizing
Vascular lesions in the skin accompany a variety of rickettsial infections granulomatous angiitis.6–8 Treponema pallidum, however, is very rarely
including epidemic typhus, scrub typhus, and Rocky Mountain spotted identified.2 Cutaneous vasculitis is an occasional feature of Lyme disease.2
Paraneoplastic vasculitis 695
A B
Fig. 16.99
(A, B) Tuberculous vasculitis: this patient with miliary tuberculosis presented with ischemic cutaneous lesions. Note the granulomatous inflammation.
The best known viral association with vasculitis is hepatitis B, which has malignancy but large-vessel vasculitis may also be seen. Of interest, vasculitis
been described in association with polyarteritis nodosa, leukocytoclastic can be present at the time of initial diagnosis and also herald the onset of
vasculitis, and mixed cryoglobulinemia, and hepatitis C associated mixed relapse.4 Solid tumors and hematological malignancy have been associated
cryoglobulinemia and leukocytoclastic vasculitis.1,9–12 Evidence of HBV with Henoch-Schönlein purpura.7,10,11 One study found that nearly a third of
infection is found in approximately 35% of all patients with polyarteritis.1 adults with Henoch-Schönlein purpura had an associated malignancy.10 For
Human immunodeficiency virus (HIV) may be present in a very wide this reason, the authors concluded that physicians should suspect underlying
spectrum of vasculitic lesions including polyarteritis nodosa, Churg- malignancy in older patients (especially men of more than 40 years) with
Strauss syndrome, leukocytoclastic vasculitis, Henoch-Schönlein purpura, Henoch-Schönlein purpura.10
lymphomatoid granulomatosis, and primary angiitis of the central nervous In contrast to solid tumors, there does appear to be a genuine relationship
system.13,14 Whether these represent a direct effect of HIV, or are a consequence between cutaneous vasculitis and hematological and lymphoreticular
of coexisting viral infections known to cause vasculitis (e.g. cytomegalovirus, neoplasms including hairy cell leukemia, acute and chronic myeloid leukemia,
HBV or Epstein-Barr virus), is unknown.10 The identification of HIV within multiple myeloma, and non-Hodgkin's lymphoma.1
endothelial cells adds some support to the former possibility.15 In general, patients present with the features of leukocytoclastic vasculitis,
and occasionally arthralgia or arthritis is evident. Cutaneous manifestations
include maculopapular eruptions, purpura, urticaria, peripheral ulcers,
Paraneoplastic vasculitis and gangrene.13 Although vasculitis is seen in patients with a spectrum of
hematological malignancies, hairy cell leukemia is particularly associated with
Clinical features leukocytoclastic vasculitis and a polyarteritis nodosa-like picture, including
Occasionally, cutaneous vasculitis is a marker of an underlying systemic systemic lesions.4–6 In one study of 42 patients with hairy cell leukemia and
malignancy (Table 16.13).1–11 Although there have been reports of an vasculitis, 21 also had leukocytoclastic vasculitis and 17 had polyarteritis
association with solid tumors, this relationship is tenuous (with the possible nodosa.4 In addition, four patients had direct infiltration of vessel walls
exception of squamous carcinoma of the bronchus): such cases probably by leukemic cells. Hodgkin's lymphoma has occasionally been linked to
represent nothing more than coincidence.1,4,6,12 Vasculitis has nevertheless erythema nodosum, and myelodysplasia has been found in conjunction with
been reported in patients with carcinoma of the kidney, breast, ovary, lung, leukocytoclastic vasculitis.14,15 Multiple myeloma is particularly associated
nasopharynx, stomach, small bowel, colon, and prostate. Leukocytoclastic with nonthrombocytopenic purpura.16 It has recently been documented
vasculitis is the most common pattern of vasculitis associated with that lymphocytic vasculitis is a relatively common form of paraneoplastic
vasculitis associated with lymphoproliferative disorders.17
Table 16.13 It is important to note that these vasculitic phenomena may antedate the
Vasculopathic syndromes associated with malignancy clinical manifestations of the underlying malignancy. Therefore, patients with
an unexplained vasculitic rash should be investigated with this in mind.2 In
• Migratory superficial thrombophlebitis hairy cell leukemia, vasculitis often follows splenectomy.5,13
• Deep venous thrombosis
• Nonbacterial thrombotic endocarditis Pathogenesis and histological features
• Anticardiolipin antibody syndrome
The pathogenesis of paraneoplastic vasculitis has not been well studied, but
• Embolic features associated with atrial myxoma
• Raynaud's phenomenon
could include immune complexes, cross-reacting antigens, and direct tumor
• Erythema nodosum (leukemic blast) infiltration of blood vessel walls.
• Hyperviscosity syndrome Leukocytoclastic, polyarteritis nodosa-like, and lymphocytic forms
• Cryoglobulinemia of paraneoplastic vasculitis have all been described and show histological
• Lambda light chain vasculopathy features similar to their nonparaneoplastic counterparts.17
• Cutaneous vasculitis Recently, cases of vasculitis in the setting of myelomonocytic or
• Systemic vasculitis monocytic leukemia cutis have been described in which the vascular injury
was mediated by leukemic blasts.18 The term ‘leukemic vasculitis’ has
Reproduced with permission from Mertz, L.E. and Conn, D.L. (1992) Current Opinion in
Rheumatology, 9, 39–46. been proposed for this form of vasculitis.18 In these cases, the vasculitis
ranged from mild microvascular injury to frank necrotizing vasculitis.18,19
The former was characterized by low-grade vascular injury with endothelial It is arguable that the term ‘vasculitis’ should not be applied to lesions
cell swelling and focal fibrin deposition. Frank necrotizing vasculitis with minimal vascular damage. Regardless of terminology, it is important
shows infiltration of the vessel wall by neoplastic cells associated with for the pathologist to render a report that distinguishes cases of low-grade
necrosis and fibrin deposition in a pattern that resembles polyarteritis vascular injury associated with a lymphocytic infiltrate from frank necrotizing
nodosa. Hairy cell leukemia may also show infiltration of vessel walls by vasculitis. Furthermore, it is important to distinguish lymphocytic from
leukemic cells.4,5 neutrophilic vasculitides.
In cases with low-grade vascular injury, we often apply the term low-
grade lymphocytic vasculitis and mention in our report that frank necrotizing
Vasculitis associated with palisaded vasculitis is not present to avoid any ambiguity. If strict criteria are used –
neutrophilic and granulomatous dermatitis requiring vascular necrosis or significant fibrinoid change for a diagnosis
of vasculitis – frank necrotizing lymphocytic vasculitis is an uncommon
Clinical features condition. The differential diagnosis of lymphocytic vasculitis is broad and
many entities associated with a perivascular lymphocytic infiltrate may, on
Occasionally, granuloma annulare, necrobiosis lipoidica, and rheumatoid
occasion, cause vascular changes that warrant a diagnosis of non-necrotizing
nodule-like lesions associated with vasculitis are encountered.1,2 This group
lymphocytic vasculitis (Table 16.14). Entities that exceptionally show features
of disorders, which is almost always associated with systemic disease,
of lymphocytic vasculitis are discussed in their appropriate chapters. Diseases
is also discussed in Chapter 9. A number of different terms have been
commonly associated with lymphocytic vasculitis include Degos' disease,
applied including palisaded neutrophilic and granulomatous dermatitis
perniosis, Behçet's disease, livedo vasculitis, and Kawasaki syndrome. Other
(of immune complex disease), interstitial granulomatous dermatitis
rare associations of lymphocytic vasculitis include leukemia and the tumor
with arthritis, rheumatoid papules, superficial ulcerating rheumatoid
necrosis factor receptor-associated periodic syndrome. The latter is a periodic
necrobiosis, cutaneous extravascular necrotizing granuloma, and Churg-
fever syndrome associated with a skin eruption presenting with macules and
Strauss granuloma.1–6 Many types of underlying systemic disease have
plaques in early life. It results from mutations in the TNFRSFIA, the gene
been reported in association with these lesions, including rheumatoid
encoding the tumor necrosis factor receptor.7,8
arthritis, lupus erythematosus, Sjögren's syndrome, thyroiditis, Raynaud's
syndrome, hepatitis, inflammatory bowel disease, lymphoproliferative
disorders, myelodysplastic syndrome, vasculitis (Wegener's, Churg-Strauss,
Takayasu's arteritis, periarteritis nodosa), hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, mixed cryoglobulinemia, drug
reactions, carcinoma, diabetes mellitus, and infection (streptococcal, HIV,
Epstein-Barr virus, erythrovirus).1–4
The lesions are usually papules and nodules, or plaques with a predilection
for the extremities or trunk in an adult.2,6,7 They are often arranged in a linear
pattern, which may be confluent linear bands or cords that are said to have
a ‘ropelike’ quality.

The pathogenesis of palisaded neutrophilic and granulomatous dermatitis
likely depends on the associated/underlying disease. An autoimmune-
mediated vasculitis probably plays an important role in at least a subset of
cases.
As noted above, this is not a single disease but rather a group of disorders
showing a broad spectrum of histology sharing the common denominator of
a prominent neutrophilic infiltrate with or without vasculitis in a background
of palisading granulomatous inflammation. When present, vasculitis usually A
shows the features of leukocytoclastic vasculitis.
The precise terminology that is preferred by the dermatopathologist is
probably not important. More significant than the nosological nuances is
rendering a report that alerts the clinician to the possibility that the patient
may have underlying systemic disease, and when such lesions are encountered
appropriate clinical evaluation is necessary.
Lymphocytic vasculitis
Lymphocytic vasculitis is sometimes diagnosed in cases in which a perivascular
lymphocytic infiltrate is associated with vascular damage (Fig. 16.100). In
many cases, the vascular changes are subtle and minimal, including only
endothelial swelling and extravasated blood cells and sometimes focal
fibrin deposition. Not surprisingly, the concept of lymphocytic vasculitis is
somewhat controversial.1–5 This category of vasculitis has been embraced by B
some authors and rejected by others. To a large extent, the controversy is
the result of a lack of precisely defined criteria for diagnosis. Kossard has Fig. 16.100
defined lymphocytic vasculitis as an overlapping spectrum of changes varying (A, B) Lymphocytic vasculitis: there is mural fibrinoid necrosis accompanied by a
from angiodestruction to endovasculitis and including a pattern defined as dense lymphocytic infiltrate. These images come from a patient with very severe
lichenoid lymphocytic vasculitis.6 perniosis.
Malignant atrophic papulosis 697
Table 16.14 face, and scalp are spared. The papules are usually asymptomatic and do not
Causes of lymphocytic vasculitis ulcerate or scar. With progression, they develop a characteristic appearance:
• Behçet's disease discrete small patches composed of a central zone with a depressed white,
• Connective tissue disease porcelain-like appearance and a fine scale, surrounded by a narrow red or
• Degos' disease violaceous rim associated with fine telangiectasia (Fig. 16.101). On rare
• Drug eruptions occasions, similar lesions are found on the buccal and genital mucosa. Penile
• ‘Gyrate erythemas’ (e.g. erythema annulare centrifugum) ulceration has rarely been documented.19 Sometimes, avascular conjunctival
• Infection (especially viral and rickettsial) pale patches are seen.20
• Insect bite reactions Intestinal manifestations are variable. While any segment of the intestinal
• Kawasaki syndrome system from the oral cavity to the anus may be involved, it is predominantly
• Livedo vasculitis/atrophie blanche
the small intestine that is affected.13 Some patients are asymptomatic
• Lymphomatoid papulosis
• Perniosis (chilblains)
while others complain of indigestion, diarrhea, constipation or abdominal
• Pityriasis lichenoides distension and pain. Laparoscopy usually reveals characteristic subserosal
• Pigmented purpuric dermatoses white, yellow or pinkish plaques, typically slightly depressed and several
• Polymorphic eruption of pregnancy centimeters in diameter. Of great importance, some patients develop small
• Polymorphous light eruption intestinal perforation with resultant peritonitis. Fistulae involving the small
• Prurigo of pregnancy bowel may develop as a complication.21 Rarely, intestinal involvement
precedes the cutaneous features.22 Acute small bowel perforation can be the
first manifestation of the disease.23 In addition, intestinal lesions sometimes
develop many years after an initial cutaneous presentation.
Malignant atrophic papulosis The condition may involve both the peripheral and central nervous system
and occasionally such lesions dominate the clinical features.24–27 Symptoms
Clinical features are variable and are occasionally multiple due to various sites being affected.
Malignant atrophic papulosis (Degos' disease, lethal intestinocutaneous For example, hemi- and quadriplegias, sensory losses, and cranial nerve
syndrome,) is a rare disorder affecting multiple systems and usually lesions may all be encountered.28,29
associated with a poor prognosis.1–4 It is of unknown etiology, shows a male Malignant atrophic papulosis is a truly systemic illness in most patients.
predominance (3:1), and usually affects the young and middle aged. The mean At autopsy, lesions are found in a variety of sites including the heart, lungs,
age at presentation is 33 years; however, a wide age range at diagnosis (from kidneys, bladder, and liver.30–33
infancy to 67 years) has been described.5,6 Occasional instances of familial Although this disease is usually associated with a poor prognosis and high
involvement have been recorded.7–9 Presentation during pregnancy may rarely mortality, there does appear to be a subset of patients in whom the cutaneous
occur.10 features are the sole manifestation and evolution is benign.10,34–40 Intestinal
The cutaneous lesions are distinctive, although similar lesions can involvement appears to correlate particularly with a poor outlook.41
be a manifestation of other diseases including SLE, systemic sclerosis, Malignant atrophic papulosis has been reported in a patient with acquired
dermatomyositis, rheumatoid arthritis, and Crohn's disease.11–17 Recently, it immunodeficiency syndrome.42
has been proposed that malignant atrophic papulosis represents a reaction
pattern mainly seen in lupus erythematosus and not a specific disease per se.17,18 Pathogenesis and histological features
Lesions, which may be quite numerous, appear in crops, initially as pinkish The precise etiology is unknown, although viral, genetic, autoimmune
or yellow–gray papules up to 5 mm in diameter and showing a predilection mechanisms, and fibrinolysis have all been implicated.43 Since lesions are
for the trunk and proximal extremities. Characteristically, the palms, soles, sometimes not associated with significant inflammation, it is debatable
Fig. 16.101
A (A, B) Degos' disease: note the typical small papules with depressed centers
and fine white scaling. By courtesy of the Institute of Dermatology, London, UK.
whether classification as a true vasculitis is appropriate. The pathogenesis is to the infarct are hyalinized and show a perivascular lymphocytic infiltrate
that of vascular thrombosis, the essential pathology of the lesions being that (Figs 16.104, 16.105). Usually, but not invariably, an endovasculitis can
of infarction.1 A focal fibrinolytic defect within the center of the infarcted be demonstrated in the blood vessels at the apex of the lesion: this consists
lesions and alterations of fibrinolysis and platelet function have been of endothelial cell hyperplasia, sometimes complicated by thrombosis.
described, but these are not consistent findings.1,44,45 It has been proposed The internal elastic lamina, media, and serosa are usually not involved.
that endothelial swelling and proliferation with secondary thrombosis is the A panniculitis mimicking lupus erythematosus profundus has been described.51
primary pathogenesis.1 Consistent with this hypothesis is the documentation Microscopic examination of the bowel lesions reveals transmural intestinal
of a patient with malignant atrophic papulosis associated with elevated inflammation with ulceration and hemorrhage. The latter may involve the
anticardiolipin antibodies.46 Others, however, have not been able to small and large intestines including the rectum (Figs 16.106–16.109).
corroborate this finding.47 Vascular changes have included gross intimal thickening with consequent
In most cases, the cause of the initial endothelial vascular insult is severe diminution in the lumen diameter, thrombosis, and acute vasculitis.52
unknown, but a mononuclear vasculitis may play a role in the pathogenesis.4
Most authors regard the mucin deposition described below as a secondary
event developing as a consequence of dermal ischemia. Differential diagnosis
The established cutaneous lesion has a characteristic appearance.48,49 The As mentioned above, the cutaneous findings are distinctive and diagnosis
overlying epidermis is hyperkeratotic and atrophic. Immediately beneath this is should be relatively straightforward. However, it should be kept in mind that
a wedge-shaped zone of dermal infarction with the base parallel to the surface although the cutaneous lesions of malignant atrophic papulosis are typical,
epithelium: it is typically pale in color, relatively acellular, and associated with similar lesions have been described in patients with other diseases such as
mucin deposition (Figs 16.102, 16.103).50 The latter is metachromatic with SLE, systemic sclerosis, rheumatoid arthritis, dermatomyositis, and Crohn's
toluidine blue and demonstrates hyaluronidase-sensitive Alcian blue staining. disease.11–16,53 A search for underlying or associated disorders is therefore
Older lesions are frequently ulcerated. Often, the vessels adjacent and deep advised.
Fig. 16.102 Fig. 16.104

Degos' disease: there is hyperkeratosis and epidermal atrophy associated with a Degos' disease: high-power view showing blood vessel wall hyalinization and a
zone of dermal infarction. Note the ectatic vessels. heavy lymphocytic infiltrate.
Fig. 16.103 Fig. 16.105

Degos' disease: high-power view showing hyalinized fat necrosis. Degos' disease: the superficial blood vessels are thickened and hyalinized.
Atrophie blanche 699
Fig. 16.106 Fig. 16.109

Degos' disease: section of jejunum showing ulceration of the mucosa with Degos' syndrome: histological section of the submucosa of the rectum. There
surrounding intense congestion. By courtesy of C.J.J. Mulder, MD, Rijnstate is acute vasculitis with thrombosis. By courtesy of C.J.J. Mulder, MD, Rijnstate
Hospital, Arnhem, The Netherlands. Hospital, Arnhem, The Netherlands.
Atrophie blanche
Clinical features
Atrophie blanche (livedo vasculitis, livedoid vasculitis, segmental hyalinizing
vasculitis) is a common dermatosis that usually occurs in the elderly,
particularly females.1–4 In its fully established state it consists of one or more
irregular, smooth, atrophic plaques surrounded by a hyperpigmented border
and telangiectases (Figs 16.110, 16.111). Ulcerative lesions of two types may
precede it:
• small (1–5 mm diameter), very painful erythematous purpuric areas that
ulcerate and heal slowly,
• chronic large areas of ulceration up to 5 cm in diameter, which, after a
long period of time, heal to form extensive areas of atrophic plaque.
Atrophie blanche shows seasonal variation, typically worsening in the
summer months. Lesions recur at periodic intervals and are predominantly
located on the lower legs, ankles, and the dorsal surfaces of the feet.
Fig. 16.107 Occasionally, however, they are found around the forearms, fingers, and
Degos' disease: histological section of jejunum shown in Figure 16.106. Note hands or even in a more widespread distribution.3,5,6 The disease is often
the acute inflammation and ulceration. By courtesy of C.J.J. Mulder, MD, Rijnstate associated with signs of venous stasis.
Hospital, Arnhem, The Netherlands. Atrophie blanche has been reported in association with lupus erythematosus
and antiphospholipid syndrome.7,8 One study found 17% of lupus patients
were affected.8 This study also noted that the pattern of cutaneous lesions was
somewhat unusual, with involvement of the knees, elbows, fingers, soles, and
the back.8 The same study suggested that patients with lupus erythematosus
who have atrophie blanche are at an increased risk of developing lupus central
nervous system involvement.8

The pathogenesis of atrophie blanche is not well understood but it appears
that ischemia may be the end result. Although increased hydrostatic
pressure certainly contributes to the development of this condition, the
finding of both immunoglobulin (usually IgM, less often IgG and IgA)
and complement within the blood vessel walls raises the possibility of
an immunological pathogenesis.9 It has been associated with a localized
defect of tissue plasminogen activator.3,10 The location of the lesions
certainly suggests that trauma may also play some role in development
of lesions. Recently, patients with atrophie blanche and disorders of
coagulation such as factor V Leiden mutation, raised anticardiolipin
antibodies, protein C or protein S deficiency, prothrombin mutation, and
Fig. 16.108 raised levels of fibrinopeptide A have been described, suggesting that,
Degos' disease: section of rectum showing focal congestion and ulceration. at least in some patients, an underlying coagulopathy is the basis of
By courtesy of C.J.J. Mulder, MD, Rijnstate Hospital, Arnhem, The Netherlands. disorder.4,11–17
Fig. 16.112
Atrophie blanche: the vessels in the papillary dermis are increased in number and
show mural fibrin deposition. There is underlying scarring.
Early and ulcerative lesions are characterized by the presence of increased

numbers of dermal vessels containing fibrin within their walls in addition to
intraluminal fibrinoid plugs (Figs 16.112–16.114). The latter are typically
diastase-resistant and periodic acid–Schiff (PAS) positive, and can also be
highlighted by use of the phosphotungstic acid–hematoxylin stain (Fig.
16.115). Inflammatory destruction of blood vessels is, however, not a
feature and therefore this disorder is not a true vasculitis. Variable degrees
of red cell extravasation are evident and hemosiderin pigment is often
present. A perivascular lymphohistiocytic infiltrate of varying intensity
is usually found and dermal mast cells are often increased in number.
Ulcerative lesions show infarction of the superficial dermis and epidermis.
B In the fully established atrophic plaque, in addition to the vascular changes,
the epidermis is atrophic and the dermis shows dense scleroderma-like
Fig. 16.110 scarring.
Atrophie blanche: (A) there is ulceration with erythema and scaling; (B) this example shows
marked hyperpigmentation with scarring and atrophy around the ankle and extending onto Differential diagnosis
the dorsum of the foot. By courtesy of the Institute of Dermatology, London, UK.
The histological features in the appropriate clinical setting are diagnostic.
Coagulopathies are associated with intraluminal fibrinoid plugs but not
extensive fibrinoid change of the vessel wall. Atrophie blanche shows some of
the features seen in stasis dermatitis such as clustering of vessels in the superficial
dermis; however, uncomplicated stasis does not show fibrinoid change.
Dermatological manifestations of
cholesterol crystal embolism and embolism
from atrial myxoma
Clinical features
Cholesterol crystal embolism is a disease of the elderly and typically occurs
in males (4:1), thereby reflecting the demographics of atherosclerosis.1,2
Cholesterol embolism may occur spontaneously or complicate trauma to the
aorta.1 It can be seen following warfarin therapy.3 Systemic symptoms due to
infarction are variable and depend upon the organ embolized. Necrotizing
vasculitis has been described following cholesterol crystal embolization.4
Multisystem involvement sometimes results in an initial diagnosis of
vasculitis.
Fig. 16.111 Patients commonly manifest pyrexia, myalgia, and a sudden onset of
Atrophie blanche: an
systemic hypertension as well as renal failure and cutaneous lesions.5 An
extensive ivory-white
area of scarring overlies
increased ESR, blood eosinophilia, and raised serum creatinine are additional
the medial malleolus. By features. Cutaneous manifestations are common and include:
courtesy of R.A. Marsden, • livedo reticularis, often bilateral, affecting the feet and legs and
St George's Hospital, sometimes extending up to involve the trunk,6
London, UK. • gangrene of the toes (Fig. 16.116),
Disseminated intravascular coagulation 701
Fig. 16.113 Fig. 16.114 Fig. 16.115

Atrophie blanche: high-power view of vessels. Atrophie blanche: occluded vessels are present. Atrophie blanche: the vessel walls are strongly PAS
There is marked red blood cell extravasation. positive, diastase resistant.
Cardiac myxomas are rare but represent the most frequent primary
cardiac tumor. Although benign, they are a marker of Carney's syndrome
and early recognition is imperative as distant embolization is an important
complication associated with high mortality. Cutaneous symptoms include
erythematous macules and papules predominantly of acral sites, digital
cyanosis, petechiae, splinter hemorrhages, telangiectasia, and livedo
reticularis.7–14

Cholesterol emboli are found in the small to large arteries and arterioles
of the deep dermis or subcutaneous fat (Figs. 16.117, 16.118). Diagnosis
depends upon the identification of typical biconvex cleft- or needle-shaped
empty spaces (representing evanescent cholesterol crystals dissolved during
tissue processing) often associated with atheromatous debris or luminal
thrombosis. It is essential, therefore, that deep biopsies are taken. Multiple
levels should also be examined because emboli tend to be patchily distributed
and are often difficult to detect. The skin supplied by the occluded vessel may
be infarcted.
Emboli from atrial myxomas are characterized by the presence of myxoid
material within medium-sized vessels. Due to vascular occlusion, this is
accompanied by fibrin deposition and a reactive vascular proliferation.
Fig. 16.116 Demonstration of the myxoid substance is often difficult and commonly
Cholesterol embolism: requires examination of multiple levels.
there is extensive
infarction of the toes of
this elderly male patient.
Disseminated intravascular coagulation
• cyanosis, Clinical features
• purple discoloration of the toes, Disseminated intravascular coagulation (DIC) is a consumptive coagulopathy
• cutaneous ulceration, that is associated with a wide variety of underlying disorders, many of them
• nodules on the legs, thighs, feet, and toes, life threatening. It is not uncommonly seen in very ill patients and may
• purpuric lesions on the legs and feet. be acute, subacute or chronic. Purpura fulminans is a term that has been
The cutaneous lesions of cholesterol crystal embolism therefore mimic applied to infection-associated DIC in children. More recently, some authors
many other vascular lesions, and biopsy is essential for diagnosis. Mortality have applied the term less restrictively to a severe form of DIC associated
is very high due to cardiac and central nervous system involvement. with high morbidity and mortality.1,2 Purpura fulminans is characterized by
A B
Fig. 16.117 Fig. 16.118

Cholesterol emboli: there is ulceration and dermal Cholesterol embolism: (A) the overlying epidermis shows full-thickness infarction; (B) high-power view of
scar tissue extending into the septa of the cholesterol clefts.
subcutaneous fat. Needle-shaped crystals are present
in the lumen of an artery in the middle of the field.
an acute syndrome of rapidly progressive and extensive hemorrhagic skin fibrin, clotting factors and platelets, vascular occlusion, tissue ischemia, and
necrosis associated with dermal vascular thrombosis and vascular collapse hemorrhage. Clotting factors may be consumed at a rate that exceeds the
due to DIC.3,4 A common presentation is symmetrical purpura of the fingers ability of the liver for synthesis. The coagulopathy, in turn, causes a hemolytic
and toes. anemia by damaging red blood cells.
DIC is commonly associated with complications of pregnancy and Purpura fulminans is sometimes a manifestation of hereditary protein
delivery such as abruptio placentae, sepsis, and amniotic fluid embolism. C deficiency, protein S deficiency, coumadin therapy, and antiphospholipid
A wide variety of infections including bacterial sepsis, meningococcemia, antibodies.3
and fungal infections may also be associated. Massive trauma, heat stroke,
shock, snakebite, poisoning, and burns can cause DIC. Malignant neoplasms
(including carcinoma of the stomach, breast and colon, small cell carcinoma
of the lung, brain, and pancreas) and hematological malignancies have also
been associated with this condition.5–14
Purpura fulminans occurs predominantly in children and has an equal
incidence in males and females. It develops as a complication of a prodromal
infectious illness, most commonly meningococcemia, scarlet fever, viral upper
respiratory tract infection, chickenpox, rubella, and other exanthemata.15
The disease shows some seasonal variation, being more common in winter
and spring. Children develop large confluent ecchymoses, which particularly
affect the buttocks, legs, and feet, and commonly appear on the upper limbs
and abdomen (Fig. 16.119). The ecchymoses frequently become necrotic,
and blood-filled blisters are often found. On occasion the limbs become
gangrenous (Fig. 16.120). Fever and hypotension accompany the cutaneous
lesions.
Hematological studies reveal thrombocytopenia, anemia, and often
a leukocytosis. The prothrombin and bleeding times are prolonged.
Fibrinogen levels are low and fibrin–fibrinogen degradation products
elevated.
Fig. 16.119
Pathogenesis and histological features Purpura fulminans:
bilateral extensive
As stated above, DIC is not a disease sui generis but represents a coagulopathy ecchymoses are present
resulting from a large number of disorders. These conditions trigger DIC on this child's legs. By
either by causing direct injury to endothelial cells, which causes platelet courtesy of D. McGibbon,
aggregation, or by increasing circulating procoagulant factors, often tissue MD, St Thomas' Hospital,
factor. The consequences are thrombosis, fibrinolysis leading to depletion of London, UK.
Cryoglobulinemia 703
Fig. 16.122
Fig. 16.120 Purpura fulminans: numerous small thrombi are seen in the superficial vessels.
Purpura fulminans: there
is complete gangrene
of the skin. By courtesy
of D. McGibbon, MD,
St Thomas' Hospital, The differential diagnosis includes other causes of coagulopathy or
London, UK. leukocytoclastic vasculitis. Serological evaluation for disorders of coagulation
is required to support the diagnosis. Finally, since successful treatment is both
supportive and aimed at the underlying disorder, patients must be evaluated
to determine the underlying causes of the DIC.
Biopsy of skin lesions in patients with DIC are characterized by fibrin,
platelet or mixed thrombi in the capillaries and venules, particularly of the
skin, but also commonly affecting the internal viscera including the kidneys, Cryoglobulinemia
bowel, bladder, and brain (Figs 16.121, 16.122).3 The number of vessels
containing thrombi ranges from scattered to nearly all vessels being involved. Cryoglobulins are immunoglobulins that precipitate at low temperatures
Variable numbers of extravasated red blood cells are seen. In patients with (4°C) and which redissolve on warming (Fig. 16.123). Typically, the greater
purpura fulminans, the thrombi are associated with diffuse and extensive their concentration, the higher the temperature at which they precipitate.
hemorrhage. Early lesions usually show few or no perivascular inflammatory This has obvious clinical implications, particularly for plasmapheresis
cells. Older lesions are often characterized by epidermal necrosis and therapy.
subepidermal blood-filled bullae. A mild perivascular inflammatory cell Cryoglobulins may be subdivided into three classes: 1,2
infiltrate of lymphocytes and polymorphs may be present. Infective DIC or • Type I cryoglobulin is composed solely of monoclonal immunoglobulin
purpura fulminans sometimes shows features of a leukocytoclastic vasculitis. (either kappa or lambda) and is usually, though not invariably, associated
Immunofluorescence studies for immunoglobulins and complement are with a variety of lymphoproliferative disorders, including multiple
uniformly negative. myeloma, Waldenström's macroglobulinemia, chronic lymphocytic
leukemia, and lymphocytic lymphoma.
• Type II (mixed) cryoglobulin is composed of monoclonal (usually IgM)
immunoglobulin reacting against polyclonal IgG.
• Type III (polyclonal) cryoglobulin is composed of polyclonal
immunoglobulins (usually IgG and IgM).
The last two subtypes (mixed cryoglobulins) function as immune
complexes and clinical manifestations are therefore due, at least in part, to
allergic vasculitis. Mixed cryoglobulinemia may be clinically subdivided into
two forms:
• Essential mixed cryoglobulinemia, in which most patients are infected
with the hepatitis C virus.2,3 Hepatitis B virus has been also described in
association with essential mixed cryoglobulinemia.2,4
• Secondary mixed cryoglobulinemia, which develops as a complication of
a variety of conditions, including connective tissue diseases such as SLE,
lymphomas or infective disease processes (e.g. infective endocarditis and
glandular fever).5
Clinical features
The eponym ‘Meltzer’s triad' has been applied to the combined features
of purpura, arthralgia, and weakness that are often present.4 Cutaneous
manifestations are common to all classes of cryoglobulinemia and are often
the presenting complaint.1,4,6 Purpura is the most frequent initial sign.
Fig. 16.121 Type I cryoglobulinemia is usually characterized by purpuric lesions
Purpura fulminans: there is epidermal infarction. including inflammatory macules and papules on the extremities, accompanied
A B
Fig. 16.123 Fig. 16.124

Cryoglobulinemia: (A) there is a large quantity of precipitated cryoglobulin in this plasmapheresis specimen; Cryoglobulinemia: there is purplish discoloration
(B) a cryoprecipitate. By courtesy of N. Slater, MD, St Thomas' Hospital, London, UK. of the third toe. By courtesy of N. Slater, MD, St
Thomas' Hospital, London, UK.
by foci of ulceration (Fig. 16.124).7 Additional features may include genome has also been demonstrated in the bone marrow cells of patients
livedo reticularis, Raynaud's phenomenon, scarring, and infarction, which with mixed cryoglobulinemia.21 Interestingly, the E2 envelope protein of the
particularly affects the digits, ears, and nose.7 Renal lesions are uncommon, hepatitis C virus binds to CD81, which is present on B lymphocytes.22 What
but some patients may manifest hematuria, proteinuria (occasionally role this interaction plays in the pathogenesis of cryoglobulinemia is poorly
amounting to the nephrotic syndrome) and, rarely, anuria.8 understood.22
Mixed cryoglobulinemia is characterized by joint involvement (arthralgia Other infective agents can also be associated with cryoglobulinemia
and arthritis), Raynaud's phenomenon, fever, purpura, weakness, renal including protozoa, fungi, bacteria, Chlamydia, and rickettsiae. Cryoglo
involvement, hepatosplenomegaly, and generalized vasculitis. Cutaneous bulinemia has been reported in patients infected with the HIV virus.23–27
manifestations include palpable purpura, inflammatory macules and papules, However, in HIV patients with circulating cryoglobulins, the clinical symptoms
necrotizing vasculitis, crural ulcers and, occasionally, cold urticaria.7,9 usually associated with cryoglobulinemia are often lacking.23 Another study
Additional rare manifestations include follicular pustular purpura, erythema has shown that in HIV-infected patients the presence of cryoglobulins is
multiforme, and necrobiotic xanthogranuloma.7,10,11 Renal involvement, most significantly associated with increased mortality and risk of developing
frequently in the form of type 1 mesangioproliferative glomerulonephritis, neoplasia (including B-cell lymphoproliferative disorders).24 Interestingly,
may be identified by proteinuria, hematuria, and red cell casts.2 Patients can disappearance of the symptoms of cryoglobulinemia following infection with
also have polyneuropathies.2 Prognosis is variable. Renal involvement, which the HIV-1 virus has also been reported. The authors of this report speculate
occurs in 50% of cases, is associated with high morbidity and mortality. on a significant role for CD4+ T cells in the pathogenesis of cryoglobulinemia
Given the frequent association of hepatitis virus infection with in a subset of patients.28
cryoglobulinemia, it comes as no surprise that some patients develop The histological features of monoclonal cryoglobulinemia are those of
hepatocellular carcinoma.12,13 vascular dilatation, endothelial swelling, and plugging of vascular lumina by
hyaline material, which is diastase resistant and PAS positive (Fig. 16.125).
Pathogenesis and histological features Intravascular rouleaux formation may also be a feature.7 On occasion,
In keeping with an immune complex-mediated pathogenesis, hypocomple monoclonal cryoglobulinemia may be associated with leukocytoclastic
mentemia is the rule. The cryoprecipitate is composed of polyclonal IgG with vasculitis.7
either monoclonal or polyclonal IgM and is associated with rheumatoid factor In addition to occasional intracapillary hyaline thrombi, patients with severe
properties.14 In some patients, hepatitis B virus surface antigen or antihepatitis renal involvement sometimes manifest features of membranoproliferative
B antibodies are identified in either the serum or the cryoprecipitate, glomerulonephritis.
suggesting a possible causal relationship. Both hepatitis C and hepatitis B Mixed cryoglobulinemia is associated with immune complex-mediated
viruses have been reported in cases of mixed cryoglobulinemia.15–17 Since acute leukocytoclastic vasculitis. The cryoglobulins precipitate in small
most patients with essential mixed cryoglobulinemia are infected with the vessels at low temperature and the resultant complement activation ensures
hepatitis C virus, it appears likely that this represents the cause of this form the changes of acute vasculitis. Immunofluorescence is positive for IgG, IgM,
of the disease and consequently this aspect has received much investigative and complement (Fig. 16.126). Occasionally, intravascular hyaline thrombi
attention. Hepatitis C virus and hepatitis C virus antigen–antibody complexes are present in early lesions. Red cell extravasation is often a feature.
have been demonstrated in cryoprecipitates.18 Hepatitis C viral RNA is In biopsies from acute cases, the renal glomeruli show intracapillary
detected by polymerase chain reaction (PCR) in peripheral blood monocytes thrombi. Other renal manifestations include membranoproliferative glomerulo
of 81–90% of patients with mixed cryoglobulinemia.19,20 Hepatitis C nephritis and vasculitis.
Antiphospholipid antibody syndrome and Sneddon's syndrome 705
The histological differential diagnosis of monoclonal cryoglobulinemia
includes other causes of thrombotic vasculopathy, for example DIC,
thrombotic thrombocytopenic purpura, protein C deficiency, and warfarin
(coumadin) necrosis. Although subtle histological clues may suggest
cryoglobulinemia, such as the waxy hyaline texture of the casts, definitive
diagnosis is based on serological testing for cryoglobulins. The differential
diagnosis of mixed cryoglobulinemia includes other causes of leukocytoclastic
vasculitis.
Antiphospholipid antibody syndrome and

Sneddon's syndrome
Clinical features
A The circulating anticoagulant known as the antiphospholipid antibody is
associated with paradoxical thrombosis, spontaneous abortion, premature
labor, intrauterine death, labile hypertension, cutaneous necrosis, gangrene,
ecchymoses, purpura, leg ulcers, atrophie blanche, livedo reticularis, and
false-positive syphilis serology – the lupus anticoagulant syndrome.1–6
The last, also known more accurately as the antiphospholipid syndrome
because not all patients have associated SLE, is due to the presence of
circulating antiphospholipid antibodies, which inhibit coagulation in vitro,
and are associated with a greatly increased risk of thrombotic phenomena
affecting both arteries and veins. The most common autoantigen in the
antiphospholipid syndrome is the protein beta-2 glycoprotein 1.7 In addition
to the ‘lupus anticoagulant’, another important type of antiphospholipid
antibody is the anticardiolipin antibody, named for its ability to bind
cardiolipin.
Although this syndrome is most often encountered in young adult women,
it has been documented in children as well as the elderly. This demographic
pattern is certainly a reflection of the association with lupus erythematosus,
which shows a marked predilection for young women (Table 16.15).
Cutaneous involvement is often the first manifestation of disease. Patients
B develop necrosis of skin, which, in some cases, is widespread and severe.8 In
addition to disfiguring necrosis, these patients suffer pain and are at risk of
Fig. 16.125 superimposed infection.9 Livedo reticularis is due to thrombotic involvement
Monoclonal cryoglobulinemia: (A) crusted ulcer with occluded vessels at its base;
of arterioles and arteries.
(B) high-power view of a hyaline thrombus.
Systemic involvement includes deep venous thrombosis, often complicated
by pulmonary embolism, renal infarcts, cerebral vascular occlusion with
resultant strokes, transient ischemic attacks, multi-infarct dementia,
myocardial infarction, and gangrene.3 The term ‘catastrophic antiphospholipid
syndrome’ is applied to patients who develop complications resulting from
multiorgan involvement.9,10 The prognosis for this pernicious form of the
disease is poor: in one study, 60% of patients died.10
The association of cutaneous thrombotic lesions, hypertension, and
cerebrovascular disease is sometimes referred to as Sneddon's syndrome.3,11
Not all patients with Sneddon's syndrome have antiphospholipid antibodies –
the prevalence in various publications has ranged from 0% to 85%.11
In addition to lupus erythematosus, the antiphospholipid syndrome has also
been documented in association with other autoimmune diseases including
rheumatoid arthritis, hemolytic anemia, thrombocytopenic purpura, and
ulcerative colitis.12 It may also complicate treatment with a number of drugs
including phenothiazines and procainamide, or develop during viral illnesses,
and can present with an underlying lymphoma.12
There is a growing body of literature documenting systemic vasculitis
in patients with antiphospholipid and anticardiolipin antibodies including
Takayasu's arteritis, temporal arteritis, polyarteritis nodosa, and Wegener's
granulomatosis.13–18 A patient with Degos' disease and anticardiolipin
antibodies has also been described.19
Carcinomas arising in lung, ovary, gastrointestinal tract, and kidney have
been reported in association with antiphospholipid syndrome.20–25
Fig. 16.126 The syndrome has been reported in patients infected with the human
Mixed cryoglobulinemia: in this example, the features of acute leukocytoclastic immunodeficiency virus.26–28 Some HIV-infected patients have antiphospholipid
vasculitis are evident. antibodies without clinical features of the antiphospholipid syndrome.26
Table 16.15
Preliminary criteria for the classification of the antiphospholipid syndrome*
Clinical criteria†
1. Vascular thrombosis: One or more clinical episodes of arterial, venous or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed
by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For histopathological confirmation, thrombosis
should be present without significant evidence of inflammation in the vessel wall.
2. Pregnancy morbidity:
(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology
documented by ultrasound or by direct examination of the fetus, or
(b) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe pre-eclampsia or
eclampsia, or severe placental insufficiency, or
(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities
and paternal and maternal chromosomal causes excluded.
In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of
subjects according to (a), (b) or (c) above.
Laboratory criteria
1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 weeks apart, measured
by a standardized enzyme-linked immunosorbent assay for β2-glycoprotein I-independent anticardiolipin antibodies.
2. Lupus anticoagulant present in plasma, on two or more occasions, at least 6 weeks apart, detected according to the guidelines of the International Society
on Thrombosis and Hemostasis (Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-Dependent Antibodies), in the following steps:
(a) Prolonged phospholipid-dependent coagulation demonstrated on a screening test, e.g. activated partial thromboplastin time, kaolin clotting time,
dilute Russell's viper venom time, dilute prothrombin time, Textarin time.
(b) Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma.
(c) Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid.
(d) Exclusion of other coagulopathies, e.g. factor VIII inhibitor or heparin, as appropriate.
Definite antiphospholipid antibody syndrome is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met.
* No exclusions other than those contained within the above criteria are needed. However, because of the likelihood that thrombosis may be multifactorial in patients with the
antiphospholipid antibody syndrome, the workshop participants recommend that: (a) patient populations being studied should be assessed for other contributing causes of
thrombosis, and (b) such populations should be stratified according to identifiable or probable risk factors (e.g. age or comorbidities). Specific limits were not placed on the interval
between the clinical event and the positive laboratory findings. However, it was the view of many at the workshop that: (a) information about such intervals should be assessed when
relevant, and (b) the relatively strict definition of laboratory criteria (including the requirement that results again be positive on repeat tests performed at least 6 weeks after the initial
test) would help to exclude antiphospholipid antibody positivity that represents an epiphenomenon to the clinical events.
† These criteria were mainly developed by Branch and Silver.
Reproduced with permission from Wilson, W.A. (2001) Rheumatic Diseases Clinics of North America, 27, 499–505.

Thrombotic thrombocytopenic purpura and
Antibodies (IgM or IgG) that are reactive with phospholipids clearly play a
role in the pathogenesis of this disorder; however, the precise pathogenesis hemolytic uremic syndrome
is not well understood. Theories include inhibition of protein C (a natural
vitamin K-dependent anticoagulant) function and a suppressive effect on Clinical features
endothelial cell prostacyclin.29 Endothelial cell injury and platelet activation Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome
may also play a role. The role of beta-2 glycoprotein, a glycoprotein with (HUS) are related disorders that are due to nonimmune thrombocytopenia.1–4
antithrombotic properties, has been investigated. Some antiphospholipid TTP is a very rare disease of unknown etiology associated with high morbidity
antibodies bind to beta-2 glycoprotein 1, which can lead to inhibition of factor and mortality.5,6 It shows a predilection for females (2.5:1) and tends to affect
XII and platelet activation and also decrease prothrombinase activity. younger age groups, with a peak incidence in the third decade. In its fully
Patients with the antiphospholipid antibody are predisposed to thrombosis developed form it consists of thrombocytopenic purpura, microangiopathic
and have prolonged partial thromboplastin and kaolin clotting times; hemolytic anemia, neurological symptoms, renal involvement, and fever.
however, it is important to note that not all patients with the antiphospholipid Hemolytic uremic syndrome is similar to TTP except that it includes severe
antibody develop thrombosis. In one study, 28% of lupus patients with renal involvement and milder CNS symptomatology.7 However, precise
antiphospholipid antibodies had no evidence of antiphospholipid antibody classification into one or the other category is sometimes difficult; therefore
syndrome.30 these related disorders are discussed together.8,9 Hemolytic uremic syndrome
Biopsy shows features of a thrombotic vasculopathy, i.e. vascular occlusion is often seen in patients with infectious colitis.10,11
of arterioles and arteries with a fibrinoid plug, which may be associated with The most common presenting symptoms are transient and usually
variable numbers of intraluminal inflammatory cells. Generally, there is recurrent neurological complaints including headaches, confusion, pareses,
minimal or no inflammation of the blood vessel wall or surrounding tissue. dysphasia, and aphasia. Renal involvement includes hematuria, proteinuria,
Marked dermal necrosis is sometimes a feature. It should be noted that false- and occasionally acute renal failure. Cardiac involvement is important and
negative biopsies may occur.11 Therefore a negative biopsy does not exclude may precipitate left ventricular failure with resultant pulmonary congestion
underlying disease. and edema. The hemorrhagic tendency is manifest predominantly in the skin
as petechiae, purpura, and ecchymoses, but hemorrhage may also be seen
Differential diagnosis in the retina, conjunctiva, and mucous membranes, including those of the
The biopsy findings are non-specific and the differential diagnosis includes gastrointestinal tract (Fig. 16.127).
other forms of thrombotic vasculopathy. Serological studies are required to TTP/HUS can be associated with connective tissue disease (especially lupus
evaluate for antiphospholipid and anticardiolipin antibodies as well as to erythematosus), contraceptive use, neoplasia, chemotherapy, adverse drug
evaluate for underlying associated disorders. reaction, bone marrow transplantation, and antiphospholipid antibodies.4,7,12–17
Immune thrombocytopenic purpura 707
Fig. 16.127
Thrombotic Fig. 16.128
thrombocytopenic Thrombotic thrombocytopenic purpura: microthrombi are present and there is
purpura: sheeted extensive red cell extravasation.
ecchymoses are present
in the groin. By courtesy
of N. Slater, MD, St
Thomas' Hospital,
London, UK.
Although most patients develop TTP for no apparent reason, it occasionally

complicates drug therapy with, for example, penicillin or sulfonamides, or may
develop after an upper respiratory tract infection. Quite a high proportion of
patients with TTP are pregnant, but the significance of this is uncertain. Rare
cases may be associated with lupus erythematosus.
Familial cases of TTP/HUS, with both autosomal dominant and recessive
patterns of inheritance, have been described.7
Laboratory investigations reveal gross thrombocytopenia and normo
chromic, normocytic anemia. Examination of peripheral blood smears
commonly demonstrates fragmented and misshapen red blood cells, typically
schistocytes and helmet cells. Coagulation studies are usually normal or
minimally disturbed with occasionally elevated fibrinogen–fibrin degradation
products. The Coombs' test is consistently negative.
Fig. 16.129
Pathogenesis and histological features Thrombotic thrombocytopenic purpura: the occlusions contain abundant fibrin
The pathogenesis of TTP/HUS is poorly understood. It appears that platelet (Martius scarlet blue).
activating substances result in thrombus formation without activation of
the coagulation cascade (hence the normal coagulation studies). Direct
endothelial injury could also play a role in this group of disorders. At autopsy the organs most severely involved include the pancreas, adrenal
TTP has been shown to be associated with deficiency of von Wille glands, heart, brain, and kidney.
brand factor-cleaving metalloprotease, ADAMTS13 (a disintegrin and
metalloprotease with thrombospondin 1 repeats-13).18–22 Most cases Differential diagnosis
in adulthood are acquired and caused by autoantibodies inhibiting the
Distinction from other thrombotic vasculopathies requires clinicopathological
function of ADAMTS13.21–23 Familial cases of TTP are due to mutations in
correlation. In contrast to disseminated intravascular coagulation, coagulation
ADMATS13, resulting in constitutional absence of this enzyme.18,21,22 HUS
studies (prothrombin time, partial thromboplastin time) tend to be normal in
is often seen in patients with colitis associated with verotoxin-producing
patients with TTP/HUS.
E. coli.1,24 In one study, 80% of patients with HUS had positive E. coli O157
lipopolysaccharide antibody titers.10 Investigators have shown that verotoxin
enhances platelet adhesion and thrombogenesis using a microvascular
endothelial cell line.25 A minority of patients with HUS have been shown to Immune thrombocytopenic purpura
have mutation in the gene coding for factor H, an alternative complement
pathway regulatory protein.26 Clinical features
The histological features of thrombotic thrombocytopenic purpura are Immune thrombocytopenic purpura (idiopathic thrombocytopenic purpura,
those of hyaline intravascular thrombi composed of aggregates of platelets ITP) is a rare disease, of which two forms – acute and chronic – are
in addition to a variable amount of fibrin (Figs 16.128, 16.129).27 They recognized:
are associated with extravasated red blood cells, but there is no evidence of • Acute ITP is a disorder that characteristically affects children following
vasculitis. There may be foci of necrosis, but true infarcts are uncommon. a viral illness.1 Patients present with petechiae, purpura, and bleeding.
Fig. 16.130
Idiopathic thrombocytopenic purpura: these legs show purpura, petechiae, and Fig. 16.131
bruising. By courtesy of N. Slater, MD, St Thomas' Hospital, London, UK. Idiopathic
thrombocytopenic
purpura: there is
Most cases are self-limiting with the majority of patients recovering hemorrhage but no
within weeks to months.2,3 A rare but serious complication is intracranial evidence of vasculitis is
seen.
hemorrhage.
• Chronic ITP is the term used when the disorder persists for 6 months
or longer.2 The chronic form tends to affect adults and is associated
with connective tissue diseases such as lupus erythematosus or Factor V (Leiden) mutation
lymphoproliferative disorders.
Thrombocytopenic purpura has also been described in patients with Clinical features
thyroid disorders, including Graves' disease and Hashimoto's thyroiditis.4,5 Mutation of factor V Leiden is the most common inherited condition
The condition may occur in association with multiple concurrent predisposing to thrombosis.1 The mutation is associated with a prothrombotic
autoimmune diseases such as diabetes mellitus, pernicious anemia, and state caused by factor V resistance to inactivation by protein C. It can be
systemic sclerosis.6 Some patients have had associated antiphospholipid identified by PCR.
antibody syndrome.7–9 Patients with Helicobacter pylori infection or those Patients with this mutation are at particular risk of deep venous thrombosis
infected with the human immunodeficiency virus may also develop immune and may also develop pulmonary embolism, stroke, and peripheral vascular
thrombocytopenia.10–13 disease.2 Women with recurrent miscarriage have an increased incidence of
The chronic form shows a predilection for women, and presents with a this condition.3,4 Among patients with no known explanation for deep venous
tendency to bruise easily following mild trauma and bleeding (Fig. 16.130). thrombosis, factor V Leiden mutation is a common cause. Patients may also
In severely affected patients, lesions develop in the mucous membranes of develop skin ulcers.
the respiratory, genitourinary, and gastrointestinal systems in addition to the
integument. Histological features
Laboratory examination reveals thrombocytopenia and a prolonged
Biopsy of skin lesions shows features of thrombotic vasculopathy. IgM and
bleeding time. Partial thromboplastin time and prothrombin time are not
C3 deposition has been demonstrated by immunofluorescence staining.5
affected.
Pathogenesis and histological features Hypergammaglobulinemic purpura

Immune thrombocytopenic purpura is an autoimmune disease caused by
IgG antiplatelet antibodies, which lead to destruction of platelets.14–16 More
Clinical features
recently, a cytotoxic T cell-mediated process has also been implicated in platelet Hypergammaglobulinemic purpura (of Waldenström) is a rare disorder
destruction.17 Molecular mimicry between HIV glycoproteins (GP120/160) that shows a marked female predilection and tends to affect the young and
and membrane antigens (i.e. glycoprotein GPIIb/IIIa) on platelets may play middle aged.1 Patients present with recurrent, symmetrical crops of purpura,
a role in the development of thrombocytopenia in occasional HIV-infected particularly affecting the lower limbs although the arms and abdomen may
patients.14,16,18,19 also be involved (Fig. 16.132).2 Wearing tight-fitting garments, heat, and
The cutaneous (and other) lesions are characterized by perivascular strenuous exercise may provoke lesions. The frequency of attacks is highly
hemorrhage; there is no evidence of vasculitis (Fig. 16.131). Bone marrow variable, ranging from several times a week to as infrequent as a single episode
examination reveals increased numbers of rather immature megakaryocytes. per year.3,4
The spleen is congested and shows reactive follicular hyperplasia and The clinical findings are those of petechiae measuring from pinhead size
sometimes conspicuous megakaryocytes. up to several millimeters. Various symptoms may be experienced, including
tingling, itching, burning, and pain. The petechiae resolve over the course
of a few days to leave hyperpigmented macules. The purpuric attacks are
Differential diagnosis recurrent and tend to great chronicity. Ecchymoses are not a feature.1
Biopsy findings are entirely non-specific. Serological and clinical correlation Laboratory investigations usually reveal a raised ESR, mild anemia
is necessary to arrive at a diagnosis. and leukopenia, and polyclonal hypergammaglobulinemia (usually IgG,
Sclerosing lymphangitis 709
minor infections may be inciting events. Fever attacks are accompanied

by abdominal symptoms, headaches, generalized lymphadenopathy, and
arthralgias of large joints.3,4 Amyloidosis is a rare complication.3 Cutaneous
manifestations include erythematous macules, papules, and nodules as well
as urticarial lesions.5 Elevated IgD levels can be demonstrated in the majority
of patients.3
The skin biopsy findings are variable and most frequently show a mild acute
vasculitis. Rarely, the features are reminiscent of Sweet's syndrome, cellulitis
or erythema elevatum diutinum.4–6
Superficial thrombophlebitis
Clinical features
Superficial thrombophlebitis is a common disease presenting as painful,
erythematous, thickened areas with a cordlike morphology. Most cases involve
Fig. 16.132 the lower limbs, particularly below the knees, and there is a predilection for
Hypergammaglobulinemic purpura: scattered, tiny, purpuric lesions. By courtesy of females. Multifocal segmental disease is frequent and recurrent episodes
J. Newton-Bishop, MD, St Thomas' Hospital, London, UK.
are often seen. The disease is usually associated with hypercoagulable
states. Predisposing factors are numerous and include varicose veins,
pregnancy, the use of oral contraceptives (particularly those with a higher
concentration of estrogen), cancer (mainly breast, colonic, pancreatic, gastric,
but sometimes IgM or IgA). Antinuclear antibodies, anti-Ro, anti-La, and
cholangiocarcinoma, hematological as well as cutaneous), Behçet's disease,
rheumatoid factor are present in many patients.1,3,5,6 Platelet levels, coagulation
factor V (Leiden) mutation, essential thrombocythemia, anticardiolipin
studies, and bone marrow examination are typically normal. Cryoglobulinemia
antibodies, and deficiencies of protein C, protein S, factor XII, antithrombin
is an occasional feature. There are no known HLA associations and family
III, and heparin cofactor 2C.1–17 Superficial thrombophlebitis developing
history is negative.1 Lymphadenopathy and splenomegaly are sometimes a
in association with secondary syphilis has been documented.18 Superficial
feature.1
suppurative thrombophlebitis occurs mainly in children and it is caused by a
It is important to note that hypergammaglobulinemic purpura may be
wide variety of microorganisms, mainly bacteria (both aerobic and anaerobic)
classified into two categories: idiopathic (Waldenström; not to be confused
and, less commonly, fungi.19–23 The most common bacteria isolated include
with Waldenström's macroglobulinemia) and secondary. In the latter group,
S. aureus, E. coli, and P. aeruginosa.19,20 Candida is by far the most common
patients have a wide variety of conditions, including SLE, polymyositis,
fungus associated with the disease.
Hashimoto's thyroiditis, Sjögren's syndrome, rheumatoid arthritis,
Superficial thrombophlebitis may be associated with deep vein
hepatitis, chronic lymphocytic leukemia, monoclonal gammopathies, and
thrombosis but the risk of this happening appears to be small unless there
sarcoidosis.1 The purpura may precede the associated illness for many
are additional risk factors.24,25 The chance of a patient with superficial
years. Patients with this disorder, therefore, merit a careful and prolonged
thrombophlebitis developing pulmonary embolism is low, but it has been
follow-up.
documented and the risk appears to be greater in patients with disease
affecting the thigh.26–28
Direct immunofluorescence examination of skin lesions reveals IgM and
C3 in blood vessel walls.7 Circulating immune complexes, with both IgG Histological features
and IgM, have also been demonstrated in patients with this disorder.8 It is Superficial thrombophlebitis typically involves veins located in the superficial
likely, therefore, that hypergammaglobulinemic purpura is another variant subcutaneous tissue. Early lesions are characterized by an infiltrate
of immune complex-mediated vasculitis, namely, a type III hypersensitivity predominantly composed of neutrophils obscuring the vessel walls. The
reaction. The precise etiology, however, remains poorly understood. neutrophils are progressively replaced by lymphocytes, histiocytes, and
Histological examination of the purpuric lesions usually reveals the typical occasional giant cells. An organizing thrombus is initially present and this
features of acute leukocytoclastic vasculitis with red cell extravasation.9 is followed by recanalization and fibrosis. The infiltrate tends to remain
Occasionally, however, lymphocytic perivasculitis is all that is evident. localized and there is very little involvement of the surrounding subcutaneous
tissue. Arteries are not affected.
The histological changes are not specific and other causes of leukocytoclastic
vasculitis must be considered. Sclerosing lymphangitis
Clinical features
Hyperimmunoglobulinemia D syndrome Sclerosing lymphangitis (Mondor's disease) is probably a misnomer as it likely
represents a variant of superficial thrombophlebitis that most commonly affects
Clinical features the genitalia, chest wall or breasts. Women with large pendulous breasts seem to
Hyperimmunoglobulinemia D syndrome is a rare autosomal recessive disease be particularly predisposed.1 In these cases, and in others, trauma probably plays
due to mutations in the mevalonate kinase (MVK) gene, a key enzyme a significant role in development. Some authors have reported an association
located on chromosome 12 and involved in the biosynthesis of cholesterol with breast carcinoma.2 Intravenous drug abuse may be an occasional cause
and isoprenoid.1,2 and sclerosing lymphangitis of the penis has been documented in association
The disease is most common in Europe and presents in childhood as with an underlying sexually transmitted disease.3,4 Sickle cell disease and
recurrent episodes of high fever lasting for 3–7 days. Vaccinations and protein S deficiency are rare associations.5,6 Patients present with sometimes
painful linear cordlike lesions. Typically, lesions are a few centimeters in length
but sometimes may be much larger. The overlying skin is erythematous without
color change. The disorder is self-limiting and usually resolves in a few weeks.7
Rarely, persistent disease requires surgical intervention.8
The pathology is characterized by organizing thrombus with variable
inflammation.
Senile purpura
Clinical features
Senile purpura affects the extensor surfaces of the forearms, hands, and lower
legs of the elderly.1,2 Corticosteroid therapy (topical or systemic) contributes
to its development in some patients. Lesions are persistent, lasting 1–3 weeks,
and consist of asymptomatic purpuric macules up to several centimeters
in diameter, in a background of actinically damaged or atrophic skin (Fig.
16.133). Senile purpura develops because of damage to the connective tissue
of the dermis, which fails to support the vasculature, rendering it more Fig. 16.133
susceptible to mild trauma. Senile purpura: trauma-
induced deep purple
ecchymoses on sun-
Histological features damaged skin. By
The lesions are characterized by red cell extravasation unassociated with courtesy of J. Newton-
any significant inflammatory cell reaction. There is usually marked solar Bishop, MD, St Thomas'
elastosis. Hospital, London, UK.
Idiopathic connective Chapter
See
for references and
additional material
tissue disorders
17
Lupus erythematosus 711 Atrophoderma of Pasini and Pierini 748 Mixed connective tissue disease 756
Systemic sclerosis 734 Eosinophilic fasciitis 749 Relapsing polychondritis 757
Localized scleroderma 743 Polymyositis/dermatomyositis 751
in up to 20% of patients with systemic lupus.11 Periungual telangiectasia, sclero-

Lupus erythematosus dactyly, and the presence of Raynaud's phenomenon may also signify potential
disease progression.10 Patients with DLE should not be made unduly worried
Lupus erythematosus is a complex disorder associated with numerous clinical about the risk of developing systemic involvement, which is not high.
signs and symptoms and a wide range of laboratory abnormalities. It shows Discoid lupus erythematosus is persistent and affects twice as many females
a spectrum of varying prognosis, ranging from a benign, solely cutaneous as males. Although any age group may be involved, it is most common in the
variant (localized discoid) through to a potentially fatal systemic illness.1–4 third, fourth, and fifth decades, with a peak incidence in the late thirties.12
The range of subtypes is shown in Table 17.1. Presentation in childhood is rare.13–18 Lesions typically arise on sun-exposed
Although the precise etiology is unknown, it is thought that interplay of sites and patients frequently experience photosensitivity; there may be spring
genetic factors, autoantibodies, immune complexes, hormones, and other fac- and summer exacerbation.5 In the localized form, the head and neck are usu-
tors is responsible for the development of the illness. There is evidence sug- ally affected, but in the generalized variant, lesions may also be present on the
gesting that the incidence of the systemic variant is increasing, but due to dorsal aspect of the arms, hands, and fingers and on the ‘V’ of the neck.
earlier diagnosis and more effective therapy, the mortality rate has signifi- Nonexposed sites, including the trunk, upper limbs, and the palms and soles,
cantly diminished and the 10-year overall survival rate in adults now exceeds are also commonly involved.19
90%.5 The presence of renal and/or neurological involvement, however, Facial plaques occur most often on the cheeks (Fig. 17.1). Other sites
remains a poor prognostic indicator.6 affected include the bridge of the nose, the ears, the neck, and the scalp (Figs
Pediatric systemic lupus erythematosus (SLE) is an aggressive illness with con- 17.2–17.6). The associated scarring of the scalp is followed by permanent
siderable mortality, largely due to the incidence of renal disease. Even with corti-
costeroid and immunosuppressive therapy the death rate is as high as 15%.7
Clinical features
Discoid lupus erythematosus
Discoid lupus erythematosus (DLE), the commonest form, is subdivided into
localized and generalized variants. This is of prognostic importance because only
about 1% of patients with localized DLE develop systemic disease, but approxi-
mately 5% of those with the generalized form (in particular those with persistent
anemia, leukopenia, thrombocytopenia, false-positive Wassermann reaction, and
high-titer antinuclear factor) develop full-blown SLE.6,8–10 Discoid lesions develop
Table 17.1
Lupus erythematosus: subtypes
Discoid lupus erythematosus (localized)

Discoid lupus erythematosus (generalized)
Verrucous lupus erythematosus Fig. 17.1
Chilblain lupus erythematosus Discoid lupus
Chronic granulomatous disease with discoid lupus erythematosus-like erythematosus: typical
dermatosis plaques are present on
Lupus erythematosus–erythema multiforme syndrome the cheek of a female.
Subacute cutaneous lupus erythematosus Note the erythema
Lupus erythematosus profundus and scale. This is a
Systemic lupus erythematosus characteristic site. From
Drug-induced lupus erythematosus the collection of the
C2 deficiency lupus erythematosus-like syndrome late N.P. Smith, MD, the
Neonatal lupus erythematosus Institute of Dermatology,
London, UK.
712 Idiopathic connective tissue disorders
Oral involvement occurs in 20–25% of patients with DLE, with the vermilion
border of the lower lip, alveolar processes, labial and buccal mucosae being par-
ticularly affected (Figs 17.15–17.17).21–26 Chronic lesions are typically erythema-
tous and atrophic with a scalloped white keratotic border and adjacent
telangiectasia.22 Erosions and ulcers are additional features.12 Lesions are some-
times indistinguishable from atrophic lichen planus. Involvement of the tongue
manifests as erythema, fissuring, and atrophy of the papillae.23 Chronic lupus
cheilitis is associated with cicatricial scarring and an increased risk of squamous
carcinoma.22 Perianal mucosal involvement has occasionally been documented.23
Discoid lupus erythematosus has been described in association with osteo-
poikilosis, α1-antitrypsin deficiency, polyarteritis nodosa, in a patient with scle-
roderma and chronic hepatitis C virus infection, and as a reaction to
tattoo.27–31
Verrucous (hypertrophic) discoid lupus erythematosus

Verrucous (hypertrophic) DLE presents as warty, hyperkeratotic papules and
plaques with a predilection for the face, scalp, mucous membranes of the lips,
and upper limbs (Figs 17.18, 17.19).5,32–34 It affects approximately 2% of
Fig. 17.2 patients with chronic discoid disease.12 Although verrucous (hypertrophic)
Discoid lupus erythematosus: close-up view showing erythema and scale. From the hyperkeratotic skin changes have been observed in patients with SLE, such
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. cases are exceptional.34,35 Sometimes the palms and soles are affected and
occasionally the nails (Figs 17.20, 17.21). Rare manifestations include nodu-
alopecia (Figs 17.7,17.8). Scalp involvement, which is more common in lar keratoacanthoma-like, squamous cell carcinoma-like, and hypertrophic
those patients affected by the disease when they were young, is chronic, and lichen planus-like lesions on the arms and hands (Fig. 17.22).33,36 A variant
correlates with longstanding severe illness.20 with associated necrosis of the subcutaneous tissue is known as lupus erythe-
Early lesions appear edematous and erythematous. An established plaque matosus hypertrophicus et profundus.37
of DLE, which may measure up to 10.0 cm across, is usually covered with Systemic symptoms are usually absent in patients with localized DLE.38
an adherent scale accompanied by epidermal atrophy, follicular dilatation, In the generalized form in which cutaneous plaques may be quite wide-
and plugging (Figs 17.9, 17.10).5,19 If the scale is removed the horny plugs spread, a small percentage may have Raynaud's phenomenon and arthral-
are often seen attached to its undersurface (‘carpet tacks’ sign). Telangiectasia gia (Figs 17.23–17.25). Laboratory abnormalities are more common in the
is a common finding and lesions heal with scarring, which is often marked. generalized than in the localized variant.38 Anemia is not seen in localized
In dark- or black-skinned individuals the plaque may be hypo- or hyperpig- DLE, but is sometimes a feature of the generalized variant. Leukopenia, a
mented and this may be particularly disfiguring (Figs 17.11–17.14).19 raised erythrocyte sedimentation rate (ESR), and hypergammaglobulinemia
Fig. 17.3 Fig. 17.4 Fig. 17.5

Discoid lupus erythematosus: there is scaling and Discoid lupus erythematosus: this severely affected Discoid lupus erythematosus: in this chronic
scarring on the ear lobe, a commonly affected site. patient shows healed ulceration with marked scarring lesion there is marked scarring. By courtesy of
From the collection of the late N.P. Smith, MD, and disfigurement. By courtesy of the Institute of R.A. Marsden, MD, St George's Hospital,
the Institute of Dermatology, London, UK. Dermatology, London, UK. London, UK.
Fig. 17.6 Fig. 17.7 Fig. 17.8

Discoid lupus erythematosus: dark-skinned races Discoid lupus erythematosus: hair loss is permanent. Discoid lupus erythematosus: there is alopecia with
are commonly affected. From the collection of the By courtesy of the Institute of Dermatology, very marked scarring. By courtesy of the Institute
late N.P. Smith, MD, the Institute of Dermatology, London, UK. of Dermatology, London, UK.
London, UK.
Fig. 17.9 Fig. 17.10

Discoid lupus erythematosus: close-up view of scale. Note the erythematous Discoid lupus
border. By courtesy of the Institute of Dermatology, London, UK. erythematosus: close-up
view showing follicular
plugging. By courtesy
can occur in both.8 Antinuclear factor (diffuse pattern), a positive of the Institute of
Wassermann reaction, and rheumatoid factor may also be features.8 Anti- Dermatology, London,
double-stranded DNA (dsDNA) antibodies are detected in a minority of UK.
patients with disseminated DLE, and these patients frequently transform to
the systemic disease; occasionally antibodies to single-stranded DNA Lupus erythematosus tumidus
(ssDNA) are present. Urinalysis and renal function tests are normal. Lupus erythematosus tumidus is a distinctive subset of cutaneous lupus clini-
Cutaneous squamous cell carcinoma and less often basal cell carcinoma cally presenting mainly in patients with DLE and rarely in patients with SLE.
may arise in patients with chronic lesions including the hypertrophic vari- It is characterized by erythematous papules, plaques or even nodules with an
ant.19,21,33,39–43 Squamous cell carcinoma occurs predominantly in males, par- urticarial appearance arising mainly on sun-exposed skin of the face, neck,
ticularly affects the scalp, and is sometimes associated with early and trunk. Scarring does not occur. This variant of lupus is discussed in more
metastases.6,44 detail in chapter 8.
Fig. 17.11
Discoid lupus Fig. 17.13
erythematosus: foci of Discoid lupus erythematosus: marked hypopigmentation may be a distressing
hyperpigmentation can complication. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
be very disfiguring in
dark-skinned patients. By
UK.
Fig. 17.14
Discoid lupus
erythematosus: in
this patient, the arm
is severely affected.
By courtesy of R.A.
Fig. 17.12 Marsden, MD, St
Discoid lupus erythematosus: close-up view. By courtesy of R.A. Marsden, MD, George's Hospital,
St George's Hospital, London, UK. London, UK.
Chilblain lupus erythematosus

Chilblain lupus erythematosus (CHLE), which accounts for approximately sole manifestation.50 Some patients with sporadic CHLE have an associated
11% of DLE cases, develops during the winter months or following expo- cryofibrinogenemia or cold agglutinin.6 About 20% of patients with spo-
sure to cold, wet, and damp conditions.45,46 Although CHLE appears most radic CHLE develop SLE, particularly those who develop discoid and perni-
frequently in sporadic patients,47 familial occurrence has recently been otic lesions simultaneously and those with DLE-erythema multiforme-like
reported.46,48,49 Patients with familial CHLE display mutations in the TREX1 syndrome in addition to perniosis.6,45,47 None with the familial CHLE have
gene located on chromosome 3p, encoding a DNA-specific 3′-5′ exonu- progressed to SLE.47
clease 1.46,48,49 Autosomal dominant inheritance has been demonstrated in
these patients.46,48,49 While familial CHLE generally presents in early child-
Lupus erythematosus-erythema multiforme-like
hood, sporadic CHLE usually affects middle-aged females.45,46,48,50 Patients syndrome
develop itchy, painful, papuloerythematous or blue-purple plaques and The lupus erythematosus-erythema multiforme-like syndrome (Rowell's syn-
nodules on the fingers, heels, and soles of the feet; the hands, calves, knees, drome) is rare.52–58 Patients, mostly middle-aged women, develop recurrent
knuckles, elbows, nose, and ears are less often affected (Fig. 17.26).6 episodes of annular lesions on the limbs and, to a lesser extent, on the face,
Hyperkeratotic fissured lesions and ulcers are sometimes also present.50 neck, chest, and mouth, in addition to the features of any variant of lupus
CHLE may present with depigmentation mimicking vitiligo.51 Although erythematosus.6,52,59–61 Involvement of palms and soles is exceptional.62 Early
patients usually develop chilblains many years after the typical discoid rash, lesions are erythematous papules, which become annular and may vesiculate
lesions may develop simultaneously and sometimes the chilblains are the at the edge. The condition usually heals without scarring, but in severe
Fig. 17.15 Fig. 17.18

Discoid lupus erythematosus: there is gross ulcerative cheilitis. The upper lip has Verrucous discoid lupus erythematosus: this lesion has a very warty appearance.
been stained with gentian violet. By courtesy of R.A. Marsden, MD, St George's By courtesy of the Institute of Dermatology, London, UK.
Fig. 17.16 Fig. 17.19

Discoid lupus erythematosus: typical scarred lesion on the buccal mucosa. By Verrucous discoid lupus erythematosus: extensive disfiguring warty plaque
courtesy of R.A. Marsden, St George's Hospital, London, UK. involving the upper lip and angle of mouth. By courtesy of J. Newton Bishop, MD,
St James's University Hospital, Leeds, UK.
disease bullae may develop, become necrotic, and ulcerate. Patients with this
variant also have erythrocyanosis, chilblains, and Raynaud's phenomenon.
Their serum contains speckled antinuclear factor, rheumatoid factor, and
anti-Ro/La antibody.6,8,52,53 In rare cases, anti-Ro/La and rheumatoid factor
are negative.63 Association with antiphospholipid syndrome has exception-
ally been documented.64,65

Lupus erythematosus profundus (panniculitis) is another uncommon variant
that may develop in association with either DLE or SLE. This is discussed in
detail in chapter 10.
DLE and chronic granulomatous disease

Occasionally, a DLE-like dermatosis develops in female carriers of X-linked
chronic granulomatous disease.66–70 Mothers of affected children may occa-
sionally show similar lesions, presenting with bluish-red, infiltrated, scaly pap-
Fig. 17.17 ules on the face and hands, sometimes associated with photosensitivity.67
Discoid lupus erythematosus: oral involvement is sometimes difficult to distinguish Additional features include recurrent aphthous-like ulcerative stomatitis and
from lichen planus. By courtesy of the Institute of Dermatology, London, UK. perniosis.
Fig. 17.20 Fig. 17.22

Verrucous discoid lupus Verrucous discoid lupus erythematosus: this example resembles a
erythematosus: note the keratoacanthoma. By courtesy of the Institute of Dermatology, London, UK.
gross hyperkeratosis. By
courtesy of J. Newton
Bishop, MD, St James's
University Hospital,
Leeds, UK.
Fig. 17.23
Generalized discoid lupus erythematosus: in this variant, lesions are widespread and
may involve the chest, shoulders, and upper limbs. Note the extensive erythema
and scaling. By courtesy of R.A. Marsden, St George's Hospital, London, UK.
Fig. 17.21
Verrucous discoid lupus
erythematosus: note
the hypertrophic cuticle,
pitting and onycholysis.
By courtesy of J. Newton
Bishop, MD, St James's
University Hospital,
Leeds, UK.
X-linked chronic granulomatous disease is inherited as a recessive trait,

and patients (usually boys) have severe and recurrent infections due to defec-
tive neutrophil bactericidal activity. Heterozygous female carriers display a
partial defect, indicated by diminished nitroblue tetrazolium reductions, but
are usually free from infections. An autosomal recessive variant in which dis-
coid lupus-like lesions may occur has also been documented.71 DLE-lesions
have been reported in both carriers and chronic granulomatous disease
patients; however, development of SLE in chronic granulomatous disease
patients is extremely rare.72–76 Subacute cutaneous lupus erythematosus-like Fig. 17.24
lesions and lupus tumidus may also occur.77,78 Discoid lupus erythematosus Generalized discoid lupus erythematosus: note the extensive erythema and scaling.
has also been described in non-X-linked hyper-IgM syndrome.79 By courtesy of R.A. Marsden, St George's Hospital, London, UK.
Fig. 17.25 Fig. 17.27

Generalized discoid lupus erythematosus: in this patient, the chest is severely Subacute cutaneous lupus erythematosus: annular lesions, many healed with
affected. By courtesy of the Institute of Dermatology, London, UK. pigmentary changes and delicate scale overlying an active lesion. From the
Fig. 17.26 Fig. 17.28

Chilblain lupus erythematosus: resolving perniosis involving the tips of the thumb and Subacute cutaneous lupus erythematosus: coalescence of annular lesions has resulted
ring and little fingers. By courtesy of R.A. Marsden, St George's Hospital, London, UK. in this bizarre eruption. By courtesy of the Institute of Dermatology, London, UK.
Subacute cutaneous lupus erythematosus of the annular lesions.85 Pityriasiform and erythema multiforme-like lesions
Subacute cutaneous lupus erythematosus (SCLE) accounts for 5–10% of have also been described, as has occasional chronic leukoderma.81 Exceptionally,
patients with lupus erythematosus.80–82 Approximately 50% have SLE as the disease may present as generalized poikiloderma93,94 or erythroderma.95 In
defined by the revised American Rheumatology Association diagnostic crite- addition, 15–30% of patients develop features of typical DLE, usually located
ria (see below).83 SCLE predominates in Caucasians and is uncommon in on the scalp or face.1,81,83,96 The malar erythema of SLE is also sometimes evi-
Blacks, Koreans and Chinese.84 Females are affected more often than males dent (15%). Subtle hypopigmentation, telangiectasia, nonscarring alopecia,
(2.3:1) and the mean age at presentation is about 40 years.85 This variant of livedo reticularis, Raynaud's phenomenon, and mucous membrane ulcers are
lupus occurs very rarely in children.86–88 Nail dystrophy affecting the majority additional features.81,85 Dystrophic calcification is exceptional.97 Cutaneous
of nails has been reported in a child with SCLE.88 leukocytoclastic vasculitis is seen in a minority of patients and appears to be
The eruption, which is often widely distributed, consists of symmetrical, self-limited and not associated with a worsened prognosis.98
nonscarring, and non-indurated erythematosquamous lesions (Fig. 17.27). Photosensitivity is of major importance and lesions are therefore typically
Unique presentation along the lines of Blaschko has also been reported.89 seen on the face, neck, upper part of back and chest, shoulders, extensor
Absence of induration has been regarded as a useful clinical discrimination fea- aspect of the arms, backs of hands, and fingers (Figs 17.29, 17.30).80,81,92
ture between SCLE and DLE.84 In addition, the absence of follicular plugging, Patients with SCLE have an increased incidence of human leukocyte
adherent scale, and dermal atrophy helps to distinguish the subacute lesion antigen (HLA)-DR3 (75%), HLA-B8, and HLA-A1, and there is a signifi-
from the discoid variant.81 Pruritus is very rare.90 Lesions may become papu- cant association with inherited homozygous C2 and C4 deficiency.81,83,84,99–102
losquamous (psoriasiform) or annular, the latter coalescing to produce polycy- HLA-DR2 is also present at a higher frequency, particularly in those with
clic and gyrate configurations (Fig. 17.28).81,91,92 In some patients both patterns papulosquamous rather than annular skin lesions.103 Antinuclear antibodies
are seen. Crusting and vesiculation are sometimes evident on the active border are found in approximately 50% of patients, while anti-Ro (SS-A) antibodies
Fig. 17.29 Fig. 17.30

Subacute cutaneous lupus erythematosus: in this patient, there is very extensive Subacute cutaneous lupus erythematosus: the lesions are intensely erythematous
involvement. By courtesy of Dr J.C. Pascual, Alicante, Spain. and there is marked scaling. By courtesy of Dr J.C. Pascual, Alicante, Spain.
are present in approximately 65%, particularly those with annular polycy- association with inclusion body myositis and interstitial myositis with mitochon-
clic lesions.6,82,86,91,102 Anti-La (SS-B) antibodies are also often evident.5 drial changes has also been documented.115,116 A relationship with lichen planus
The course of SCLE tends to be relatively benign, but systemic manifestations is exceptional.117 Clinically and histologically identical cases have been
are quite common and may be severe.104 Severe extracutaneous disease appears to documented following therapy with hydrochlorothiazide, griseofulvin, antihista-
be more common in men with papulosquamous SCLE.104 The type of cutaneous mines, terbinafine, calcium channel blockers, nifedipine, angiotensin-converting
lesion, however, has not always been proven to correlate with the severity of the enzyme (ACE) inhibitors, proton pump inhibitors, interferon, phenytoin, bupro-
extracutaneous manifestations.105 Renal disease has been reported to be uncom- pion, ticlopidine, capecitabine, lansoprazole, leflunomide, fluorouracil, leuprore-
mon but a recent study found its frequency to be as similar and equally severe as lin, efalizumab, acebutolol, tamoxifen, docetaxel, and statin.118–147
in SLE.85,106 Rarely, patients develop other more serious manifestations of SLE.83
Patients with SCLE have an increased incidence of both rheumatoid arthritis Systemic lupus erythematosus
and Sjögren's syndrome.82,107,108 Those with SCLE and Sjögren's syndrome have In addition to the variable cutaneous manifestations, lesions may be found in
high titers of anti-Ro antibodies, a high incidence of cutaneous vasculitis, and an virtually any organ or system in the body in SLE.148–150 The guidelines of the
increased risk of severe neuropsychiatric and pulmonary involvement.109 SCLE American Rheumatology Association are valuable in establishing the diagno-
has been documented in association with porphyria cutanea tarda, hepatitis B sis: any patient who has experienced four or more of the criteria, either seri-
virus infection, radiotherapy, squamous cell carcinoma of the head and neck ally or concurrently, is considered to have SLE (Table 17.2).151,152 The
region, breast, hepatocellular, and lung carcinoma.110–115 An exceptional condition is characterized by a marked female predominance (9:1) and usually
Table 17.2
Systemic lupus erythematosus: diagnostic guidelines of the American Rheumatology Association
Malar rash Fixed erythema, flat or raised, over malar eminences tending to spare nasolabial folds
Discoid rash Erythematous, raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in old lesions
Photosensitivity Skin rash as result of unusual reaction to sunlight (observed by physician or recounted by patient)
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician
Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling or effusion
Serositis Pleurisy (convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion) Pericarditis (confirmed by ECG or
rub or evidence of pericardial effusion)
Renal disorder Persistent proteinuria (> 0.5 g/day or > 3 if quantification is not performed) Cellular casts (may be RBC, hemoglobin, granular, tubular or mixed)
Neurological Seizures (in absence of offending drugs or known metabolic derangements, e.g., uremia ketoacidosis or electrolyte imbalance)
disorder Psychosis (in absence of offending drugs or known metabolic derangements, e.g., uremia ketoacidosis or electrolyte imbalance)
Hematological Hemolytic anemia with reticulocytosis Leukopenia (< 4000/mm3 on two or more occasions) Lymphopenia (< 1500/mm3 on two or more
disorder occasions) Thrombocytopenia (< 1500/mm3 in absence of offending drug therapy)
Immunological Positive LE cell preparation Anti-DNA (antibody to native DNA in abnormal titer) Anti-SM (presence of antibody to SM nuclear antigen)
disorder False positive serologic test result for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum
immobilization or fluorescent treponemal antibody absorption test
Antinuclear Abnormal ANA titer by immunofluorescence or equivalent assay at any time and in absence of drugs known to be associated with
antibody drug-induced lupus syndrome
ANA, antinuclear antibody; LE, lupus erythematosus; RBC, red blood cell.
Reproduced with permission from Tan, E.M. et al. (1982) Arthritis and Rheumatism, 25, 1271–1277.
presents in the third, fourth, and fifth decades. There is a high incidence Afro-Caribbeans, have lesions similar to those of DLE, apparently associated
among Afro-Caribbeans, with a maximum prevalence of 1/150 females in with a less severe disease and a lower frequency of renal involvement.3,10,92,148
Jamaica. In the United States the incidence is approximately 1/100.5 SCLE-like features are present in 10–15% of patients.153 It has been suggested
Cutaneous involvement occurs in 75–88% of patients.92 Lesions are highly that patients with SLE and SCLE lesions have a more favorable prognosis.154
polymorphic and may mimic many other dermatoses (Table 17.3). The ‘but- Alopecia is important, occurring in about 20% of patients, and may be
terfly rash’ is typical and is a slightly scaly, sometimes edematous, erythema scarring or nonscarring. The nonscarring lesions, which are more common,
that is particularly distributed on the bridge of the nose and on the cheeks often constitute a fairly diffuse hair loss occurring as a non-specific response
(Fig. 17.31). Photosensitivity is common, affecting more than 50% of to stress (telogen effluvium).92 Fractured frontal hairs are characteristic.19
patients, and erythematous or violaceous maculopapular eruptions may Raynaud's phenomenon occurs in 10–40% of patients.92 Purpura and ecchy-
develop, particularly in white patients, at other light-exposed areas such as moses are common and may be partly due to corticosteroid therapy, but throm-
the ‘V’ of the neck, and the forearms.92 Sensitivity is towards both ultraviolet bocytopenia and immune complex-mediated vasculitis also play a role in the
(UV) A and B light. Approximately 15% of patients, particularly pathogenesis. Vasculitis, which occurs in up to 30% of patients, may also result
in infarcts, ulcers, digital nodules, scars, and gangrene (Figs 17.32–17.34).92
Table 17.3 Livedo reticularis that particularly affects the arms and thighs and periarticular
Systemic lupus erythematosus: cutaneous manifestations
sites may be a presenting feature in up to 10% of patients, and the changes of
atrophie blanche have been documented occasionally (livedoid vasculitis) (Fig.
Malar erythema (butterfly rash)
Inflammatory periorbital edema
17.35).92 Livedo reticularis is often a feature of the anticardiolipin syndrome
Mucous membrane lesions
Oral and nasopharyngeal ulceration
Alopecia
– fractured frontal hair
– scarring and nonscarring hair loss
Raynaud's disease with or without skin changes
Cutaneous vasculitis
– urticarial lesions
– palpable purpura
– digital nodules
– cutaneous infarcts
– leg ulcers
– peripheral gangrene
– thrombophlebitis
– livedo reticularis
– periungual erythema and telangiectasia
– hemorrhagic bullous lesions
So-called bullous SLE
Lichen planus-like lesions
Perniotic lesions
Lupus profundus
Chilblain lesions
Sjögren's syndrome Fig. 17.32
Calcinosis cutis Systemic lupus
Rheumatoid nodules erythematosus:
Pigmentary changes erythematous vasculitic
lesion on the fingertip. By
Reproduced from Moschella, S.L. (1989) Journal of Dermatology, 16, 417–428, with courtesy of M.M. Black,
permission from Blackwell Publishing Ltd. MD, St Thomas' Hospital,
London, UK.
Fig. 17.31 Fig. 17.33

Systemic lupus erythematosus: characteristic ‘butterfly erythema’ on the cheeks Systemic lupus erythematosus: involvement of the palms is rare and may be
and nose. By courtesy of Dr J.C. Pascual, Alicante, Spain. vasculitic. By courtesy of the Institute of Dermatology, London, UK.
urpura, mixed cryoglobulinemia, and soft tissue calcifications.5,19,161,162

p
Vesicles and bullae in SLE may complicate extreme basal cell hydropic degen-
eration, represent coexpression of an autoimmune bullous dermatosis, or sig-
nify a specific dermatitis herpetiformis-like eruption (bullous dermatosis of
SLE). There is a recognized association with porphyria cutanea tarda.163
Approximately 5–10% of patients with SLE are antinuclear antibody neg-
ative. This seems to correlate with a specific subtype. Patients are usually
HLA-DR3 positive and have Sjögren's syndrome and an increased incidence
of pulmonary involvement, psychiatric manifestations, cutaneous vasculitis,
and hypergammaglobulinemic purpura.5
Non-specific symptoms are common and include chronic tiredness, weight
loss, fever, malaise, and weakness. Arthralgia and myalgia occur in 90% of
patients. The myalgia may be disabling, but objective muscle weakness is rare.164
Similarly, although arthralgia may be marked, there is usually little clinical evi-
dence of joint damage. Effusions are common.148 Approximately 25% of patients
have frank arthritis, either a migratory polyarthritis or a chronic progressive
polyarthritis with deformity. Patients sometimes develop avascular bone necro-
sis due either to the primary disease or to steroid therapy.148,164 Very rarely,
involvement of the tendons is associated with the development of contractures.
Fig. 17.34 Lesions of the cardiovascular system manifest as cardiomegaly, pericardi-
Systemic lupus erythematosus: erythematous nodules are present on the back of
tis, pericardial effusion and/or endocarditis (Libman-Sacks valvulitis).165 In
the hand and on the fingers. By courtesy of Dr J.C. Pascual, Alicante, Spain.
SLE, the mitral valve is predominantly affected, but patients with the lupus
anticoagulant syndrome appear to have a particular risk of developing aortic
valve disease.165,166 Conduction defects and congestive cardiac failure are
additional features.
Respiratory involvement may present as pleurisy, with or without effusion,
bacterial pneumonia or, very rarely, lupus pneumonitis.164 Pulmonary hyper-
tension has been estimated to be present in 0.5–14% of SLE patients, espe-
cially those associated with antiphospholipid antibodies.167
Involvement of the central nervous system is an important cause of mor-
bidity and mortality.148,164 It may affect up to 40% of patients.6 Encephalitis,
meningitis, vasculitis, and coagulation defects give rise to a wide range of
clinical manifestations, including convulsions, hemiplegias, chorea, and psy-
choses.19 Convulsions and coma are an indication of severe involvement and
portend a grave outcome. Peripheral neuritis affects up to 12% of patients;
ocular lesions, including conjunctivitis, fundal hemorrhages, and cotton wool
exudates, occur in 25%.19
Fig. 17.35 Renal manifestations develop in approximately 45% of patients, and pro-
Systemic lupus
gressive renal involvement is an important cause of morbidity and mortality
erythematosus: livedo
reticularis develops
(nephrotic syndrome and lupus glomerulonephritis). Evidence of active renal
as a consequence of disease includes the presence in the urine of more than five red blood cells/
relative ischemia in the high-power field.164 Proteinuria of greater than 1 g/24 hours, oval fat bodies,
watershed zones. There granular, hyaline, and red blood cell casts may also be detected.19
are numerous causes, Generalized lymphadenopathy is present in about 50% of the patients,
particularly connective hepatomegaly in 20%, and splenomegaly in 10%.
tissue disease. By Gastrointestinal manifestations are uncommon; the most important is
courtesy of the Institute esophageal involvement leading to loss of peristalsis and dilatation reminis-
of Dermatology, London, cent of that seen in scleroderma.164
UK.
Laboratory investigation commonly reveals anemia, leukopenia, lym-
phopenia, thrombocytopenia, and a raised ESR. False-positive reactions to
and presenting lesions identical to those seen in Degos' disease (malignant atro- reagin and treponemal tests for syphilis are common, 10–20% of patients are
phic papulosis) have been described occasionally.155,156 Vasculitic features cor- positive for the Coombs' test and rheumatoid factor, and 10–50% have circu-
relate with renal and central nervous system involvement.92 Urticaria is lating anticoagulants.148
frequently found.157 While lupus erythematosus (LE) cell preparation used to be the basic screening
Erythromelalgia, a burning sensation accompanied by erythema following test for SLE, it has now been superseded by testing for antinuclear factor. This and
exposure to heat, has also been noted.21 Localized and diffuse hyperpigmen- other autoantibodies will be discussed further under pathogenesis. Serum comple-
tation and urticarial lesions, including urticarial vasculitis, are less commonly ment levels are often low in patients with active disease (CH50 and C3); estima-
found. Digital manifestations, in addition to infarction and ulceration, include tions of C3 levels are of particular value in following disease activity.5,19
periungual and knuckle erythema, nail fold telangiectases, cuticular lesions, SLE is characterized by relapses, with remissions of variable duration
and splinter hemorrhages. Telangiectases may also be seen on the fingertips sometimes lasting a decade or more. There is still, however, significant mor-
and palms.91 Some patients develop red lunulae.158,159 The associated ery- tality. Causes of death include nephritis, infections, and central nervous sys-
thema multiforme-like and perniotic lesions are described above. Involvement tem involvement.
of the mucous membranes occurs in about 10% of patients: painless ulcer- An association between SLE and inherited complement deficiency, involving
ation is most common, but other features include erythema, petechiae, ero- the early components of the classic pathway including C1r, C1s, C1q, C4, and
sions, and hemorrhage. The central part of the hard palate, lips, and buccal C2, has been described.168–170 Deficiency of C2 is inherited in an autosomal
mucosa are particularly affected.24,156,160 recessive fashion; up to 60% of homozygotes develop lupus erythematosus
Additional lesions that are occasionally seen include rheumatoid-like nod- characterized by an erythematous, papulosquamous, SCLE-like photosensitive
ules, dermal mucinosis, bullous variants, thrombotic thrombocytopenic dermatosis, a low incidence of renal involvement, and arthralgia. Additional
features may include urticarial vasculitis, malar erythema and nail fold abnor-
malities.100 Discoid lesions are sometimes evident, and recently a patient with
C2 and C4 deficiency and LE panniculitis has been documented.12,171 Patients
are, however, often (but not invariably) negative for antinuclear factor and
manifest a negative lupus band test on unaffected skin. There is an association
with HLA-DR2, and over 60% of patients possess anti-Ro antibodies.80
Numerous drugs have been implicated in the induction of SLE including:
• isoniazid, hydralazine, procainamide, rifampicin, quinidine,
penicillamine, terbinafine, carbamazepine, phenytoin, sertraline,
valpromide, amiodarone, atenolol, sulfonamides, methimazole, COL-3,
hydrochlorothiazide, minocycline, spironolactone, captopril, methyldopa,
gold salts, penicillin, streptomycin, phenylbutazone, reserpine,
griseofulvin, clonidine, oral contraceptives, captopril, interleukin (IL)-2,
hydroxyurea, clobazam, clozapine, ciprofloxacin, cefuroxime, nafcillin,
celiprolol, hydralazine, para-amino salicylic acid, yohimbine, infliximab,
adalimumab, pegylated interferon alpha-2B, conjugated estrogens,
anti-tumor necrosis factor alpha (TNF-α), and etanercept.172–231
Transient skin and serological manifestations of SLE have been docu-
mented in two children with trichophyton mentagrophytes infection.211 The
disease has also been linked to hepatitis B vaccination and with exposure to Fig. 17.36
Neonatal lupus erythematosus: note the presence of erythematous, slightly
insecticides.232–235
scaly plaques on the cheeks, forehead, and scalp. By courtesy of the Institute of
Sjögren's syndrome coexists in approximately 10–20% of patients with Dermatology, London, UK.
SLE.91 SLE has also been described in association with scleroderma, morphea,
rheumatoid arthritis, eosinophilic fasciitis, dermatomyositis, lichen sclerosus,
pemphigus (including pemphigus vulgaris, foliaceous, and paraneoplastic
pemphigus), hypergammaglobulinemia of Waldenström, dermatitis herpeti-
formis, ulcerative colitis, alopecia areata, autoimmune thyroiditis, myasthe-
nia gravis, acanthosis nigricans, Sweet's syndrome, porphyria, gout,
sarcoidosis, psoriasis, lichen planus, and cutaneous T-cell lymphoma. It is
likely that many of these associations are chance associations except for those
diseases with an autoimmune basis.163, 236–260
Neonatal lupus erythematosus

Neonatal lupus erythematosus is very rare, occurring in approximately 1 in
20 000 live births261 and most commonly presents in female infants.261–263 It is
associated with maternal anti-Ro (SS-A) antibodies (95%) and/or anti-La (SS-B)
antibodies.262,263 Anti-U1-ribonucleoprotein (RNP) antibodies may also be
present.264–268 Anticardiolipin antibodies have been described in a single case.269
Transplacental transfer of anti-Ro and anti-La antibodies results in a SCLE-
like eruption consisting of erythematous annular scaly plaques that particu-
larly affect the periorbital region (‘owl-eye’ or ‘eye-mask’) and scalp, and to a
lesser extent, the trunk and extremities (Figs 17.36, 17.37).5 These cutaneous Fig. 17.37
lesions often appear after exposure to ultraviolet light. Photosensitivity in neo- Neonatal lupus erythematosus: in this child, there is intense erythema affecting the
natal lupus erythematosus patients appears to show racial differences, being cheeks and nose and around the eyes.
more frequent in Caucasian and Americans than in Japanese infants.270 Crusted
lesions and cutis marmorata telangiectasia congenita are additional features in
some cases.271,272 Exceptionally, discoid lesions, panniculitis (lupus profundus), ortality of about 10% due to heart disease.262 Mothers of affected infants
m
multiple morphea, erosions, and alopecia may also occur.273–275 Atrophy and are commonly asymptomatic initially but they may have systemic lupus,
scarring are very rare but residual hypopigmentation and telangiectasia are Sjögren's syndrome, leukocytoclastic vasculitis or an overlap syndrome.286
present in about 25% of patients.276 Babies in subsequent pregnancies may A number of mothers who present with no symptoms, often subsequently
present manifestations of the disease277,278 and the overall recurrence rate for develop evidence of connective tissue disease, particularly systemic lupus (in
neonatal lupus-associated cardiac disease is 17%.279 about 20% of cases) and Sjögren's syndrome.262
Neonatal lupus erythematosus is often associated with complete heart
block, and sometimes liver disease (cholestatic hepatitis), splenomegaly, Pathogenesis and histological features
thrombocytopenia, leukopenia, and anemia are also evident.262,275 Circulating Despite enormous research efforts, the precise etiology and pathogenesis are
autoantibodies to annexin A6 were detected in a single patient with neonatal unknown, but the condition is certainly multifactorial.287,288 Lupus erythemato-
lupus erythematosus-related dilated cardiomyopathy.280 Multiple mucocuta- sus is characterized by B-cell hyperactivity in association with defective sup-
neous and visceral hemangiomas have been reported in a single patient.281 pressor T-cell function. Patients develop a wide range of autoantibodies, many
The mortality associated with cardiac involvement is around 19%.277 Severe of which result in immune complexes with resultant systemic manifestations
hematological and liver involvement without evidence of cutaneous or car- including vasculitis and glomerulonephritis. In addition to immunological fac-
diac involvement has exceptionally been reported.282 By 6 months of age the tors, familial, genetic, and hormonal influences play a part. It is believed that in
cutaneous, but not the cardiac manifestations, usually fade. The levels of lupus erythematosus there is a genetic predisposition; sex-associated and envi-
maternal autoantibodies in the infant decrease quickly during the first weeks ronmental factors are necessary to promote the development of the disease.
of life and generally become undetectable by the age of 1 year.283 Autoantibodies are important in the diagnosis of lupus erythematosus and
The disease also occurs in identical and nonidentical twins.284 A single case have a significant role in its pathogenesis, either by direct cytotoxic effects (such
has been described in association with Turner's syndrome.285 Neonates who as the lymphopenia induced by antilymphocyte antibodies) or by immune com-
survive until infancy have a fairly good prognosis, but there is an overall plex deposition. Until the 1960s the presence of LE cells in a patient's blood
was regarded as pathognomonic for lupus erythematosus. This was changed,

however, by the discovery of antinuclear factor (antinuclear antibody) with
direct immunofluorescent techniques. Antinuclear antibody is present in the
serum of 90–95% of patients with SLE, in 30% of patients with localized DLE,
and in 50% of patients with generalized DLE. It should also be noted that 10%
of the normal population have antinuclear antibody in the serum, albeit at low
concentration. Antinuclear antibody has at least four subtypes:
• A homogeneous or diffuse pattern is most commonly seen (Figs. 17.38,
17.39).
• Speckled fluorescence representing an antibody to saline-soluble nuclear
protein is present in patients with the lupus erythematosus-erythema
multiforme syndrome (Fig. 17.40).
• The nucleolar pattern (representing antinucleolar RNA antibody) is
occasionally evident in lupus erythematosus, although it is more common
in systemic sclerosis.
• The peripheral (outline) staining pattern reflects high titer anti-DNA
antibody and is a marker of active systemic disease.6,19
Patients with lupus erythematosus develop antibodies to a variety of nuclear
and cytoplasmic antigens; these autoantibodies, both singly and in combina-
tion, have varying associations, which may allow a prediction of (to some Fig. 17.39
Systemic lupus erythematosus: high-power view. By courtesy of G. Swana, MD,
extent, at least) the course of the disease in individual patients (Table 17.4).
St Thomas' Hospital, London, UK.
Antibodies to native (double-stranded) DNA (nDNA) are pathognomonic for
Fig. 17.38 Fig. 17.40

Systemic lupus erythematosus: homogeneous antinuclear antibody in rat liver. By Systemic lupus erythematosus: speckled antinuclear antibody – HEP II. By courtesy
courtesy of G. Swana, MD, St Thomas' Hospital, London, UK. of G. Swana, MD, St Thomas' Hospital, London, UK.
Table 17.4
Systemic lupus erythematosus: antibodies
Antigen Antibody Significance Comment
Nuclear constituents Anti-native DNA Highly specific for SLE associated with Found in NZB/NZW model
Antihistone hypocomplementemia and glomerulonephritis Found in high titer in drug-induced
Anti-single stranded DNA 30% of SLE patients lupus-like disease
90% of SLE patients, associated with May be detected in ANF-negative
glomerulonephritis SLE patients
Small nuclear ribonuclear Sm Highly specific for SLE 15% of SLE patients
protein nRNP May occur in SLE but also present in MCTD
La (SS-B) and PSS May be associated with low
Found in 10% of SLE incidence of renal disease
Small cytoplasmic Ro (SS-A) Found in 25% of SLE patients May be detected in ANF-negative
ribonuclear protein Found in SCLE SLE
Found in 50% of complement-deficient LE-like
syndromes
Found in all neonatal lupus
ANF, antinuclear factor; LE, lupus erythematosus; MCTD, mixed connective tissue disease; PSS, progressive systemic sclerosis; SCLE, subacute cutaneous lupus erythematosus;
SLE, systemic lupus erythematosus.
Table 17.5
Diagnostic criteria for the antiphospholipid syndrome
Group Criteria
I. Clinical conditions Thrombosis
venous:
recurrent deep vein thrombosis
axillary
retinal vein
arterial:
cerebrovascular accident
retinal artery
coronary
other:
pulmonary hypertension
livedo reticularis
neurological syndromes – transient
ischemic attack; progressive dementia
(repeated cerebrovascular stroke)
Recurrent fetal loss
Thrombocytopenia
Fig. 17.41
Systemic lupus erythematosus: anti-dsDNA (Crithidia luciliae). By courtesy of II. Laboratory* Positive anticardiolipin antibody assay; isotype
G. Swana, MD, St Thomas' Hospital, London, UK. IgG or IgM
Positive lupus antiocoagulant test
III. Other clinical Hemolytic anemia/positive direct Coombs' test
idiopathic (classic) SLE (Fig. 17.41).6,19 They are rarely seen in the drug-induced conditions Migraine
variant and are only very occasionally present in patients with DLE.2 The pres- Endocardial/valvular lesions
ence of anti-nDNA antibody in association with hypocomplementemia is indic- Transient visual loss
ative of active disease and is often accompanied by severe renal involvement. Chorea
Antihistone antibodies may be found in approximately 30% of patients IV. Histopathological 1. Thrombotic type (characterized by
with idiopathic SLE, but are particularly associated with the drug-induced classification dominating non-inflammatory bland
variant.289 The latter is caused by a wide variety of drugs, including hydrala- of lesions in occlusive or mural thrombosis and its
zine, procainamide hydrochloride, phenytoin, and isoniazid.14,290,291 Symptoms antiphospholipid consequences)
develop in up to 20% of patients taking procainamide and antinuclear anti- syndrome a. Large- and medium-sized arterial
bodies are present in 50%.291 Procainamide-induced SLE-like syndrome is and venous, cardiac (Libman-Sacks
characterized by the presence of leukocyte-specific antinuclear antibody.291 endocarditis), recent or organized
Clinical features include malaise, pneumonitis with pleural effusion, arthral- b. Microvascular (capillaries, arterioles and
small arteries)
gia, arthritis, and serositis; renal, central nervous system, and cutaneous
2. Microangiopathic type (characterized
lesions are less common and are usually mild. Although antinuclear antibod-
by dominating endothelial cell injury,
ies are often present, anti-DNA antibodies are not formed in most cases of subendothelial plasma insudation often
drug-induced lupus.164 Drug-induced lupus usually, but not invariably, under- associated with thrombotic necrotizing
goes remission on withdrawal of the drug.291 lesions) affecting capillaries, arterioles,
Antibodies to ssDNA occur in 90% of patients with classic SLE and in small arteries
approximately 20% of patients with disseminated DLE, and may also be 3. Ischemic type, secondary to vascular
found in other connective tissue diseases.10 Their presence in disseminated occlusion
DLE correlates with an increased risk of developing SLE.10 Patients with SLE 4. Tentatively associated pathology,
who are negative for antinuclear antibody may have anti-ssDNA antibodies in like accelerated atherosclerosis and
membranous glomerulopathy
their serum.6 Antibodies to the soluble nuclear antigen Sm are highly specific
5. Coincidental underlying disease related
for SLE.289 They may also be found in a group of patients with good prognosis
pathology
who are positive for antinuclear factor, but anti-nDNA-negative, and who 6. Coincidental drug-induced pathology
have mild nonprogressive glomerulonephritis, hypocomplementemia, mild
central nervous system involvement, and conspicuous cutaneous eruptions. At least one finding from each of groups I and II must be present to constitute a
Antibodies to ribonucleoprotein are detected in 23% of patients with SLE, diagnosis.
Group III represents features occasionally present in these patients.
but are much more commonly associated with mixed connective tissue dis-
* Laboratory tests should be positive on two occasions 2 months apart.
ease: they may also be found in patients with progressive systemic sclerosis.289 Modified from ASCP check sample (TH 88-6), American Society of Clinical Pathologists,
Anti-La (SS-B) antibodies are detected in the serum of 10% of patients with 1989; with permission. Histopathological classification modified from Praprotnik, S.,
SLE. Anti-La antibodies, which are often present in Sjögren's syndrome, are Ferluga, D., Vizjak, A., et al. (2009) Clinic Rev Allerg Immunol, 36, 109-125.
almost invariably accompanied by anti-Ro (SS-A) antibodies.289 The latter are
particularly associated with SCLE, complement-deficient lupus erythemato-
sus, circulating IgG or IgM anticoagulant, and neonatal lupus erythematosus.
About 15–20% of patients with SLE have detectable antineutrophil cytoplas- SLE. It is due to the presence of circulating antiphospholipid antibodies which
mic antibodies (ANCA).292 inhibit coagulation in vitro, but more importantly are associated with a
The circulating anticoagulant (antiphospholipid or lupus anticoagulant) is greatly increased risk of thrombotic phenomena affecting both arteries and
associated with paradoxical thrombosis, spontaneous abortion, premature veins (Figs. 17.42, 17.43). About 50% of patients with SLE present with
labor, intrauterine death, labile hypertension, cutaneous necrosis, gangrene, antiphospholipid antibodies but only half of these will develop manifesta-
ecchymoses, purpura, leg ulcers, atrophie blanche, livedo reticularis, and tions of the disease.305 Presentation in the skin may also be with papules and
false-positive syphilis serology – the lupus anticoagulant syndrome (Table nodules or lesions resembling pyoderma gangrenosum.306,307 Interestingly,
17.5).289,293–304 The lupus anticoagulant syndrome is more accurately known patients with antiphospholipid antibodies and SLE appear to be more at risk
as the antiphospholipid syndrome because not all patients have associated of developing anetoderma.308–310 The incidence, however, is not high. Rarely,
been substantiated.320 The antiphospholipid syndrome has also been docu-

mented in other autoimmune diseases including rheumatoid arthritis, hemo-
lytic anemia, thrombocytopenic purpura, ulcerative colitis, factor V Leiden
mutation, and mesothelioma.321,322 It may also complicate treatment with a
number of drugs including phenothiazines and procainamide, develop during
viral illnesses including acquired immunodeficiency syndrome (AIDS), and
can present with an underlying lymphoma.323,324 The antiphospholipid syn-
drome is futher discussed elsewhere.
Anti-Ro antibodies have been shown to bind to the epidermis in neonatal
and subacute lupus erythematosus, and to the conducting system and myocar-
dium in neonatal lupus erythematosus.262 They also bind to keratinocytes in
vitro and have been shown to react with the epidermis when infused into
human-skin-grafted mice.325,326 This – combined with the disappearance of the
cutaneous manifestations as maternal IgG is removed from the circulation –
suggests that in neonatal lupus erythematosus, anti-Ro antibodies are of major
pathogenetic significance. Ro antigens are present in the nuclei and cytoplasm
of keratinocytes and it has been demonstrated that UVB is capable of translo-
cating these antigens to the surface of cultured keratinocytes. Anti-Ro anti-
bodies in the sera bind to the antigens in keratinocytes and appear to be
Fig. 17.42 important in inducing antibody-dependent keratinocyte damage.327,328
Lupus anticoagulant Immune complexes have been shown to be important in the pathogenesis of
syndrome: extensive both vasculitis and glomerulonephritis in SLE; their presence may be inferred
gangrene with ulceration by the detection of immunoglobulin and complement in blood vessel walls in
affecting the nose and
skin biopsies (Fig. 17.44). High concentrations of anti-nDNA, anti-ssDNA,
cheek. By courtesy of
C. Stephens, MD, Poole
and anti-Ro (SS-A) antibodies have been detected in the renal cortex of patients
Hospital, Poole, UK. with lupus glomerulonephritis. The finding of large numbers of T lymphocytes
and macrophages with minimal or no B cells in the dermal infiltrate of skin
lesions suggests that cell-mediated immunity may be particularly important in
the pathogenesis of lesions at this site.327,329 Both delayed hypersensitivity and
antibody-dependent cellular cytotoxicity mechanisms have been proposed.323
There is a striking female predominance in SLE, suggesting that female sex
hormones are of pathogenetic significance.19 Interestingly, in the experimental
model of SLE in rabbits, females have a much more serious form of glomeru-
lonephritis than do their male counterparts and this difference can be negated
by castration or the administration of male sex hormones.323
There is, without question, a genetic predisposition to the development of
SLE.330 There are many examples of familial incidence, and immunoglobulin
abnormalities have often been documented in asymptomatic relatives; indeed,
as many as seven members in a single family have been recorded.164 Lupus ery-
thematosus has also been reported in identical twins.164 HLA typing has revealed
an increased incidence of HLA-A1, HLA-B8, HLA-B15, HLA-DR2, and
HLA-DR3 in SLE.12 It has been suggested that expression of the disease may be
inherited as an autosomal dominant trait. HLA-DR4 is associated with hydral-
azine-induced lupus erythematosus. The frequencies of HLA-DRw6 and HLA-
Fig. 17.43
Lupus anticoagulant
syndrome: the leg was
also involved. By courtesy
of C. Stephens, MD,
Poole Hospital, Poole, UK
patients develop reactive angioendotheliomatosis.311,312 Systemic involvement

includes deep venous thrombosis often complicated by pulmonary embolism,
arterial occlusion with resultant strokes, transient ischemic attacks, multi-
infarct dementia, myocardial infarction, and gangrene.289
The association of cutaneous thrombotic lesions, livedo racemosa, hyper-
tension, and cerebrovascular disease is known as Sneddon's syndrome.291,313–317
This presents mainly in young females and is exceptional in children.318
Antiphospholipid antibodies are present in around 41% of patients.319
How antiphospholipid antibody induces thrombosis is unknown. Theories Fig. 17.44
of inhibition of protein C (a natural vitamin K-dependent anticoagulant) Systemic lupus erythematosus: immunoperoxidase reaction demonstrating IgG
function and a suppressive effect on endothelial cell prostacyclin have not yet within a blood vessel wall.
B8 are increased in DLE.12 It has recently been demonstrated that patients with s pecific for lupus erythematosus. Other factors that may be identified include
polymorphic light eruption and HLA-DRB1*0301 have a higher risk of devel- properdin, C1q, and C4.346 Deposition of the membrane attack complex
oping either subacute or discoid lupus erythematosus.331,332 The familial cluster- (MAC) has also been shown to be a relatively sensitive and specific marker of
ing of polymorphic light eruption in relatives of persons with lupus erythematosus cutaneous lupus erythematosus.347,348 Although deposits are usually homoge-
suggests that these diseases may share a similar pathogenesis.333 neous, granular and thready (reticular) patterns are also recognized.345
SCLE has been demonstrated to be associated with the TNF-308A Homogeneous bands are typical of chronic lesions, granular bands are seen in
allele.334,335 Association between SCLE and single nucleotide polymorphism in uninvolved skin, and thready deposits are usually a feature of early lesions.348
the TNF-alpha (TNF-α) gene promoter and gene that encodes C1qA chain of Ultrastructurally, the immunoreactants are present in the sub-basal lamina
C1q has been demonstrated.169,335 Transcription of TNF-α appears to be pho- connective tissue and intimately associated with reduplicated lamina densa
toregulated in subacute lupus.335 TNF-alpha, produced by keratinocytes, has (Fig. 17.46).12 The immunoglobulin deposition does not necessarily correlate
been localized within refratory lesions of SCLE, suggesting its potential role with the clinical or histological presence of cutaneous lesions and is therefore
in the pathogenesis of SCLE.336 Abnormal regulation of DNA metylation in unlikely to be of pathogenetic significance.
CD4+ T lymphocytes has recently been implicated in the pathogenesis of The lupus band test is positive in involved skin in approximately 50–94%
SCLE.337 Triggering mechanisms in lupus erythematosus include UV light of patients with SLE, 60–80% of those with the discoid variant, 60% of
(both naturally occurring and artificial), drugs and, possibly, viruses. Sunlight patients with SCLE, and 50% of infants with neonatal lupus erythemato-
commonly worsens the cutaneous manifestations and may exacerbate sys- sus.345,346,348–351 Lesional mucosa also shows immunoreactant deposition and
temic disease.164,338,339 Antibodies to UV DNA have been identified in patients this can be of particular value in patients where histological distinction from
with SLE.340 These may be important in the pathogenesis of the photosensi- lichen planus proves impossible.23 It may also be positive in uninvolved skin
tivity-induced lesions. Lesions are typically worse in spring and summer, and in up to 67% of patients with systemic disease.350 The prevalence of a positive
cutaneous lesions can be induced artificially by UV irradiation. Dysregulation test in uninvolved skin depends upon the site, with the highest incidence in
of apoptosis has been suggested as an important mechanism in the pathogen- skin from the shoulder (70%). Sun-exposed skin, such as the dorsal aspect of
esis of lupus erythematosus. A reduction of bcl-2 expression in epidermal the forearms, is more frequently positive (60–70%) than nonsun-exposed
basal cells is associated with overexpression of FAS antigen and this appears skin (50–60%). However, the observation that 20% of specimens of sun-
to correlate with the extent of apoptosis in the epidermis.341 exposed normal skin from healthy young adults show a positive lupus band
Despite early enthusiasm for a viral etiology for lupus erythematosus, test indicates that nonsun-exposed skin is the substrate of choice.352
extensive research has not provided convincing evidence. For many years Positivity also depends upon the duration of the disease (lesions less than
paramyxovirus-like inclusions within the cytoplasm of endothelial cells were 3 months old are often negative) and the effect of previous steroid therapy.353
thought to represent evidence of a viral cause.342 They are now known to rep- Much less often, positive immunofluorescence is seen in the uninvolved skin
resent a non-specific membranous byproduct (tubuloreticular body) of organ- of patients with DLE.354 The results must, however, be taken in the context of
elle degeneration. An association with parvovirus (erythrovirus) B19 has been the clinical information. A positive IgM lupus band test may be seen in unre-
suggested.343 Two experimental virus-induced animal models – Aleutian mink lated conditions such as solar keratosis, polymorphous light eruption, rosa-
disease and New Zealand black–white hybrid mouse disease – have been cea, lymphocytic infiltrate, and dermatomyositis, and as a consequence of UV
described.19 Recent investigations have shown that the latter is associated radiation.348,350 These latter conditions are usually associated with C3 deposi-
with a primary stem cell defect. Bone marrow grafts can therefore transfer the tion or a single immunoglobulin class, particularly IgM, in contrast to the
disease to previously irradiated normal recipients and induce tolerance multiple immunoglobulin subclasses found in lupus erythematosus.348 In non-
defects.344 Bone marrow cultures produce B cells with an increased capacity lupus conditions the lupus band is usually fainter and patchy.354 With such a
for antibody synthesis.335 Murine lupus shows a striking similarity to its significant false-positive rate, it is stressed that the results of a lupus band test
human counterpart. must be interpreted with considerable caution and always in the context of
The lupus band test is particularly important in the diagnosis of lupus ery- the clinical information and histological features.
thematosus. It is also, to a lesser extent, of some value in assessing prognosis. A characteristic particulate dust-like deposition of immunoglobulin (pre-
By either immunofluorescence or immunoperoxidase techniques, the pres- dominantly IgG) affecting the basal cells of the epidermis has been described
ence of immunoglobulin and complement is sought at the epidermodermal in patients with SCLE.326,355 Sometimes suprabasal epidermis, adnexal epithe-
junction (Fig. 17.45). IgM is most commonly identified, although IgG, IgA, lium, and the dermal cellular infiltrate show similar fluorescence.346,355 This
and C3 are also frequently present.345 IgG deposits appear to be the most pattern of deposition correlates with the presence of Ro antibodies.350 It is
Fig. 17.45 Fig. 17.46

Systemic lupus erythematosus: positive band test (IgG). By courtesy of the Lupus band test: immunoelectron microscopy (frozen section) showing IgM
Department of Immunofluorescence, Institute of Dermatology, London, UK. deposition below the lamina densa.
also occasionally evident in SLE. In some cases speckled nuclear staining of

keratinocytes for IgG is seen in connective tissue diseases.356 In the setting of
SLE, this finding appears to be associated with a lower incidence of renal
disease.356
The histopathological features of the various subsets of lupus erythemato-
sus (with the exceptions of lupus erythematosus profundus and bullous der-
matosis of SLE) show considerable overlap and their distinction by microscopic
techniques is often difficult.357,358
Discoid lupus erythematosus

Discoid lupus erythematosus displays variable features, depending upon the
stage of the disease.12,351,352 The active lesion is characterized by hyperkerato-
sis and follicular dilatation with keratin plugging; occasionally focal parak-
eratosis is present (Figs 17.47–7.49). The epidermis is usually atrophic and
rather flattened, although sometimes there is acanthosis (Fig 17.50). The
most significant features seen at the dermoepidermal junction are:
• liquefactive degeneration of the basal layer of the epidermis (Fig. 17.51),
• basement membrane thickening (Fig. 17.52), which may be accentuated
by use of the periodic acid-Schiff (PAS) reaction.
Fig. 17.49
These two features may additionally affect follicular epithelium, and Discoid lupus erythematosus: there is marked follicular plugging.
basement membrane thickening of the dermal blood vessels is also sometimes
Fig. 17.47
Discoid lupus erythematosus: this scanning view shows hyperkeratosis, follicular
plugging, an atrophic epidermis, and a perivascular and periadnexal chronic
inflammatory cell infiltrate. Fig. 17.50
Discoid lupus
erythematosus: there
is hyperkeratosis and
atrophy of the epidermis.
evident (Fig. 17.53). Liquefactive degeneration of the basal layer of the epi-
dermis is often accompanied by pigmentary incontinence (Fig. 17.54). In
some instances the epidermal changes are accompanied by cytoid body for-
mation, but this is not usually as conspicuous as in lichen planus (Fig. 17.55).
Amyloid formation may occasionally be seen.
The papillary dermis is edematous, and telangiectatic vessels are often
present (Fig. 17.56). Focal extravasations of red blood cells are sometimes
seen (Fig. 17.57). Characteristic of DLE is a perivascular and periappenda-
geal chronic inflammatory cell infiltrate of lymphocytes and variable num-
bers of histiocytes (Figs 17.58, 17.59). The most common cells are the T
lymphocytes, both helper and suppressor cells.329, 330 Neutrophil polymorphs
and plasma cells are not usually evident. However, the presence of neutro-
phils and leukocytoclasia has been described in the lupus-like lesions of a
patient with a lupus-like dermatosis with X-linked chronic granulomatous
disease.68 CD4+ cells predominate in DLE skin lesions.329 The majority of
Fig. 17.48 these T lymphocytes are Ia+, indicating an activated state. Occasional CD4+
Discoid lupus erythematosus: note the perifollicular lymphocytic infiltrate. cells are present in the epidermis closely related to foci of basal keratinocyte
Fig. 17.51 Fig. 17.54

Discoid lupus erythematosus: in this view there is hyperkeratosis, epidermal Discoid lupus erythematosus: note the pigmentary incontinence.
atrophy and basal cell hydropic degeneration.
Fig. 17.52 Fig. 17.55

Discoid lupus erythematosus: note the very marked thickening of the basement Discoid lupus erythematosus: several cytoid bodies are present in the papillary
membrane and pigmentary incontinence. dermis. Note the hydropic degeneration.
Fig. 17.53 Fig. 17.56

Discoid lupus erythematosus: there is marked blood vessel wall thickening with Discoid lupus erythematosus: note the telangiectatic vessels in the superficial
hyalinization. dermis.
damage.329 Epidermal Langerhans cells are usually reduced in number.328 B

lymphocytes are generally present in only small numbers. The infiltrate is
typically sparse in the papillary dermis, but focal dense aggregates are char-
acteristically found in the reticular dermis and may sometimes extend into the
subcutaneous fat.
An increase in glycosaminoglycans (acid mucopolysaccharides) in the der-
mis is a common feature of the acute lesion (Fig 17.60); in tumid lupus this
is very marked (Figs 17.61, 17.62). Very rarely, dermal calcification has been
documented (Fig. 17.63).359 Exceptionally ‘fibrinoid’ change of the dermal
collagen is present (Fig. 17.64).
In the healing lesion of DLE there is hyperkeratosis and the epidermis may
be atrophic or, more commonly, slightly thickened. The basement membrane
region is characteristically markedly thickened. The dermis is fibrosed, some-
times to a degree that resembles lichen sclerosus (Fig. 17.65). In hair-bearing
sites, particularly the scalp, there may be very marked follicular plugging with
associated chronic inflammation, and in advanced disease there is often com-
plete loss of the pilosebaceous structures with replacement by collagenous
fibrous strands (Fig. 17.66).358 Sebaceous gland atrophy or loss occurs early
in scalp involvement and the chronic inflammatory changes are centered at
Fig. 17.57 the level of the mid follicle.20 It has been suggested that this may represent a
Discoid lupus erythematosus: in addition to hyperkeratosis and epidermal atrophy
focus of follicular stem cells and therefore chronic inflammation at this site
there is quite marked red cell extravasation.
could readily result in permanent hair loss.
Fig. 17.58 Fig. 17.60

Discoid lupus erythematosus: blood vessels and hair follicles are surrounded by Discoid lupus erythematosus: stromal mucin deposition, as seen in this field, is not
a characteristic heavy lymphohistiocytic infiltrate. uncommon.
Fig. 17.59 Fig. 17.61

Discoid lupus erythematosus: the follicular epithelium shows basal cell hydropic Tumid discoid lupus erythematosus: in this rare variant, there is very marked mucin
degeneration and there is a heavy lymphocytic infiltrate. deposition. By courtesy of J. Cohen, MD, Dermatopathology Laboratory, Tucson, USA.
Fig. 17.62 Fig. 17.66

Tumid discoid lupus erythematosus: the mucin stains with Alcian blue, pH 2.5. Discoid lupus erythematosus: note the complete absence of hair follicles in this
By courtesy of J. Cohen, MD, Dermatopathology Laboratory, Tucson, USA. scalp specimen.
Rarely DLE may present as a dense superficial and deep perivascular and Biopsy from patients with lupus pernio reveals a cuffed perivascular lym-
periappendageal infiltrate in the absence of significant epidermal changes: phocytic infiltrate with edema, red cell extravasation, and variable vascular
distinction from lymphocytic infiltrate of Jessner and polymorphous light fibrinoid change (Figs. 17.67–17.70). Some biopsies show frank lympho-
eruption is, therefore, histologically impossible.358 cytic vasculitis. The inflammatory infiltrate often extends into the deep der-
In hypertrophic lesions there is marked hyperkeratosis, hypergranulosis, mis and subcutaneous adipose tissue. Interface epidermal changes, ranging
and irregular acanthosis with papillomatosis in addition to the features of from focal vacuolar changes to a lichenoid tissue reaction, are often pres-
basal cell damage.12 Cytoid bodies are often conspicuous in the lower epider- ent.2,15 Chronic inflammation around sweat glands is sometimes seen.9,16
mis.358 Amyloid deposition has been reported as a frequent finding.360 The fea- Mucous membrane lesions are frequently difficult to distinguish from lichen
tures are commonly histologically indistinguishable from hypertrophic lichen planus.22,23,358 They are characterized by hyperkeratosis, often accompanied by
planus. The presence of intraepidermal elastic fibers, frequently associated parakeratosis. The epithelium may be atrophic or acanthotic. Hydropic degen-
with transepidermal elimination of the elastotic material, has been reported in eration of basal keratinocytes, sometimes associated with cytoid body forma-
hypertrophic lupus erythematosus.33,36 This is not a feature of lichen planus. tion, accompanies a dense lymphohistiocytic infiltrate in which plasma cells
Resolving or evolving keratoacanthoma may sometimes be mimicked.36 are often numerous. The presence of a deep perivascular chronic inflammatory
Fig. 17.63 Fig. 17.64 Fig. 17.65

Discoid lupus erythematosus: calcification is a Discoid lupus erythematosus: note the presence of Discoid lupus erythematosus: in this example,
rare feature. In this example, there is striking fibrinoid necrosis. This is more usually a feature of the presence of superficial dermal sclerosis is
transepidermal elimination. the systemic variant. reminiscent of lichen sclerosus.
Fig. 17.67 Fig. 17.70

Chilblain lupus erythematosus: there is irregular acanthosis and a superficial Chilblain lupus erythematosus: there is a dense lymphocytic infiltrate.
lymphocytic infiltrate. Ectatic vessels are conspicuous.
cell infiltrate favors the diagnosis of DLE.359 Direct immunofluorescence is,
however, frequently necessary to establish the diagnosis.22,23

The histological features of lupus erythematosus profundus are considered on
chapter 9.
Subacute cutaneous lupus erythematosus

Although the histological features of SCLE show considerable overlap with
those of DLE, there are diagnostic pointers.82,361,362 In SCLE, the hyperkera-
tosis tends to be mild, atrophy is more marked, and the epidermal ridge pat-
tern is often effaced (Fig. 17.71).362 Parakeratosis may sometimes be a
feature. Basement membrane thickening is minimal or absent, and hair fol-
licles are often unaffected or show only slight keratin plugging.361,362 In
DLE, the inflammatory cell infiltrate is denser, occupies the papillary and
reticular dermis, and often shows perifollicular accentuation. In SCLE, lym-
phocytic exocytosis may be conspicuous and satellite cell necrosis is not
uncommon (Fig. 17.72).362 Liquefactive degeneration of the basal layer of
the epidermis is usually present although often it is only mild (Figs 17.73,
Fig. 17.68 17.74). Sometimes, however, it is sufficiently marked that subepidermal
Chilblain lupus erythematosus: in this field, there is marked edema of the papillary vesiculation results.81,85 Homogenization of the papillary dermal collagen is
dermis.
Fig. 17.69 Fig. 17.71

Chilblain lupus erythematosus: there is focal basal cell hydropic degeneration, Subacute cutaneous lupus erythematosus: low-power view showing slight
and cytoid bodies are conspicuous. hyperkeratosis. A perivascular chronic inflammatory cell infiltrate is present.
Fig. 17.72 Fig. 17.74

Subacute cutaneous lupus erythematosus: in this example, in addition to basal Subacute cutaneous lupus erythematosus: in this example, there is marked basal
cell hydropic degeneration, there is intercellular edema of the epidermis with cell hydropic degeneration and apoptosis. Only a patchy chronic inflammatory cell
lymphocytic exocytosis. infiltrate is present.
Fig. 17.73 Fig. 17.75

Subacute cutaneous lupus erythematosus: note the presence of numerous cytoid Systemic lupus erythematosus: although the changes may be identical to the
bodies and focal satellite cell necrosis. discoid or subacute variants, sometimes the features are mild, as in this case. There
is focal basal cell hydropic degeneration, apoptosis, and telangiectasia.
occasionally seen.362 Colloid body formation and pigmentary incontinence

are often inconspicuous, but sometimes they are a major feature.85 The seen between collagen bundles. In most cases, this feature is subtle, but mucin
inflammatory cell infiltrate is typically mild, superficially located, and deposition may be very prominent.364 A thick basal membrane is more com-
perivascular in distribution. In some examples, however, it presents as a monly seen in lesions of DLE. As with DLE, the commonest cell type is the T
lichenoid band.85,91,362 lymphocyte, but which subset predominates is uncertain. Both CD4+ and
The histopathological features in cutaneous lesions of patients without CD4+ subset preponderance have been documented.328, 329 It may be that dif-
SCLE and antibodies to SS-A (Ro) are very similar to those seen in lesions of ferences in the age of the lesion, effects of treatment, and antibody specificity
patients with SCLE.363 These patients often have different clinical diseases can account for this apparent anomaly. CD4+ lymphocytes are present in
including Sjögren's syndrome and rheumatoid arthritis. large numbers in the epidermis at sites of basal keratinocyte hydropic
degeneration.328
Systemic lupus erythematosus The histopathological features of the cutaneous lesions of the antiphos-
The histological features of SLE are variable. The changes in early lesions, pholipid syndrome comprise both venous and arterial thrombosis in the
which may be very mild and subtle, often comprise only slight epidermal absence of any evidence of vasculitis (Figs 17.77–17.79). In early lesions,
basal cell liquefactive degeneration, papillary dermal edema, and a mild endothelial cell damage may be marked and erythrocyte extravasation is
chronic inflammatory cell infiltrate and are seen, for example, in malar ery- common. Older lesions are characterized by marked vascular proliferation,
thema (Fig. 17.75).92,347 On other occasions the appearances are similar to commonly in a lobular distribution accompanied by hemosiderosis. Hobnail
those of SCLE. reactive endothelial cells and eosinophilic hyaline globules are sometimes evi-
The histology of SLE is often indistinguishable from that of the discoid dent.323 A lymphocytic infiltrate accompanied by variable numbers of plasma
variant (Fig. 17.76). Fibrinoid degeneration of the dermal collagen is, how- cells is often seen.323,365,366 In some patients, the clinical and histological fea-
ever, more common in SLE than in DLE. Dermal mucin deposition is often tures of Degos' disease and anetoderma have been documented.366
Fig. 17.76 Fig. 17.79

Systemic lupus erythematosus: in this example, the features resemble the discoid Lupus anticoagulant syndrome: the presence of fibrin is confirmed in this
variant. Note the hyperkeratosis, epidermal atrophy, follicular involvement, and phosphotungstic acid–hematoxylin stained section.
gross basal cell hydropic degeneration. A perivascular and perifollicular chronic
inflammatory cell infiltrate is present.
Renal lesions may be detected in 70–80% of patients. The histological fea-
tures are subdivided into six classes according to the International Society of
Nephrology/Renal Pathology Society 2003 classification of lupus nephritis,
representing an evolution of the previous WHO classification:367,368
• In class I lesions (minimal mesangial lupus nephritis) no abnormalities
can be detected by light microscopy. Mesangial deposition of immune
complexes can be identified by immunofluoresecence, electron
microscopy or both.
• Class II lesions (mesangial proliferative lupus nephritis) are characterised
by any degree of mesangial hypercellularity (defined as three or more
mesangial cells per mesangial area in a 3-micron thick section) associated
with mesangial immune deposits. Rare small immune deposits involving
peripheral capillary walls can occasionally be detected by
immunofluorescence or electron microscopy. Features not acceptable are
subendothelial deposits on light microscopy as well as any segmental or
global glomerular scars resulting from previous glomerular endocapillary
proliferation, necrosis or crescents. Immunofluorescence reveals
mesangial deposition of IgG and complement and mesangial electron-
dense deposits may be detected by electron microscopy. Mesangial lupus
glomerulonephritis is the mildest form of glomerular lesion and is present
Fig. 17.77 in about 10% of patients with renal involvement.367
Lupus anticoagulant syndrome: low-power view showing superficial blood vessels • Class III lesions (focal lupus nephritis) are distinguished by active or
occluded by small thrombi. inactive focal, segmental or global endo- or extracapillary
glomerulonephritis involving <50% of all glomeruli, associated with
focal subendothelial immune deposits, with or without mesangial
proliferation. Focal segmental proliferative glomerulonephritis is found
in about 30% of patients. In this variant, only scattered glomeruli are
affected (focal) and usually only a portion of the tuft is involved
(segmental).367 Lesions may be proliferative and necrotizing. Involved
glomeruli usually show mesangial and endothelial proliferation,
polymorph infiltration, fibrin deposition, and karyorrhexis; occasionally,
hematoxylin bodies are evident. Hematoxylin bodies are regarded as the
histological hallmark of SLE. They are round-to-oval structures, which
stain purple/red–pink/blue with hematoxylin and eosin. They stain
positively with the Feulgen reaction and are von Kossa negative.
Hematoxylin bodies are thought to be the in vivo counterpart of the LE
cell phenomenon. Although frequently sought they are often very difficult
to find. Electron microscopy typically reveals mesangial and
subendothelial electron-dense (immune complex) deposits. Clinically,
patients present with hematuria and proteinuria, although a proportion
may develop chronic renal failure.
• Class IV lesions (diffuse lupus nephritis) are characterised by active or
Fig. 17.78 inactive focal, segmental or global endo- or extracapillary
Lupus anticoagulant syndrome: close-up view of occluded vessel – note the nuclear debris. glomerulonephritis involving ≥50% of all glomeruli, associated with
diffuse subendothelial immune deposits, with or without mesangial Neonatal lupus erythematosus
proliferation. They can be further subclassified as diffuse segmental The histological features and immunofluorescence pattern of the cutaneous
(IV-S) and diffuse global (IV-G) lupus nephritis. Diffuse lupus lesions in neonatal disease are similar to those seen in SCLE.164,371 The most
glomerulonephritis occurs in about 50% of patients with SLE who have frequently documented findings include hydropic degeneration of basal kera-
the nephritic/nephrotic syndrome or hypertension.367 Almost all glomeruli tinocytes and adnexal epithelium, dermal edema as well as a superficial and
are affected and, in addition to mesangial and endothelial proliferation, occasionally deep perivascular and periadnexal lymphohistiocytic chronic
the epithelial cells may participate, with the formation of crescents. inflammatory cell infiltrate.343, 372 Eosinophils may be prominent in urticaria-
Careful examination of the periphery of the glomerular tuft often reveals like SCLE lesions.372
regularly thickened capillaries – ‘wire-loop’ lesions, thought to be specific
for SLE. Differential diagnosis
• Class V (lupus membranous glomerulonephritis) lesions show global or
Lupus erythematosus must be distinguished from other dermatoses that mani-
segmental subepithelial granular immune deposits with or without
fest basal cell liquefactive degeneration, particularly lichen planus and poikilo-
mesangial alterations. Scattered subendothelial immune deposits can also
derma. Lupus erythematosus lacks the wedge-shaped hypergranulosis and
be present. Class V lesions can be associated with both class III and class
sawtooth acanthosis of lichen planus. The inflammatory cell infiltrate is typi-
IV lesions. Lupus membranous glomerulonephritis is found in about
cally periappendageal, rather than adopting a bandlike distribution. Occasionally,
10% of patients with SLE and presents as proteinuria or the nephrotic
hypertrophic lupus erythematosus shows considerable overlap with lichen
syndrome.367 Histologically, there is uniform thickening of the glomerular
planus; in such instances a positive lupus band test resolves the problem.
capillaries without any significant inflammatory cell infiltration.
Poikiloderma, whether congenital or associated with dermatomyositis
Advanced glomerulosclerosis can be present. Ultrastructurally, the
(and rarely SLE) or as a manifestation of mycosis fungoides, is characterized
electron-dense deposits are found subepithelially.
by epidermal atrophy and marked basal cell liquefactive degeneration associ-
• Class VI lesions (advanced sclerosis lupus nephritis) are characterized by
ated with pigmentary incontinence. A patchy lymphohistiocytic infiltrate is
global sclerosis without residual activity in ≥90% of glomeruli, related to
evident in the upper dermis. Papillary dermal edema and telangiectases are
lupus nephritis. They can represent progression of class III, IV or V lesions.
typically present. Although there is obviously histological overlap, the very
In addition to glomerular lesions, patients with renal involvement may
different clinical manifestations should obviate any diagnostic difficulties.
manifest acute necrotizing vasculitis.
The presence of atypical lymphocytes will clearly distinguish the variant
The heart is involved in about 50% of patients with SLE. Acute lesions of
associated with mycosis fungoides.
fibrinoid degeneration and hematoxylin bodies may be seen in the pericar-
The histological features of lupus erythematosus are sometimes difficult to dis-
dium, but it is more common to find obliteration of the pericardial sac by
tinguish from polymorphic light eruption, particularly when the latter is associ-
fibrous, sometimes gelatinous, adhesions. Fibrinoid necrosis of the myocar-
ated with a positive band test (see above). Polymorphic light eruption, which is
dial collagen is usually found in the connective tissue septa and occasionally
the most common photodermatosis, usually presents in young people, particu-
also affects the associated arteries. Libman-Sacks endocarditis is the best-
larly females, as recurrent, erythematous papules, vesicles and/or plaques follow-
known cardiac manifestation of SLE and is believed to occur in 30–60% of
ing exposure to ultraviolet light (Figs 17.80, 17.81).373 Lesions, which develop
the patients who come to autopsy.166 Small granular vegetations have been
after a latent period of hours to days, commonly subside completely within days
found on the surfaces of all valves, although the mitral and tricuspid are most
and heal without sequelae.362 Histologically, superficial dermal edema and a mild
often affected. The vegetations may spread to involve the chordae tendinae
to moderate superficial and deep perivascular lymphohistiocytic infiltrate are
and adjacent endocardium. Histologically, they consist of fibrin overlying
often seen.373 In early lesions helper-inducer T lymphocytes predominate and
degenerate collagen, with an associated chronic inflammatory cell infiltrate.
increased numbers of dermal Langerhans cells are present.374 With chronicity,
Infective endocarditis is an occasional, but important, complication. Increased
cytotoxic-suppressor T cells become more conspicuous. Basal cell hydropic
quantities of glycosaminoglycans are usually evident and sometimes hema-
degeneration is usually absent and epidermal atrophy is not a feature.
toxylin bodies are present.
The histological lesions of pulmonary involvement include interstitial
pneumonitis, fibrosing alveolitis, and infarction. In a large autopsy study of
patients with SLE, pleuropulmonary involvement has been detected in 97.8%
of patients, and included pleuritis (77.8%), bacterial infections (57.8%), pri-
mary and secondary alveolar hemorrhage (25.6%), distal airways alterations
(21.1%), opportunistic infections (14.4%), and thromboembolism (7.8%).369
Direct immunofluorescent examination of lung biopsies may reveal the pres-
ence of both immunoglobulin and complement.
Lymph nodes often show reactive hyperplasia; occasionally there are strik-
ing pathological features, which may be confused with a lymphomatous infil-
trate. These changes consist of a necrotizing lymphadenitis with prominent
hematoxylin bodies. Surviving follicles show reactive hyperplasia and conspic-
uous plasma cells and immunoblasts. The thymus may show prominent germi-
nal center formation, with an increase in the size and number of Hassall's
corpuscles. Perisplenitis (‘sugar icing’) of the splenic capsule is common and a
characteristic histological finding is concentric fibrosis (‘onion skinning’) of the
adventitia of the central (penicillary) arteries of the malpighian corpuscles.
Joint manifestations include fibrinoid degeneration within the synovium,
rheumatoid features, and arteritis. A variety of lesions may be seen in the
liver, including fatty change, focal hepatocyte necroses, and evidence of vas- Fig. 17.80
culitis. Central nervous system manifestations have an ischemic pathogenesis, Polymorphic light
eruption: patients present
most probably on an immune complex-mediated vasculitic basis. There is
with erythematous
some evidence to incriminate an antineuronal autoantibody. The cardiac papules and vesicles on
pathology of neonatal lupus erythematosus comprises fibrosis and calcifica- sun-exposed skin. By
tion of the atrioventricular node and, to a lesser extent, the sinoatrial node.370 courtesy of the Institute
Focal lymphocytic myocarditis and endocardial fibroelastosis may also be of Dermatology, London,
evident.262 UK.
dermatomyositis, different sets of antibodies in the serum (anti-PM-Sci and

anti-U1RNP), and improved survival.16–18 Cardiopulmonary diseases have
predictive value for survival in juvenile systemic sclerosis.16,17
Systemic sclerosis has a high overall mortality, 5-year survival rates vary-
ing from 34% to 73%.1 It has been demonstrated that improvement of skin
thickening is associated with improved survival.19,20 Older patients and males
generally fare worst.
Limited cutaneous systemic sclerosis

In the limited variant, the cutaneous manifestations, which often initially
affect the hands, include early edematous, sclerotic, and late atrophic stages.1
The edema is characteristically nonpitting, bilateral, and symmetrical. The
fingers are commonly described as having a sausage-like appearance (Fig.
17.82). The face, forearms, feet, and legs are sometimes affected. As the
edema subsides the skin becomes thickened and tight and is bound down to
the subcutaneous tissues. Typically, the fingers become tapered and, due to
ischemia, show pulp atrophy and absorption of the terminal phalanges, with
the fingertips often not protruding beyond the free margin of the nails (Figs
Fig. 17.81 17.83–17.85). The latter may show longitudinal ridging and brittleness or
Polymorphic light eruption: the eruption is typically symmetrical and is usually may even be shed. The affected skin has a very characteristic appearance,
pruritic. By courtesy of the Institute of Dermatology, London, UK.
Systemic sclerosis
Clinical features
Progressive systemic sclerosis includes two major variants:1–5
• In the more serious diffuse form, patients have widespread cutaneous
lesions proximal to the metacarpo- and metatarsophalangeal joints
(proximal scleroderma) in addition to involvement of the internal viscera,
particularly the kidneys, lungs, heart, esophagus, and intestinal tract. The
illness often has an acute onset with fatigue, weight loss, arthralgia, and
carpal tunnel syndrome. Tendon friction rubs are characteristic. Anti-
Scl-70 (anti-DNA topoisomerase) and RNA polymerase III antibodies are
often present and the outlook is generally poor.
• The other major variant is associated with limited peripheral cutaneous
sclerosis and an absence of severe systemic disease except for esophageal
involvement, small intestinal malabsorption, and pulmonary
hypertension; it usually has a better prognosis.2,6 This form is associated
with an anticentromere antibody.
Systemic sclerosis has also occasionally been recorded in the absence of Fig. 17.82
cutaneous manifestation (sine scleroderma variant) and overlap syndromes Systemic sclerosis: early stage showing characteristic swollen, sausage-shaped
have been described.7,8 Limited scleroderma also includes the CREST (calci- fingers. By courtesy of the Institute of Dermatology, London, UK.
nosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telang-
iectasis) syndrome (Thibierge-Weissenbach syndrome, acrosclerosis) where
cutaneous disease expression is restricted to the fingers and toes (sclerodac-
tyly) and face (see below).9 Other generalized variants include sclerodermato-
myositis, mixed connective tissue disease, and the chemically induced
scleroderma-like syndromes.
Because of the variety of systems that can be affected in systemic sclerosis,
patients may be primarily under the care of dermatologists, rheumatologists,
nephrologists or other specialists, resulting in difficulties in determining the
exact incidence of the disease; it is estimated to be in the order of 20 new
cases per million of the population per year.10 In a large series, the diffuse and
limited forms were equally common.11 About 10% were classified as overlap
syndromes. The disease occurs more frequently in families and it is regarded
as the strongest risk factor identified for this condition.12 However, the abso-
lute risk for each family member is low.12 Systemic sclerosis is associated with
a marked female predominance (3–4:1); although any age group may be
affected, patients most often present in their fourth, fifth, and sixth decades.13,14
Young black females constitute a definite subset with a particularly high risk.
Occasional familial instances, usually in children, have also been docu-
mented.10 Juvenile systemic sclerosis represent about 3% of systemic sclerosis Fig. 17.83
patients.15 No sex predilection is seen before the age of 8 years.15 In contrast Systemic sclerosis: the fingers are erythematous and shiny and the skin appears
to adult-onset systemic sclerosis, juvenile systemic sclerosis is associated slightly bound down. By courtesy of R.A. Marsden, MD, St George's Hospital,
with higher incidence of overlap syndromes, especially with polymyositis/ London, UK.
Systemic sclerosis 735
Fig. 17.84 Fig. 17.86

Systemic sclerosis: the fingertips are tapered. By courtesy of R.A. Marsden, MD, Systemic sclerosis: note the flexion contractures. The skin is bound down and
St George's Hospital, London, UK. appears atrophic. There is periungual erythema. By courtesy of R.A. Marsden, MD,
Fig. 17.85 Fig. 17.87

Systemic sclerosis: note the marked atrophy of the fingertip. By courtesy of R.A. Systemic sclerosis: there is perioral scarring with atrophy. By courtesy of the
Marsden, MD, St George's Hospital, London, UK. Institute of Dermatology, London, UK.
being shiny, smooth and rather waxy. Patients often have markedly dimin- The cutaneous changes in CREST syndrome are located predominantly
ished mobility of their hands and feet, and flexion contractures are common distal to the metacarpophalangeal joints, although the dorsum of the hands
(Fig. 17.86). In advanced disease, many patients acquire a dramatically rigid, and mouth can sometimes also be affected. The inflammatory stage is persis-
expressionless face with beaked nose, thinned lips, and perioral furrowing tent in the CREST syndrome.
and wrinkling, and an inability to open the mouth fully (Figs 17.87, 17.88).21 Raynaud's phenomenon, either alone or with swollen puffy fingers, is by
Tightness of the lower eyelids may also be noticed and the forehead can far the most common mode of presentation and telangiectases tend to be
appear smooth and free of creases.2 Ulceration is a common complication, much more numerous (often numbering hundreds) than in patients with dif-
particularly where taut skin is stretched over bony prominences susceptible to fuse systemic sclerosis. They particularly affect the fingers and hands, face,
trauma (Fig. 17.89). tongue, and mucous membranes (Figs 17.90–17.92). The telangiectasias
Vascular changes are common and include peripheral gangrene, digital seen in this variant of scleroderma may be difficult to distinguish from those
autoamputation, and Raynaud's phenomenon.21 The last occurs so frequently seen in hereditary hemorrhagic telangiectasia.23 The esophageal dysfunction
(in both limited and diffuse forms) that it is often taught that a patient who is identical to that seen in the diffuse variant, but it tends to be more severe
has it must be presumed to have systemic sclerosis, until proven otherwise. In and affects the majority of patients.
limited cutaneous systemic sclerosis, Raynaud's phenomenon may precede The value of the designation ‘CREST syndrome’ has, however, diminished
the onset of cutaneous lesions by many years in a large proportion of considerably since the discovery that many patients with limited cutaneous
patients.10 A useful diagnostic feature of systemic sclerosis is loss of many of disease fail to fulfill all of its criteria and the observation that ‘CREST’ mani-
the nail fold capillaries and dilatation of the remainder. It has recently been festations may be seen in many patients with diffuse disease.8 For example,
demonstrated that the nail fold capillaroscopy abnormalities correlate with there is a variant consisting of digital necrosis, Raynaud's phenomenon, and
diffuse form of systemic sclerosis, severity of cutaneous involvement, number anticentromere antibodies without sclerodactyly.24 The term should probably
of affected tracts, and the presence of anti-Scl-70 antibodies.22 be abandoned and all patients with limited distal disease classified as a single
Fig. 17.88 Fig. 17.90

Systemic sclerosis: note Systemic sclerosis: telangiectasia as seen on these fingers is a common finding.
the thinned lips and By courtesy of S. Parker, MD, West Middlesex Hospital, London, UK.
characteristic radiating
furrows. By courtesy
London, UK.
Fig. 17.91
Systemic sclerosis: numerous telangiectases are present. The hand is a commonly
affected site. By courtesy of the Institute of Dermatology, London, UK.
Fig. 17.89
Systemic sclerosis: ulceration is a particularly distressing complication. By courtesy
subtype. However, considering the frequency with which CREST syndrome

appears in the current literature, this is unlikely to happen, at least in the fore-
seeable future. It was originally thought that the limited variant was associ-
ated with a relatively benign outcome, but it is now known that if patients are
followed for sufficient time a significant proportion will develop severe pul-
monary hypertension with its sequelae. There is also an increased risk of
Sjögren's syndrome, biliary cirrhosis, discoid lupus erythematosus, and thy-
roid dysfunction, such as Hashimoto thyroiditis and Graves' disease.1,25–27
Sjögren's syndrome has been found in 14% of patients with systemic sclerosis
and was more common in the limited cutaneous variant of systemic sclero-
sis.28 More than one of the associated autoimmune conditions may coexist
with CREST syndrome.26 It has been suggested that patients with coexistent
primary biliary cirrhosis have a distinctive subset of the disease, which tends Fig. 17.92
to be milder and have a better prognosis.29 An exceptional case of antimito- Systemic sclerosis: extensive telangiectasia as seen in this patient is more often
chondrial antibody positive primary biliary cirrhosis developing after an a feature of the limited variant. By courtesy of S. Parker, MD, West Middlesex
acute myocardial infarction has been reported.30 Although clinically significant Hospital, London, UK.
primary biliary cirrhosis develops in 2.5% of systemic sclerosis patients, a

recent study has demonstrated the presence of antimitochondrial antibodies
in 15% of systemic sclerosis patients.31 Overlap syndrome between primary
biliary cirrhosis and autoimmune hepatitis has also been found in systemic
sclerosis.32 A multicenter French–Italian study has found coexistence of sys-
temic sclerosis and autoimmune disease in 21% of the patients, with Sjögren's
syndrome (12%) and thyroiditis (6%) being the most frequent associations.33
Systemic sclerosis patients with associated autoimmune conditions appear to
follow a milder course of the disease.33 Systemic sclerosis is associated with
rheumatoid arthritis in about 5% of the patients, and likely represents a dis-
tinctive disease subset associated with HLA-DR3, HLA-DR7, HLA-DR11,
and HLA-DRw53.34
Hyperpigmentation, from light brown to dark bronze reminiscent of Fig. 17.94
Addison's disease, is a frequent manifestation and is often associated with the Systemic sclerosis:
presence of small foci of hypopigmentation, giving a characteristic ‘salt and radiograph demonstrating
pepper’ appearance. The pigmentary changes particularly affect the backs of a more widespread
the hands and forearms, and the upper part of the chest and back. Sometimes example. By courtesy
the degree of accompanying hypopigmentation is so marked that it resembles
vitiligo.35
London, UK.
The cutaneous changes are often associated with the development of calci-
nosis cutis, particularly in females.2,36,37 It is dystrophic in type and is due to
hydroxyapatite crystal deposition. Patients have no abnormalities of calcium and correlates with extensive systemic involvement.10 Although the cutaneous
and phosphorus metabolism and their serum alkaline phosphatase levels are features cause considerable distress, the systemic manifestations are more
normal. The sites of calcium deposition particularly include the metacarpo- important in terms of severe morbidity and potential mortality. The early
phalangeal joints of the thumbs and the fingertips, although the extensor investigation of a patient with systemic sclerosis should establish baseline val-
aspect of the forearms, the buttocks, the olecranon bursae, and the prepatel- ues of respiratory, cardiac, and renal function so that progress may be accu-
lar region may also be affected (Figs 17.93, 17.94). The deposits are often rately monitored.
exceedingly painful and commonly associated with ulceration and leakage of Clinical involvement of the lung is common and an important cause of
white granular calcified debris. The combination of phalangeal reabsorption morbidity and mortality. It is thought to occur to a greater or lesser extent in
and calcinosis cutis is said to be pathognomonic of systemic sclerosis.38 most patients.44 There are three major forms: interstitial pneumonitis, bron-
Calcinosis cutis has also been reported in patients with systemic sclerosis sine chiolitis, and pulmonary vascular disease.44
scleroderma.39 • Pulmonary interstitial involvement results in shortness of breath on
Systemic sclerosis is sometimes associated with an erythema nodosum-like exertion and a nonproductive cough. Dyspnea is a feature in almost 60%
panniculitis syndrome and patients may also develop livedo reticularis and of unselected patients with diffuse scleroderma.45 Symptoms tend to be
atrophie blanche affecting the lower limbs.40 particularly evident in patients who have associated Sjögren's
CREST has been documented in association with familial lichen sclerosus, syndrome.44 Interstitial lung disease is the commonest cause of death in
chronic myelogenous leukemia, idiopathic myelofibrosis, and porphyria cuta- systemic sclerosis. There is evidence suggesting an increased risk of
nea tarda.41–43 pulmonary fibrosis in patients with the haplotype HLA-DR3/-DRw52A
and anti-Scl-70 antibody.46,47
Diffuse systemic sclerosis • Bronchiolitis is evident in approximately 13–25% of patients, but this is
In diffuse (progressive) systemic sclerosis, cutaneous lesions are particularly usually asymptomatic.44
common on the proximal extremities, thorax, and abdomen. The course • Pulmonary hypertension, which may be a primary manifestation of
tends to be progressive and often there is a more severe superficial vascular systemic sclerosis or develop secondary to interstitial fibrosis, is more
involvement.2 Skin thickening affecting the trunk indicates a poor prognosis common in patients with the limited form of the disease.48,49 A study has
found that the postmenopausal state with or without the presence of
HLA-B35 is the main risk factor for the development of pulmonary
hypertension.50
Pulmonary radiographs typically show bilateral basal fibrosis, either as
diffuse mottling or linear infiltrates; cyst formation (‘honeycomb lung’) is a
not uncommon feature.
The cardiac, renal, peripheral nervous, gastrointestinal, and skeletal systems
are also involved:
• The majority of patients have subclinical primary cardiac involvement.51
Cardiac involvement may present as dyspnea on exertion, paroxysmal
nocturnal dyspnea, pericarditis, pericardial effusion, congestive heart
failure, arrhythmias, valvular abnormalities, myocardial hypertrophy or,
occasionally, atypical angina.51–53 Vasospasm of the small coronary
arteries and arterioles has been observed as an early cardiac
manifestation.51 Significant cardiac abnormalities including pericarditis
and effusion are common pathological findings, being present in more
than 50% of cases at autopsy.54 Usually, however, they are asymptomatic.
Occasionally, severe acute pericarditis may develop and rare instances of
fatal cardiac tamponade have been documented.52 Large pericardial
effusions correlate with acute renal failure and are a bad prognostic
Fig. 17.93 indicator.54 Patchy myocardial scarring is common, and usually occurs
Systemic sclerosis: there is a large calcified nodule on the fingertip. By courtesy of later in the course of systemic sclerosis.51 When severe, myocardial
R.A. Marsden, MD, St George's Hospital, London, UK. fibrosis is associated with a poor outlook.55 It occurs independently of
coronary artery disease and has been described in up to 70% of patients Table 17.6
in postmortem series.52 The major coronary arteries are patent and American Rheumatology Association (ARA) guidelines for the classification
normal (unless there is coexistent atherosclerosis), but the small vessels of scleroderma*
and arterioles may undergo endothelial and intimal proliferative changes
with scarring, resulting in an increased risk of arrhythmia and the 1. Proximal scleroderma is a single major criterion: sensitivity is 91% and
specificity is more than 90%.
consequent sudden death of the patient. A recent study has found
2. Sclerodactyly, digital pitting scars of the fingertips or loss of substance
association between myocardial perfusion defects, skin thickness, digital
of the finger pad, and bibasilar pulmonary fibrosis contribute further
ulcers, and esophageal involvement.56 minor criteria in the absence of proximal scleroderma.
• Renal involvement presenting as ‘scleroderma renal crisis’ is an extremely 3. The major or two more minor criteria are present in 97% of definite
important complication with high mortality and occurs in approximately systemic sclerosis patients, but in only 2% of comparison patients
10% of patients with systemic sclerosis.57 The use of ACE inhibitors has, with systemic lupus erythematosus, polymyositis–dermatomyositis or
however, significantly diminished the mortality. It is defined as ‘the new Raynaud's disease.
onset of accelerated arterial hypertension and/or rapidly progressive oliguric * Preliminary clinical criteria for systemic sclerosis exclude localized scleroderma and
renal failure’.57 Patients develop headache and blurred vision. Seizures are pseudodermatous disorders. Reproduced with permission from Masi, A.T. et al and
sometimes a feature. The renal failure is commonly asymptomatic and the ARA Subcommittee for scleroderma (1980) Arthritis and Rheumatism, 23, 581–590.
detectable only from abnormal renal function tests including proteinuria,
microscopic hematuria with casts, raised creatinine levels, and
hyperreninemia.57 Microangiopathic hemolytic anemia is sometimes If a patient has either the major or two minor criteria there is 97% sensi-
present, particularly in normotensive patients.58 Anti-RNA polymerase III tivity for definite systemic sclerosis and 98% specificity. These criteria have
antibodies have been detected in about one-third of the patients with gained wide popularity, but have the disadvantage of excluding at least 10%
‘scleroderma renal crisis’.59 A minority of patients with systemic sclerosis of cases where, despite a concrete diagnosis of systemic sclerosis, neither
develop renal pathology other then ‘scleroderma renal crisis’.60 ANCA- major nor minor criteria are fulfilled. Unclassifiable and overlap syndromes
related glomerulonephritis has occasionally been reported.61,62 are also excluded. Other classifications have included two, three, and even
• Peripheral neuropathy may lead to neuropathic ulceration.63 Intrauterine four subtypes based upon the extent of cutaneous sclerosis (Table 17.7).74
fetal death has been described in pregnant women with the disease.64 Limited cutaneous systemic sclerosis may therefore involve the hands, feet,
Papular and nodular mucinosis has been documented as a presenting sign forearms, and face, or skin lesions can be absent, whereas in diffuse disease
of systemic sclerosis.65 the trunk skin is also involved. In a comparison of classification by two sub-
• Clinically relevant gastrointestinal lesions occur in up to 50% of patients types (diffuse and limited) or three subtypes (diffuse, intermediate, and lim-
with systemic sclerosis.66,67 Widening of the periodontal space, determined ited), the latter correlated best with antibody specificity and survival.75
radiographically, is characteristic. Patients frequently have symptoms A number of chemical-induced scleroderma-like syndromes have been
relating to esophageal involvement including heartburn, dysphagia, and described:
regurgitation. Gastrointestinal reflux is common and patients can develop • Workers in the vinyl chloride polymerization industry may develop
esophagitis, hemorrhage, stricture, Barrett's esophagus (gastric Raynaud's phenomenon, acral osteolysis, dermal thickening of the skin
metaplasia), and aspiration.66 Radiographs may show esophageal of the arms, hands, face, and trunk, and pulmonary and hepatic
dilatation and abnormalities of peristalsis. Epigastric fullness is a frequent fibrosis.76–78 Examination of the capillaries of the nail folds reveals
symptom, which might be related to restricted distension of the gastric abnormalities similar to those seen in systemic sclerosis.
antrum.67 Gastric antral vascular ectasia appears to develop earlier in • Bleomycin therapy may also be associated with sclerodermiform
those systemic sclerosis patients that display a rapidly progressive infiltrated plaques and nodules that particularly affect the hands.79
cutaneous disease.68 Systemic sclerosis often involves the small intestine, Patients may develop hyperpigmentation, peripheral gangrene, and
symptoms ranging from epigastric pain, nausea and vomiting, through to pulmonary fibrosis.
the effects of pseudo-obstruction; a malabsorptive state due to stasis is an • A high incidence of systemic sclerosis is found in those who work in
important complication. Celiac disease can develop in patients with coalmines or who have excessive exposure to silica for other reasons.80
systemic sclerosis.69 Colonic lesions may result in diarrhea or constipation. • A generalized morphea-like variant with Raynaud's phenomenon,
Saccular diverticula along the mesenteric border of the colon are esophageal dysfunction, and pulmonary fibrosis has been described
characteristic; they sometimes also affect the small bowel.66 following chronic exposure to industrial solvents.81
• Osteoarticular involvement, presenting with arthralgia or frank arthritis • A variety of autoimmune diseases have been documented following the
is seen in the majority of patients.70 Joint lesions are usually mild and use of silicone breast implants. Systemic sclerosis appears to be the most
affect the wrists, hands, knees, and ankles, although a more serious common.82
rheumatoid arthritis-like variant has been documented.71 Osteoarthrosis • Toxic oil and eosinophilia myalgia syndromes are discussed in the section
and psoriatic arthropathy-like manifestations have also been described.70 on eosinophilic fasciitis.
It is important in patients with significant joint manifestations that Systemic sclerosis is associated with increased risk of malignancies, which
overlap syndromes and mixed connective tissue disease are excluded. develop in between 3.6% and 10.7% of patients.83 Population-based studies
Contractures and ankyloses resulting in immobility are important have found most frequent association with breast cancer, lung cancer, and
complications and osteoporosis is common due to a combination of hematological malignancies, such as non-Hodgkin's lymphoma.84–87 Increased
immobilization and ischemia. incidence of squamous cell carcinoma of the tongue has also been detected.88
The diagnosis of systemic sclerosis may be readily apparent, but early dis- Rare associations include basal cell carcinoma, melanoma, nasopharyngeal
ease, particularly the diffuse form, may clinically mimic a variety of other carcinoma, and gastric MALT lymphoma.86,89,90
diseases, for example, scleredema of Buschke. Late graft-versus-host disease
(GVHD) and chronic lesions of porphyria cutanea tarda are typically sclero- Pathogenesis and histological features
dermatous.72 The American Rheumatology Association has guidelines for The etiology and precise pathogenesis are unknown. A complete understand-
classification, of which the major criterion is proximal scleroderma (Table ing must take into account vascular changes and abnormalities of collagen
17.6).73 Minor criteria are: deposition and distribution, in addition to the significance of the inflamma-
• sclerodactyly, tory cells that characterize the early stages and their role in the control of
• digital pitting scars on the fingertips or loss of substance of the distal fibroblast growth and function.91 Systemic sclerosis has stimulated an enor-
fingerpad, mous research effort, which has resulted in an increased awareness of the
• bilateral basal pulmonary fibrosis. multiplicity of factors that may be involved, either singly or in concert, and
Table 17.7 has also greatly increased our knowledge of the basic processes involved in
Classifications of systemic sclerosis the mechanisms of collagen synthesis and scarring. The two main areas of
investigation have revolved around:
Subsets of systemic sclerosis (SSc)
• primary blood vessel endothelial cell damage and its sequelae,
Diffuse cutaneous Onset of Raynaud's phenomenon within 1 year of • abnormalities of collagen and its synthesis.92,93
SS* onset of skin changes (puffy or hidebound) Inherent to both are the possible initiating and moderating roles of cell-
Truncal and acral skin involvement mediated and humoral immunity.
Presence of tendon friction rubs
It has long been recognized that many of the features of systemic sclerosis
Early and significant incidence of interstitial
–lung disease, oliguric renal failure, diffuse
may have an ischemic basis.94 Alterations have been described in capillaries,
gastrointestinal disease and myocardial venules, and arteries and it has been suggested that the initial injury involves
involvement capillary endothelial cells.95 The cause of this is unknown, although a circu-
Absence of anticentromere antibodies lating specific cytotoxic substance reactive for endothelial cells has been iden-
Nail fold capillary dilatation and capillary tified.95,96 It has been suggested that this may represent a protease.97
destruction† Interestingly, specimens of early lesions and uninvolved skin have shown
Antitopoisomerase antibodies (20–60% of patients) ultrastructural evidence of endothelial cell damage combined with decreased
Limited Raynaud's for years (occasionally decades) uptake of tritiated adenosine and diminished stores of immunodetectable von
cutaneous SSc Skin involvement limited to hands, face, feet, and Willebrand factor, suggesting that the vascular changes may well initiate the
forearms (acral) or absent connective tissue damage seen in this disease.98
A significance late incidence of pulmonary Although immunoreactants (IgG and complement) have been detected in
hypertension, with or without interstitial lung the walls of renal glomerular capillaries by immunofluorescent techniques,
disease, trigeminal neuralgia, skin calcifications, they have not been found in the cutaneous vasculature.98,99 If Raynaud's phe-
telangiectasia
nomenon is induced in patients with systemic sclerosis, there is a concomitant
A high incidence of anticentromere antibody
Dilated nail fold capillary loops, usually without
reduction in both renal and pulmonary blood flow, implying a circulating fac-
capillary dropout tor, as yet unidentified.
The dermal capillaries show a variety of ultrastructural changes. The earli-
Subsetting of SSc by early cutaneous involvement†
est finding is separation of the endothelial cells; this may result in fluid leakage
Digital Finger or toes, minimal non-extremity and therefore be responsible, at least in part, for the edema that characterizes
involvements allowed: eyelid, neck and axillary the early stages.1 Evidence of more severe damage is manifest by the presence
changes
of endothelial cell vacuolation, increased numbers of intermediate filaments,
Proximal Proximal extremity or face, but not trunk reduction in pinocytotic vesicles and Weibel-Palade bodies, and abnormal
extremity endothelial surface cytoplasmic blebs.98
Truncal Thorax or abdomen Evidence of endothelial cell injury can be monitored clinically by estimating
Systemic sclerosis subsets according to skin sclerosis extent plasma von Willebrand factor levels.93 Elevated levels of supranormal von
Willebrand factor multimers are typically seen in systemic sclerosis and may have
pathogenetic significance as they are known to bind to subendothelial tissues,
causing platelet aggregation and adhesion with resultant vascular proliferation
and thrombosis.93,100 ACE levels have been shown to be reduced in systemic scle-
rosis and this may also be of value in assessing the presence of endothelial cell
damage.93 Increased levels of the endothelial cell-derived peptide, endothelin,
which causes vasoconstriction, have been identified.82 Endothelin also has fibro-
blast mitogenic activity and stimulates the synthesis of collagen.101
The end stage appears as complete destruction of the capillary wall; the
nuclei are granular and homogeneous, cell membranes are disrupted, and
cytoplasmic contents are found in the capillary lumen and extravascular
spaces. Endothelial cell uptake of tritiated adenosine has been shown to be
reduced.98 Basement membrane thickening and reduplication is often present
and perivascular fibrosis is a common late accompaniment. The end result of
vascular damage can be demonstrated most easily by nail fold capillaroscopy.
It is likely that the dilatation of the residual vessels represents a compensatory
ssSSc lcSSc icSSc dcSSc measure. Increased proliferation of the endothelial cells in these residual ves-
ssSSc = sine scleroderma systemic sclerosis sclerotic sels has been confirmed by tritiated thymidine uptake studies.91
lcSSc = limited cutaneous systemic sclerosis skin Arterioles are also involved in the vasodestructive phenomenon, character-
icSSc = intermediate cutaneous systemic sclerosis uninvolved ized by vessel wall thickening due to a combination of smooth muscle hyper-
plasia, fibrosis, and the deposition of excessive glycosaminoglycans. Arteries
dcSSc = diffuse cutaneous systemic sclerosis skin
show very marked intimal thickening, which is particularly well seen in the
Skin sclerosis extent in four SSc subsets. LcSSc patients may present renal arcuate vessels and is often referred to as ‘onion skinning’ due to the
minimal sclerotic lesion at eyelids, neck and axillae
concentric lamination. It develops as a consequence of myxoid change, cellu-
*Experienced observers note some patients with dcSSc who do not develop organ lar proliferation, and fibrosis.
insufficiency and suggest the term chronic dcSSc for these patients. Most of the inflammatory cells in the skin of patients with systemic sclero-
†Nail fold capillary dilatation and destruction may also be seen in patients with
dermatomyositis, overlap syndromes and undifferentiated connective tissue disease.

sis are CD4+ T cells.
These syndromes may be considered as part of the spectrum of scleroderma- A number of cytokines have been linked to the pathogenesis of systemic
associated disorders. sclerosis. Transforming growth factor beta (TGF-β) and IL-4 increase fibro-
‡ The subject is defined within 1 year from presentation.
blast proliferation and collagen synthesis and may be important in the induc-
Top panel reproduced with permission from Leroy, E.C. et al (1988) Journal of
tion of fibrosis in this disease. IL-17 is a cytokine secreted by T cells that
Rheumatology, 15, 202–205; middle and lower panels reproduced with permission
from Valentini, R. (1994) Clinics in Dermatology, 12, 217–223. activates and induces proliferation of fibroblasts and activation of endothelial
cells. This cytokine has been demonstrated to be increased in the skin and
blood of affected patients, particularly in the early stages of the disease. It It has been shown by immunoelectron microscopic techniques that there is
activates fibroblasts to secrete the proinflammatory cytokines IL-6 and -8 and to retention of the amino peptide at the site of the collagen fibril.1
increase surface expression of intercellular adhesion molecule-1 (ICAM-1).102–104 In addition to increased quantities of collagen, the skin of early lesions
IL-17 also activates endothelial cells to secrete IL-6 and -1 and to express of systemic sclerosis contains excessive quantities of glycosaminoglycans,
ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). IL-6 is also capa- notably dermatan sulfate and chondroitin 4- and 6-sulfate.120 There is some
ble of inducing proliferation of fibroblasts and collagen synthesis. The com- evidence to show that the increase in glycosaminoglycans may be due, at
bined effects of IL-17 and other cytokines induced by it lead to damage to the least in part, to diminished degradation; their presence is associated with
microcirculation and to fibrosis in the skin and internal organs. It has been water binding in vivo and presumably is therefore also responsible for
suggested that connective tissue growth factor, the production of which is edema.
induced by TGF-β, may play an important role in the pathogenesis of fibro- Systemic sclerosis is associated with abnormalities of both humoral and
sis.105 It has recently been demonstrated that CD8+ effector T lymphocytes cellular immunity.121 In contrast to SLE, anti-DNA antibodies are not usually
are the source of increased IL-13 in the sera of patients with systemic sclero- present. Almost all patients, however, do possess antinuclear antibodies; these
sis.106 IL-13 has well-known profibrotic activities by direct fibroblast stimula- may be speckled, homogeneous or nucleolar in type (Fig. 17.95). The last are
tion and, indirectly, by stimulation of TGF-β.107 found in 7–46% of patients, but are not specific, being found in a number of
The fibroblasts in systemic sclerosis are capable of assembling microfibrils other connective tissue diseases.8 They form a heterogeneous group reacting
but these are unstable (probably due to an inherent defect of fibrillin 1, the against a variety of antigens including U3-RNP (fibrillarin), RNA polymerase I,
extracellular matrix protein) and this may also play a role in the pathogenesis Th ribonucleoprotein, and PM-Scl, and have some prognostic significance
of the disease.108 Interestingly, duplication in the fibrillin-1 gene has been and subtype specificity (Table 17.8).8,10 Anti-U3 RNP antibodies are present
implicated as the cause of tight skin,1 which is an animal model of systemic in 5–8% of systemic sclerosis, and are associated with African-American
sclerosis.108 Antibodies against fibrillin are raised in the sera of patients with race, male gender, higher incidence of skeletal muscle pathology, and
systemic sclerosis. Although this appears to be highly disease specific, it varies
amongst ethnic groups. Native Americans and Japanese patients have a high
frequency of anti-fibrillin-1 antibodies.109
Male cells have been found in multiple organs in women with systemic
sclerosis but not in healthy women.110 The migration of fetal cells into mater-
nal circulation and their survival in different organs is known as microchime-
rism. It is still not clear what role, if any, microchimerism plays in the
pathogenesis of systemic sclerosis.
The predominant histological feature of systemic sclerosis is scarring.
Intensive investigations have confirmed the presence of increased quantities
of collagen, but as yet the precise pathogenetic mechanism(s) remain uncer-
tain. Increased proline hydroxylase activity and increased uptake of labeled
proline, both indicators of active collagen synthesis, have been demonstrated
in patients with systemic sclerosis.111 There is typically an elevated level of
reducible aldimine cross-links, a feature of newly synthesized collagen.112
Raised serum concentration of the N-terminal propeptide of type III collagen
and increased urinary excretion of hydroxyproline have also been
documented.93
Cultures of fibroblasts from patients with systemic sclerosis synthesize
more collagen than do those from normal controls.113 Although diminished
levels of tissue collagenase have been reported, other workers have not con- Fig. 17.95
firmed this finding and its significance is therefore uncertain.114 The amino Systemic sclerosis: antinucleolar antibody (HEP II). By courtesy of G. Swana, MD,
acid composition of the collagen fibers is normal. Electron microscopy of St Thomas' Hospital, London, UK.
evolving lesions has revealed the presence of immature collagen fibrils, char-
acterized by a narrow caliber (30 nm), immature banding pattern, and dou-
Table 17.8
ble-stranded beaded filaments.1 In the more mature lesion the collagen fibers Systemic sclerosis: main autoantibody specificities giving a nucleolar pattern
approach normal thickness (100 nm), but their distribution is highly disorga- of fluorescence
nized. Luse bodies are sometimes a feature.
Histological examination of active lesions often reveals increased numbers Frequency
Antigen in SSc (%) Clinical associations
of fibroblasts. It has been shown that fibroblasts from the lower dermis syn-
thesize more collagen than do those derived from the upper dermis, suggest- Fibrillarin 8 Men with more lung and heart, less
ing two different populations in systemic sclerosis.115 The fibrosis, which is (U3–RNP) joint involvement; dcSSc with
telangiectasia
due to the deposition of types I, III, V, and VI collagen, is accompanied by
excessive fibronectin.93,116 RNA 4 DcSSc with high frequency of
Recently, abundant type VII collagen has also been demonstrated within polymerase I internal and musculoskeletal
the dermis of involved skin accompanied by elevated expression of TGF-β.116 involvements and shorter disease
duration at presentation
The latter is known to upregulate the activity of the type VII collagen gene.
This finding is of potential importance as type VII collagen distribution is Th 4 LcSSc with reduced survival;
normally restricted to the anchoring fibrils at the dermoepidermal junction. pulmonary hypertension, small
Increased expression of types I and III collagen mRNA has been demonstrated bowel involvement
in cultured fibroblasts from patients with scleroderma.117,118 Systemic sclero- PM-Scl 3 LcSSc in overlap with myositis;
sis is characterized by a normal concentration of collagen per unit weight. In higher frequency of renal
contrast, however, there is a greatly increased collagen content per unit sur- involvement
face area.119
dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc; SSc, systemic sclerosis.
Collagen synthesis has a negative feedback control. Therefore, following Reproduced with permission from Valentini, R. (1994) Clinics in Dermatology, 12,
cleavage of the amino terminal of the procollagen molecule by the amino 217–223
terminal peptidase, the released amino terminal inhibits collagen formation.
ulmonary arterial hypertension.122 Anti-U11/U12 RNP antibodies have been

p Histologically, the edema of the early stage produces a picture that is indis-
demonstrated in about 3% of systemic sclerosis, and have increased risk of tinguishable from scleredema of Buschke.146,147 In an established lesion the
pulmonary fibrosis and gastrointestinal involvement.123 Anti-Ku antibodies epidermis sometimes appears normal or there may be loss of the rete ridge
are detectable in 2.2% of systemic sclerosis and have been related to muscu- pattern. There is often increased pigmentation of the basal cells, and melano-
loskeletal abnormalities, such as myositis, arthritis and joint contractures, as phages are common in the superficial dermis. The characteristic change is
well as fingertip ulcers and telangiectasias.124 that of thickening of the dermis by broad, elongated, swollen collagen bun-
There are a number of subsets of antinuclear antibodies, which also have dles that often appear orientated parallel to the surface epithelium (Figs
clinical predictive value: 8,125–127 17.96, 17.97). The individual fiber borders are frequently indistinct, giving
• Anticentromere antibody (which is almost specific for systemic sclerosis) the collagen a rather homogenous appearance. The elastic fibers are usually
is particularly common in the limited cutaneous variant.128 It is usually unaffected. The fibrosis characteristically involves the subcutis and therefore
found in patients with less severe disease and a more favorable outcome.8
Calcinosis and telangiectasia may be conspicuous, but interstitial
pulmonary fibrosis is less likely.
• Scl-70 antibody (anti-DNA topoisomerase) is found in 20–60% of
patients with systemic sclerosis, particularly the diffuse variant.129 It is
also highly specific.8,130 Scl-70 antibody correlates with severe systemic
involvement including pulmonary interstitial fibrosis and a poor
prognosis.
• Anticentriole antibody occurs in both the limited and diffuse forms.
Although these antibodies are of great diagnostic importance they do not
appear to have any pathogenetic significance.
The presence of Ro (SS-A) and La (SS-B) antibodies suggests the coexis-
tence of Sjögren's syndrome.1 Autoantibodies against matrix metalloprotei-
nase-3 have been detected in about 50% of patients with systemic sclerosis.131
They are significantly higher in patients with diffuse cutaneous systemic scle-
rosis than those with limited cutaneous systemic sclerosis, and are signifi-
cantly correlated with skin fibrosis, lung fibrosis, and thickening of the renal
blood vessels.131
Antibodies to types I and IV collagen have been described, but it is not
clear whether they represent primary pathogenetic agents or are secondary
phenomena.132 More recently, antiendothelial cell antibodies have been
documented in scleroderma.133 Circulating immune complexes have been Fig. 17.96
Systemic sclerosis:
reported, but are not a constant feature, and their significance, if any, is
scanning view of acral
unknown.98,134 skin showing dermal
Various T-cell abnormalities have been reported, most of which point fibrosis. The specimen
towards a diminished concentration of circulating T lymphocytes, particu- was a foot amputation
larly of the suppressor subset.93 An increased T helper:suppressor ratio has performed because
been described.135 Soluble cytotoxic T lymphocyte-associated molecule-4 of severe vascular
(sCTLA-4) has been found to be increased in patients with diffuse cutaneous involvement.
systemic sclerosis and elevated levels of sCTLA-4 appear to correlate with the
diseased severity and activity.136 Clonal expansion of T cells have been
detected in both blood (61%) and skin (45%) of patients with systemic scle-
rosis, which is significantly higher than in normal matched controls.137
Investigations have recently been directed towards the role of cytokines in
the development of the fibrosis in systemic sclerosis. Evidence suggests that
they are major regulators of fibroblast function and collagen synthesis. It has
been proposed that in systemic sclerosis there is excessive fibroblast stimula-
tory activity, due, for example, to fibroblast chemotactic factors including
fibronectin, collagen fragments, platelet-derived growth factor, epidermal
growth factor and C5a.1 Fibroblast growth stimulating factors, including
IL-1, -2, and -3, TGF-β, and platelet-derived growth factor, are also of major
importance.93,138,139
As yet no consistent strong class I or II major histocompatibility (MHC)
antigen associations have been discovered in systemic sclerosis.10,140 There
are, however, significant HLA associations with individual autoantibodies.
Therefore, PM-Scl antibody correlates with HLA-DR3 and Scl-70 antibody
with HLA-DR5.46,141
Susceptibility genes recently described to be associated with the develop-
ment of systemic sclerosis include STAT-4, IRF5, and BANK-1.142–144
A useful working hypothesis for the pathophysiology of systemic sclerosis
was suggested by Fleischmajer and Lebwohl.145 They proposed that following
vascular injury, possibly caused by an autoimmune mechanism, exposure of
type IV collagen or other substances leads to the recruitment of both B and T Fig. 17.97
lymphocytes in addition to monocytes and mast cells. Excess T-helper cells Systemic sclerosis: the
stimulate the production of autoantibodies by B cells, whereas the activated dermis is homogenized.
T cells, macrophages, and mast cells secrete a variety of cytokines, which in Note the compressed
turn promote collagenosis. eccrine ducts.
Fig. 17.98 Fig. 17.100

Systemic sclerosis: severe vascular involvement characterized by intimal fibrosis Systemic sclerosis: high-power view.
and obliteration of the lumen. Note the surrounding chronic inflammation and
scarring.
numbers.150 Palisaded neutrophilic and granulomatous dermatitis has been
reported in a single patient with limited systemic sclerosis.151 Deposition of
fat cells are usually incorporated into the dermis.148 Atrophic skin append- amyloid in the dermis and subcutis in a patient with CREST syndrome has
ages, particularly eccrine sweat glands, are a common feature. also been reported.152
The arteries, especially the digital vessels, typically show endothelial cell It is usually not possible to distinguish localized scleroderma (morphea)
swelling, intimal thickening, and medial hypertrophy. Later they may become from systemic sclerosis on histological grounds, although the epidermis is
hyalinized (Fig. 17.98). In early lesions, endothelium-associated platelets are usually normal in the localized form and vascular changes are less severe. In
significantly increased in number.98 Fibrin deposition is sometimes present and contrast, the inflammatory cell infiltrate is often heavier in the localized vari-
occasionally complete occlusion results in digital ulceration and gangrene. ant and commonly affects the reticular dermis.149
With chronicity there is a progressive reduction in the number of vessels, Examination of skeletal muscle may reveal focal scarring and a chronic
particularly in the more superficial dermis.98 Perineural fibrosis is sometimes a inflammatory cell infiltrate (Figs 17.101, 17.102).153 Features of muscle
feature and calcification is not uncommon (Figs 17.99, 17.100). degeneration (vacuolation, homogenization with eosinophilia, and loss of
In early lesions there may be a chronic inflammatory cell infiltrate com- cross-striations) and regeneration (basophilia and sarcolemmal nuclear pro-
prising lymphocytes, histiocytes, and a few plasma cells around blood vessels liferation) similar to that seen in dermatomyositis may also be present. In the
and at the interface between the dermis and the subcutaneous fat.1,149 T-helper sclerotic phase there is atrophy and fibrosis.
cells predominate and increased numbers of dermal Langerhans cells have Macroscopic examination of the kidney often reveals multiple infarcts,
been described.98 Mast cells, usually activated, are often present in increased foci of hemorrhage and, occasionally, the features of renal cortical necrosis.64
The histological appearances are similar to those of malignant hypertension
and are characterized by the presence of fibrinoid necrosis, which particularly
affects the interlobular and arcuate arteries, and ischemic glomerulosclero-
sis; an inflammatory cell infiltrate is not a feature.59,154 Characteristic of
systemic sclerosis is the presence of edema and mucoid change in the initima
Fig. 17.99
Systemic sclerosis: there Fig. 17.101
is dramatic perineural Systemic sclerosis: myositis characterized by a lymphohistiocytic infiltrate and focal
fibrosis. skeletal muscle regeneration.
Localized scleroderma 743
Localized scleroderma
Localized scleroderma (morphea) constitutes a group of diseases characterized
by thickening or sclerosis of the dermis with loss of subcutaneous fat, some-
times with involvement of the underlying skeletal muscle.1–6 There is predilec-
tion for children and young adults, with the peak incidence between 20 and 40
years, and females being more frequently affected.7–9 Rare congenital cases
have been documented.10–12 About 15% of cases develop before the age of 10
years.13 Localized scleroderma is not usually associated with severe systemic
symptoms or Raynaud's phenomenon, is often self-limited, and in general has
a good prognosis, although the linear variant in particular may be very dis-
abling and often disfiguring, especially in children.2 The linear and deep vari-
ants can be associated with arthralgias, synovitis, uveitis, and joint
contractures.14 A large study of patients with morphea has found mild internal
involvement consisting of abnormal lower sphincter pressure and peristaltic
failure in the esophagus and slightly impaired carbon monoxide diffusion in
the lung in up to 19% of patients.15 These abnormalities do not result in clini-
cal symptoms and do not affect prognosis adversely. A rare case has been doc-
Fig. 17.102 umented in which morphea induced severe extrapulmonary thoracic
Systemic sclerosis: Note the focal cytoplasmic basophilia on the left side of restriction.16 Extracutaneous involvement is present in about one-fifth of the
the field. children, and includes articular, neurologic, vascular, ocular, gastrointestinal,
respiratory, cardiac, and renal manifestations, in decreasing order of fre-
of the interlobular arteries. There is also increased cellularity, giving rise to a quency.13 Although the plaques and, to a lesser extent, the linear lesions often
characteristic ‘onion skin’ appearance with reduction in the lumen of the improve with time, the contractures and hemiatrophy are permanent.3 Imaging
vessel. studies frequently reveal muscle atrophy and leg length discrepancy.17 Localized
The histological features of sclerodermatous interstitial pneumonitis are scleroderma may occur after trauma, laparoscopy, radiotherapy, tattooing,
indistinguishable from those seen in idiopathic fibrosing alveolitis. Early and silicone implants.18–24 It has also been described in association with bro-
stages are characterized by intra-alveolar edema with reactive pneumocytes mocriptine, balicatib, valproic acid, and ibuprofen therapy.25–28 Localized
and a variable infiltrate of macrophages, lymphocytes, and occasional neu- scleroderma has also been reported following silica dust exposure.29
trophils.46,155 Interstitial accumulations of lymphocytes and plasma cells are The precise relationship between localized scleroderma and systemic scle-
evident, sometimes associated with focal lymphoid hyperplasia; in older rosis is uncertain. Because of clinical and pathological overlap, some authors
lesions, these are accompanied by the deposition of glycosaminoglycan-rich believe that the two conditions represent extreme ends of a spectrum of con-
new collagen. End-stage disease is characterized by the development of vari- nective tissue damage in a manner similar to the relationship between discoid
ably sized cysts lined by metaplastic bronchiolar epithelium and containing and systemic lupus erythematosus. Indeed, patients rarely have both morphea
abundant collagen and hyperplastic smooth muscle in their walls.156 and progressive systemic sclerosis (the former usually preceding the latter);
The features of pulmonary hypertension are commonly present, particu- this phenomenon occurs so infrequently, however, that most believe that the
larly in patients with the CREST variant. Muscular arterioles are predomi- relationship is purely coincidental.2 Alternatively, the features of these two
nantly affected, although in late stages venules may also be involved, and show disorders may merely represent a common manifestation of tissue damage
medial muscular hypertrophy and concentric myxoid-rich new collagen depo- caused by quite different mechanisms, analogous to the wide range of patho-
sition in the intima with variable reduction in the diameter of the lumen.156 In genetic factors which may result in the histological appearance of allergic
late stages, muscular atrophy and medial elastosis may be evident. Focal lym- vasculitis.
phocytic/plasma cell endovasculitis has been documented, suggesting a possi-
ble autoimmune pathogenesis.156 Fibrosis of pulmonary veins and venules can
Clinical features
be similar to the changes observed in pulmonary veno-occlusive disease.157 Localized scleroderma includes a variety of conditions, which may arise inde-
Pulmonary hypertension correlates with the presence of anticentromere anti- pendently, but which frequently occur together:
body. Bronchiolitis predominantly affects the terminal and respiratory bron- • plaque-form (the most common variant),
chioles. In addition to chronic inflammation, bronchiolar squamous metaplasia • bullous morphea,
and variable scarring with luminal constriction may be seen.156 • guttate lesions,
The most important gastrointestinal lesion is atrophy with fibrosis of the • linear morphea including facial hemiatrophy,
esophageal smooth muscle; similar changes may also develop in the small and • generalized morphea,
large intestines. Vascular myointimal proliferation with luminal narrowing is • subcutaneous scleroderma (morphea profunda),
also usually evident.66 Reflux esophagitis may show erosions and areas of • disabling pansclerotic morphea of children.2,30–32
ulceration in addition to chronic inflammatory changes. In contrast to con-
ventional diverticulae, those of systemic sclerosis are composed of all layers Plaque-form and linear morphea
of the bowel wall. Plaque-form and linear morphea are more common in females (3:1) and, in
Early myocardial changes are characterized by necrosis of muscle fibers contrast to progressive systemic sclerosis, often occur in childhood.1 Linear
accompanied by a chronic inflammatory cell and histiocytic infiltrate.58 morphea develops before the end of the first decade in up to 20% of patients
Subsequent fibrosis affects the right and left ventricles with equal frequency.57 and by the fourth decade in up to 75%. Localized plaques occur a little later
The major coronary arteries appear normal in systemic sclerosis, but arterio- in life, although 75% of patients are between 20 and 50 years of age at
lar, endothelial, and intimal proliferation accompanied by mural scarring is presentation.
common.158 Morphea usually develops slowly and the onset may manifest as ery-
In active lesions, synovial biopsies show a heavy surface fibrin deposit.70 thema and edema. An established lesion is typically circumscribed, ivory or
There is adjacent chronic synovitis with an admixture of lymphocytes and white in color, and densely sclerotic (Fig. 17.103).2 A characteristic feature
plasma cells. Lymphoid follicles with germinal center formation as seen in is the presence of a violaceous border, an indicator of disease activity (Figs
rheumatoid arthritis are not a feature. With chronicity, synovial scarring 17.104, 17.105).2 As the lesion subsides, atrophy, loss of hair and
supervenes. sebaceous glands, and variable hypo- and hyperpigmentation become
evident (Fig. 17.106).30 Vesicles, bullae, purpura, and telangiectasia may

rarely be present, particularly in the generalized variant.1,33 Tense bullae,
due to subepidermal edema, are a rare manifestation that has been described
in morphea, including the profunda variant.34 They are thought to develop
as a consequence of both trauma and lymphatic obstruction. The latter is
suggested by the finding of lymphatic dilatation in 77% of biopsies from
patients with this variant of morphea.35 It has also been suggested that this
type of morphea may be related to release of major basic protein from
eosinophils.35
The plaque form of morphea usually consists of multiple, round or oval,
sometimes pruritic, 2–15-cm diameter lesions, which are usually bilateral and
asymmetrical in distribution (Fig. 17.107). Lesions occur (in decreasing order
of frequency) on the thorax and neck, the lower extremities, the upper extrem-
ities, and the face; the axillae, umbilical region, perineum, and perianal area
are usually spared (Fig. 17.108).
The so-called linear atrophoderma of Moulin, which presents with band-
like lesions following Blaschko's lines, is likely to represent a variant of linear
morphea.36
Linear morphea is usually solitary and unilateral in distribution. Lesions
Fig. 17.103
are found (in decreasing order of frequency) on the lower limbs, the upper
Morphea: characteristic white sclerotic plaque. By courtesy of the Institute of
limbs, the frontoparietal region (e.g., en coup de sabre), and the anterior
Fig. 17.104 Fig. 17.106

Morphea: in this example the violaceous border is apparent. From the collection of Morphea: atrophic lesions showing variable hypo- and hyperpigmentation.
the late N.P. Smith, MD, the Institute of Dermatology, London, UK. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 17.105 Fig. 17.107

Morphea: multiple lesions are present on the abdomen. From the collection of the Morphea: multiple asymmetrical lesions are present. Note the characteristic en
late N.P. Smith, MD, the Institute of Dermatology, London, UK. coup de sabre. By courtesy of D. McGibbon, MD, St Thomas' Hospital, London, UK.
Fig. 17.108 Fig. 17.110

Morphea: extensive lesions can be very disfiguring, as in this patient showing Linear morphea: en coup de sabre. By courtesy of the Institute of Dermatology,
bilateral breast involvement. By courtesy of the Institute of Dermatology, London, UK. London, UK.
Fig. 17.109 Fig. 17.111

Linear morphea: Linear morphea: severe
atrophic lesion on the facial hemiatrophy.
thigh. By courtesy of By courtesy of
R.A. Marsden, MD, D. McGibbon, MD,
St George's Hospital, St Thomas' Hospital,
London, UK. London, UK.
t horax (Fig. 17.109). Linear lesions may involve both the upper and lower
extremities simultaneously and, on occasion, plaque-type morphea is also is the development of facial hemiatrophy (Romberg's disease) (Fig.
present.2 Although the clinical appearances of linear scleroderma are very 17.111).2,52 Exceptionally, central nervous system involvement may occur,53
similar to those of the plaque form, lesions tend to show more pigmentary with presentations such as intractable partial seizures and cerebral vasculitis. 54,55
change and the violaceous border is less conspicuous. Linear morphea may Linear morphea has also been described in association with hereditary
affect the underlying skeletal muscle and even bone, giving rise to contrac- deficiency of C2.56
tures and deformities. Calcification of skeletal muscle may exceptionally
occur.37 An association with melorheostosis has been described.38,39 Cases pre- Guttate morphea
senting with hypertrichosis are also documented.39–41 Occasionally it follows In guttate morphea lesions are multiple, small (2–10 mm), nonindurated,
Blaschko's lines.42–47 and yellowish-white, and are limited by a delicate lilac border.1,30
Frontoparietal linear morphea presents as a densely sclerotic plaque Typically, there is no hyperkeratosis or follicular plugging. Coalescence
extending from the eyebrow onto the scalp and may be associated with alo- of lesions to form plaques is not uncommon. Guttate morphea most com-
pecia. Involvement of the cheek, nose, and upper lip has also been docu- monly presents on the upper back and shoulders, but the lower back,
mented.30 Progression of the lesion results in the development of a groove chest, and abdomen may also be affected.1 There is much clinical (and
and hence the term ‘en coup de sabre’ (Fig. 17.110). Gingival recession has histological) overlap between the lesions of guttate morphea and lichen
occasionally been documented.48 Familial occurrence is exceptional and sclerosus and it is worthy of note that the two disorders are frequently
bilateral lesions are rare.49–51 A further complication, particularly in children, seen together.2,57
Generalized morphea permanent, and is fortunately very rare. Some patients have had abnormal
Generalized morphea, which most commonly affects the trunk and abdomen, respiratory function tests and diminished esophageal motility, suggesting
is characterized by widespread large lesions resembling plaque-type mor- overlap with systemic sclerosis.80 Blood eosinophilia is also seen.80 A rare
phea.1,58 These may merge and in many patients almost the entire skin surface complication of squamous cell carcinoma has been documented.84,85 A further
is involved. Extension to the subcutaneous fat and muscle sometimes results exceptional association is that of hypogammaglobulinemia.86
in severe contractures and disabling and disfiguring deformities (Fig. 17.112).
Generalized morphea may occasionally prove fatal, for example, due to pneu- Associated conditions
monia. Rarely, systemic involvement supervenes.2 When generalized morphea Localized scleroderma has been associated with a variety of conditions includ-
and systemic sclerosis coexist, the activity of the generalized morphea may be ing arthralgia, carpal tunnel syndrome, unilateral Raynaud's phenomenon,
independent of the lesions of systemic sclerosis.59 An association with por- intermittent abdominal pain, and spina bifida.30,31 Concurrent lichen planus,
phyria cutanea tarda, eosinophilic fasciitis, and childhood sclerodermatomy- often in the company of lichen sclerosus, has also been documented.1 Other
ositis has been described.60–62 Occurrence with Felty's syndrome and after associations include vitiligo, alopecia areata, granuloma annulare, pigmented
antitetanus vaccination has also been reported.63,64 Unilateral generalized purpuric dermatosis, psoriasis vulgaris, cutaneous amyloid deposition, lupus
morphea has been documented.65,66 A patient with this form of the disease anticoagulant, DLE, SCLE, SLE, xanthomatosis, elastosis perforans serpigi-
developed multiple acral adult myofibromas.67 Multiple squamous cell carci- nosa, B-cell lymphoma, human T-cell lymphoma/lymphotropic virus type 1
nomas of the skin developing in the background of generalized morphea are infection, chronic hepatitis B and C virus infection, posthepatitis C cirrhosis,
an exceptional finding.68 primary biliary cirrhosis, Rosai-Dorfman disease, sarcoidosis, necrotizing
vasculitis, and necrobiotic xanthogranuloma.1,2,87–112 A recent analysis of 245
Subcutaneous scleroderma patients with localized scleroderma has found concomitant rheumatic or
Subcutaneous scleroderma (morphea profunda, nodular scleroderma, keloi- autoimmune disorder in 17.6%.113 Generalized morphea is the most frequent
dal scleroderma) presents clinically as nodular or keloid-like lesions.30,34,69–75 subtype associated with autoimmune diseases, which are present in 45.9% of
Association with systemic sclerosis can be present.74,76 The abdomen, sacral patients with this form of the disease.113
region, and the extremities are affected most commonly.2 Osteoma cutis can
rarely develop in subcutaneous scleroderma.77 Two cases of morphea pro- Pathogenesis and histological features
funda, as well as an atrophic variant of morphea profunda mimicking local-
The etiology and pathogenesis of localized scleroderma are unknown.
ized lipoatrophy, have been reported at the site of previous intramuscular
Theories of causation include trauma, hormonal influences, and familial
vaccination.78,79
aspects.30,114,115 Thus localized scleroderma may present or worsen during
pregnancy, the menarche or the menopause. The condition has also been
Disabling pansclerotic morphea of children described following chickenpox and measles.1,116 An infectious etiology has
Disabling pansclerotic morphea of children is a particularly aggressive and received some support with the identification by immunohistochemistry, sil-
mutilating variant, which involves fascia, muscle, and bone in addition to the ver stains, and polymerase chain reaction (PCR) of Borrelia burgdorferi in
deep dermis and subcutaneous fat. It usually affects the scalp, face, trunk, and biopsies of lesional skin combined with the presence of elevated antibody lev-
extremities.1,80–82 An adult-onset variant of disabling pansclerotic morphea els.117–124 Lymphoproliferative responses to this organism have also been
has also been reported.83 Patients have tendencies for chronic nonhealing reported in patients with morphea.125 Most studies, however, have cast doubt
ulceration, most commonly involving legs, followed by upper extremities, on the association between morphea and B. burgdorferi.126–135 It has also been
trunk, and head.82 Patients may also have arthralgias, contractures that par- shown that false-positive tests for B. burgdorferi with indirect immunofluo-
ticularly affect the extensor surfaces of the extremities, and osteoporosis.30,80 rescence and even enzyme-linked immunosorbent assay (ELISA) are not
This exceedingly severe variant of localized scleroderma is unremitting and uncommon.136 It is therefore more likely that B. burgorferi is not etiologically
linked to localized morphea. A further possibility is that only certain subspe-
cies of Borrelia are capable of inducing the disease.137,138 However, this theory
has not been substantiated by different studies from the same country.138
The occasional simultaneous occurrence of localized scleroderma and sys-
temic sclerosis has led some authors to postulate a shared pathogenetic
mechanism.31,139 In both conditions increased serum levels of procollagen
type I carboxyterminal propeptide have been reported.140 Similarly, the pres-
ence of localized scleroderma in both discoid and systemic lupus erythema-
tosus and dermatomyositis has been cited as additional evidence for an
immunological basis.1,141–143 It is also of interest that the clinical appearances
and histology of late GVHD are very similar to those of scleroderma.
Increased expression of connective tissue growth factor has been detected in
sclerotic fibroblasts of nodular scleroderma by immunohistochemistry and
in situ hybridization.76
Antinuclear antibodies may be detected in approximately 70% of patients
with morphea.144 Homogeneous, nucleolar, and speckled patterns have all been
recognized, but the first is the most common variant.145 Rheumatoid factor,
anti-dsDNA, anticentromere, and anti-Scl-70 antibodies have also been docu-
mented but are rare.58 Anti-ssDNA antibodies are present in 38–75% of
Fig. 17.112 patients, are frequently of the IgM subclass, and are found more often in linear
Generalized morphea: a and generalized morphea than in the plaque form.58,146 Antihistone antibodies
very advanced extreme have been reported in up to 50% of cases.147 Most antibodies are more com-
example showing almost
monly seen in patients with active or widespread disease.143 Antinuclear anti-
complete involvement of
the skin, hair loss, and
bodies are frequent in children with localized scleroderma and often have
contractures. By courtesy specificity for denatured DNA and for high mobility group proteins.148 Anti
of R.A. Marsden, MD, Cu/Zn superoxide dismutase antibodies are present in the serum of 89% of
St George's Hospital, patients with localized scleroderma, and 100% of patients with the generalized
London, UK. variant.149 Anti-DNA topoisomerase IIα antibodies have been detected in 76%
of patients with localized scleroderma, and 85% of patients with the general- particularly conspicuous in the dermis in addition to the subcutaneous fat
ized variant.150 Increased serum levels of ICAM-1 have also been reported, (Fig. 17.118). In the linear and generalized variants in particular, the inflam-
particularly in patients with prominent involvement.151 Peripheral eosinophilia matory changes may affect the underlying skeletal muscle.
is sometimes a feature, particularly in the pansclerotic morpheic variant.1,80 In the late stages, dermal sclerosis is still evident, but the dermis appears
Direct immunofluorescence studies have demonstrated immunoglobulin thinned due to concomitant atrophy.2 Vascular changes similar to those
(usually IgM) and complement at the basement membrane region and around described for systemic sclerosis may be evident and consist of thickening of
the dermal vasculature in about 35% of patients.1 Generalized morphea is the walls of small blood vessels. Vasculitis is not a feature. Calcinosis cutis is
more often positive than the plaque and linear variants. Immunohistochemical occasionally seen and neuritis similar to that seen in indeterminate leprosy
studies of established lesions reveal increase in the number of factor XIIIa+ has also been documented.157,158
cells and decrease in the number of CD34+ cells.152–154 In lesions of deep morphea the infiltrate is much more prominent and is
The histological features of localized scleroderma involve both the dermis located predominantly in the junction between the dermis and subcutaneous
and subcutaneous fat; a deep incisional biopsy is therefore indicated if sclero- tissue with extension into the subcutaneous tissue. The infiltrate and the scle-
derma is suspected.58,146 Biopsies from early lesions often show very subtle rotic collagen have a more nodular distribution.
histological findings and are frequently non-specific. The histological diagno- Several patterns have been described in bullous morphea.35,159,160 The most
sis may be more difficult to establish in biopsies of lesions from guttate mor- common is that of prominent superficial edema with prominent lymphatic
phea as the changes tend to be more focal and superficial. In an established dilatation.35 A further pattern is one identical to that seen in lichen sclero-
indurated plaque, the epidermis is usually normal or occasionally flattened. sus.160 It is worth remembering that autoimmune blistering diseases such as
Mucin deposition is not usually a feature but may be occasionally present. epidermolysis bullosa acquisita may occur concomitantly with morphea, and
Abundant mucin throughout the reticular dermis has been described excep- immunofluorescence may be indicated in cases in which a subepidermal blis-
tionally in nodular morphea.47,155 The papillary dermis either appears unaf- ter is present.159
fected or shows a rather homogenized change (Fig. 17.113). The most In addition to the features described above, generalized morphea and dis-
striking features are seen in the reticular dermis, where the collagen bundles abling pansclerotic morphea of childhood may show a lymphocytic and hya-
are swollen, intensely eosinophilic, and orientated parallel to the surface (Figs line panniculitis with lymphoid follicle formation reminiscent of lupus
17.114–17.116). There is also involvement of the septa of the subcutaneous profundus.58,80 Eccrine squamous syringometaplasia and syringomatous
fat; this is associated with atrophy of the adipocytes and subsequent fibrosis, hyperplasia have been described in linear scleroderma.161
resulting in an apparent increase in thickness of the dermis.1 Hair follicles and
sebaceous glands may be atrophic or absent and the eccrine ducts often
appear compressed within the densely sclerotic dermis. Due to fibrous replace- Differential diagnosis
ment of the subcutaneous fat, the eccrine glands appear to be situated abnor- The lesions of localized scleroderma may be histologically indistinguishable
mally high within the dermis rather than at the dermosubcuticular interface. from those of systemic sclerosis, but the inflammatory cell infiltrate tends to
In rare cases only the superficial reticular dermis is affected.156 be more pronounced in the former, at least in the early stages. Also, involve-
An important feature of localized scleroderma, especially in the early stages, ment of the papillary dermis may be a feature in some cases of localized
is a dense, chronic inflammatory cell infiltrate of lymphocytes, histiocytes, and scleroderma.162
plasma cells; some authors believe this to be the initial feature (Fig. 17.117).58 Other diseases that enter the differential diagnosis include late porphyria
The infiltrate may surround blood vessels and appendages and tends to be cutanea tarda and chronic GVHD. Adequate clinical information will resolve
Fig. 17.115
Fig. 17.113 Fig. 17.114 Morphea: the changes are highlighted with this
Morphea: the dermis is thickened by dense collagen Morphea: the collagen fibers are eosinophilic and Masson's trichrome stained section. In this example,
bundles. Note the heavy perivascular infiltrate. swollen. the papillary dermis is involved.
Fig. 17.116 Fig. 17.117 Fig. 17.118

Morphea: this is a chronic lesion. There is loss of Morphea: a perivascular chronic inflammatory cell Morphea: the infiltrate often involves the
elastic tissue (van Gieson). infiltrate is usually present, particularly in early lesions. subcutaneous fat.
most diagnostic dilemmas, but where doubt exists, the presence of PAS-positive Phenylketonuria has also been reported to show sclerodermatous
thickened dermal vessels is indicative of porphyria, whereas epidermal features.2
lichenoid features with cytoid body formation strongly support the diagnosis Histological distinction between morphea and late lesions of acroder-
of chronic GVHD. matitis enteropathica may be difficult and occasionally impossible.163
The relationship between localized scleroderma, particularly the guttate Close clinicopathological correlation allows distinction between these
variety, and lichen sclerosus has been the source of considerable controversy. entities.
However, basal cell liquefactive degeneration with a lichenoid inflammatory
cell infiltrate is not a feature of morphea, and sclerosis of the reticular dermis
and subcutaneous fat with atrophy or loss of appendage structures is not seen Atrophoderma of Pasini and Pierini
in lichen sclerosus (Fig. 17.119).57
Marked dermal sclerosis may also be a feature of atrophie blanche and Clinical features
chronic radiation dermatitis. Vascular changes, including thromboses, purpura, Atrophoderma is a rare, primary dermal atrophic process of uncertain nature.
and hemosiderosis, however, are conspicuous in the former, while bizarre fibro- Since its first description by Pasini in 1923 there has been controversy as to
blasts, elastosis, and endarteritis obliterans are characteristic of the latter. whether it represents a distinct entity sui generis or whether it is a variant of
localized scleroderma (morphea).1–5 It presents usually in the second or third
decade with a mean age of onset of 30 years and shows a predilection for
females (5:1).6 A congenital variant of atrophoderma of Pasini and Pierini has
also been described.7
The typical lesion is a gray–brown or violaceous, atrophic, round to oval,
depressed macule with a ‘cliff-drop’ border (Fig. 17.120).3 The distribution
is usually bilateral and symmetrical.6 Widespread unilateral involvement is
rare.8 While previous studies demonstrated the lower back as the most com-
monly affected site,6 recent analysis of 16 patients revealed predominance of
lesions on lower extremities (62.5%), followed by upper extremities and
trunk.9 Lesions may also be found on the chest, arms, and abdomen. A case
with a zosteriform distribution has been documented.10 The lesions are
frequently hypopigmented.9
Atrophoderma of Pasini and Pierini may coexist with lichen sclerosus and
morphea, and progression to systemic sclerosis has been documented.10–14 In
contrast to localized scleroderma, it lacks the violaceous border, is primarily
atrophic rather than indurated, and tends to great chronicity, lesions often
being present for decades rather than resolving after a few years, as is often a
feature of morphea.3
Fig. 17.119 An entity described as atrophoderma elastolytica discreta clinically simu-
Morphea: intense papillary dermal edema is present, producing a lichen sclerosus- lates atrophoderma of Pasini and Pierini but the histopathological changes
like appearance. are those of anetoderma.15
Eosinophilic fasciitis 749
The clinical features of painful, tender swelling, stiffness, and sclerodermi-

form induration affect (in decreasing order of frequency) the forearms, upper
arms and lower legs, thighs, hands, trunk, neck, and feet.1,11 The face and fin-
gers are only rarely affected. Localized involvement of a limb has rarely been
documented.12 Unilateral presentation is rare.13 Early cutaneous manifesta-
tions include pitting edema, peau d'orange or a cobblestone appearance.1,14
At least 50% of patients relate the onset of their illness to an episode of stren-
uous physical activity.15–18 Patients have a variety of non-specific features
including malaise, weakness, fever, and weight loss.1 Raynaud's phenomenon
is typically absent and the nail fold capillaries are normal – points of distinc-
tion from systemic sclerosis.19 Pediatric disease commonly progresses to scle-
rodermiform cutaneous scarring.7,16,20 Blood eosinophilia and
hypergammaglobulinemia have been reported.4,21 Hypogammaglobulinemia
is exceptional.22
Extracutaneous involvement is becoming increasingly recognized.23
Patients may develop arthralgia and synovitis. Inflammatory arthritis (pre-
dominantly involving the hands, wrists, and knees) and carpal tunnel syn-
drome occur in about 25% of patients.1,16,19,20,24 Contractures develop in up to
75% of patients and particularly affect the shoulders, elbows, wrists, hands,
Fig. 17.120 and knees.11,25 Subclinical myositis is common.1 Posterior ischemic optic neu-
Atrophoderma: lesions ropathy has also been described.26 Clinically significant systemic features are
present as depressed rare, but have included esophageal dysmotility, pericardial and pleural effu-
atrophic plaques with a sions, and lung and kidney involvement.1,27,28
typical cliff-drop border.
A number of other associations have recently been documented including
By courtesy of the
aplastic anemia, polycythemia rubra vera, thrombocytopenia, hemolytic ane-
London, UK. mia, monoclonal gammopathy, abnormal circulating T-cell clone, peripheral
T-cell lymphoma, leukemia, lymphoma, multiple myeloma, alogenic stem cell
transplantation, chronic graft-versus-host disease, combined immunodefi-
Pathogenesis and histological features ciency, Hashimoto's disease, idiopathic hypercalcemia, psoriasis, IgA neph-
It is still controversial whether this disease represents a variant of morphea. A ropathy, primary biliary cirrhosis, eosinophilic colitis, serositis, miliary
large study of 139 patients suggested that the disease represents an atrophic tuberculosis, SLE, myelodysplasia, acquired ichthyosis, absence of the spleen,
abortive variant of morphea in which the sclerotic phase fails to develop.16 A vitiligo-like changes and peripheral neuropathy, local irradiation for breast
study of lesional skin of two patients showed a decrease in the total amount cancer, toxic thyroid adenoma, metastatic choroidal melanoma, and meta-
of disaccharide and a normal or decreased amount of DeltaDi-4S(DS), the static colorectal carcinoma.1,15,29–61 The association with serious hematologi-
main disaccharide unit of dermatan sulfate.17 This is in contrast with findings cal abnormalities has led to the suggestion that all patients with the disease
in patients with morphea in which there is increase in the total amount of should have a bone marrow examination to exclude myelodysplasia.62 An
disaccharide and increase in DeltaDi-4S(DS). This finding suggests that the exceptional familial case in association with breast cancer has been
two diseases are different. However, a further study of lesional and normal documented.63
skin revealed an increase in the amount of dermatan sulfate in lesional skin as Laboratory investigations reveal a raised ESR, peripheral blood eosino-
is a feature of morphea.18 The identification in the serum of antibodies to philia, and hypergammaglobulinemia (usually IgG).15 Antinuclear antibodies
Borrelia burgdorferi in 20–53% of patients, combined with occasional reports (speckled and homogeneous), rheumatoid factor and, rarely, anti-nDNA anti-
of culture of the organism from lesional material, raises the possibility of a bodies may be present.11,16 Serum aldolase levels appear to be a useful indica-
causal relationship.6 tor of disease activity.64 Cytoplasmic antineutrophilic cytoplasmic antibodies
Histologically, atrophoderma often shows very subtle features. The epider- (c-ANCA) have been demonstrated in a patient with recurrent eosinophilic
mis may be atrophic or normal and is often hyperpigmented. Within the fasciitis.65
superficial dermis is a perivascular and interstitial chronic inflammatory cell Characteristically, eosinophilic fasciitis responds well to corticosteroid
infiltrate consisting of lymphocytes and histiocytes. The lymphocytes are T therapy – a diagnostic pointer. Spontaneous resolution occurs in some
cells and the helper-inducer subset predominates.19,20 Rarely, plasma cells may patients. Progression to scleroderma and coexistence with lesions of localized
be conspicuous. In early lesions the collagen bundles are homogenized and morphea may sometimes occur.7,66–69
swollen but, with progression, sclerosis often supervenes in the deeper reticu-
lar dermis.10,21 The appendage structures are usually normal. The elastic fibers Pathogenesis and histological features
commonly show no change, but diminution and fragmentation have been The etiology and pathogenesis of eosinophilic fasciitis are unknown. The clin-
documented.6,9 The late stages of atrophoderma are indistinguishable from ical findings of hypergammaglobulinemia, occasional antinuclear antibodies,
localized scleroderma. and positive immunofluorescence suggests a humoral immune mechanism.1
Even in those instances when eosinophilic fasciitis has followed strenuous
physical activity, it is unlikely that trauma, on its own, is responsible. There
Eosinophilic fasciitis are occasional reports of possible drug toxicity following, for example, anti-
tuberculous therapy, phenytoin, subcutaneous heparin and fosinopril, sim-
Clinical features vastatin, atorvastatin, and an eosinophilic fasciitis-like picture sometimes
The precise nosological status of eosinophilic fasciitis (Schulman's syndrome) constitutes part of the eosinophilia–myalgia syndrome (see below).19,70–73 The
is uncertain: some authors regard it as a variant of morphea (morphea pro- disease has also followed exposure to trichloroethylene, radiotherapy, subcu-
funda) but others consider it an entity in its own right.1–4 For the purpose of taneous injection of phytonadione, and after the initiation of dialysis.74–77
this text it is classified separately. Borrelia burgdorferi has been associated with some cases of eosinophilic
Eosinophilic fasciitis occurs equally in males and females, and most fasciitis (Fig. 17.121).78–80 However, positive serology for Borrelia bugdorferi
patients are in their third to sixth decades.1 Female predominance has been in patients with eosinophilic fasciitis without direct confirmation of the pres-
demonstrated in some studies.5,6 Pediatric disease has, however, also been ence of the organism by polymerase chain reaction has been regarded insuf-
documented.7–10 White Caucasians are predominantly affected.11 ficient for establishing a pathogenetic link.81
Fig. 17.121 Fig. 17.122

Eosinophilic fasciitis: a spirochete is present in the center of the field (Dieterle Eosinophilic fasciitis: the fascia is thickened and there is marked fibrin deposition.
stain) (arrow).
In some patients, elevation of serum IL-2, -5, and -10, transforming growth
factor β1, tissue inhibitor of metalloproteinase-1, manganese superoxide dis-
mutase, interferon gamma (IFN-γ), and leukemia inhibitory factor has been
documented.10,82–84 The increase in IL-5 and -10 possibly leads to eosinophilia
and immune globulin overexpression.82 Eosinophils have been shown to stim-
ulate DNA synthesis and matrix production in dermal fibroblasts, leading to
increased collagen deposition.85
Immunofluorescence has revealed deposition of IgM at the dermoepider-
mal junction, immunoglobulin and complement around blood vessels in the
deep dermis, and IgG and complement in the deep fascia and skeletal
muscle.11,16,86
The pathology of eosinophilic fasciitis predominantly affects the deep sub-
cutaneous fat and fascia and therefore a substantial incisional biopsy is neces-
sary for diagnosis. The epidermis, papillary dermis, and superficial adnexal
structures are usually unaffected.11 A mild chronic inflammatory cell infiltrate
consisting of lymphocytes, plasma cells, histiocytes, and variable numbers of
eosinophils may be present in the deeper reticular dermis, which is also often
fibrosed with atrophy of sweat glands.86 Immunophenotyping of mononuclar
inflammatory cell infiltrate demonstrated predominancy of macrophages and
CD8+ lymphocytes.87 Occasionally, the dermal changes are indistinguishable Fig. 17.123
Eosinophilic fasciitis: high-power view.
from morphea.16
The most dramatic changes are found in the superficial fascia, which is
markedly thickened, fibrosed, and sclerotic, and in the acute stages may show
focal fibrinoid necrosis and/or myxoid degenerative changes due to excessive
glycosaminoglycan deposition (Figs 17.122, 17.123).1,86 A chronic inflam-
matory cell infiltrate is present within the fascia in both a diffuse distribution
and centered around blood vessels (Fig 17.124).67 Primary vascular lesions,
however, are not a feature. Tissue eosinophilia is focal and often transitory.
Its absence in no way precludes the diagnosis. Lymphoid follicles, sometimes
with germinal centers, are also occasionally evident.86 The inflammatory
changes usually extend into the septa of the subcutaneous fat and fibrosis
may result in fat entrapment.15 There may also be superficial infiltration by
inflammatory cells into the underlying skeletal muscle, which occasionally
shows focal necrosis, degeneration, and foci of regeneration.1,86,88
While there is obvious overlap with morphea, the diffuse nature of the indu-
ration clinically, the high peripheral eosinophilia, and history of preceding
strenuous exercise, combined with the usually less severe dermal changes and
preservation of the skin appendages on histology, commonly serve to distin-
guish the two disorders.
Sclerodermoid and eosinophilic fasciitis-like syndromes have been Fig. 17.124
described as features of the toxic oil and L-tryptophan-related eosinophilia– Eosinophilic fasciitis: the infiltrate consists of lymphocytes with only one or two
myalgia syndromes.89–94 eosinophils.
Polymyositis/dermatomyositis 751
• The toxic oil syndrome arose as a consequence of contaminated Table 17.10

rapeseed oil and presented in Spain in 1981.94,95 Patients developed Variants of polymyositis
myopathy, peripheral neuropathy, and arthralgia in addition to Type Variant
morphea-like skin induration affecting the face, trunk, and extremities.94 I Polymyositis
Xerostomia was common and Raynaud's phenomenon was not
II Dermatomyositis
infrequent.
• The eosinophilia–myalgia syndrome is due to contaminated (Peak E) III Type I or II plus malignancy
commercial L-tryptophan. Patients develop a wide variety of clinical and IV Childhood polymyositis or dermatomyositis
laboratory abnormalities involving the skin, muscles, nerves, fascia, and
V Overlap syndromes
lungs.91 Acute cutaneous involvement is most commonly seen as a
non-specific erythematous macular eruption affecting the trunk and After Bohan, A. and Peter, J.B. (1975) Parts 1 and 2. New England Journal of Medicine,
extremities.91 Chronic lesions include edema of the extremities followed 292, 344–347, 403–407.
by the development of sclerodermiform and/or eosinophilic fasciitis-like
features.89
Variable histological features have been documented, presumably reflect- dermatomyositis or dermatomyositis sine myositis has been the source of
ing different stages of evolution. In some patients the most conspicuous much controversy.10–15 In addition to a prolonged follow-up, adequate elec-
changes have included fibrosis involving the papillary dermis, periappenda- tromyographic studies and muscle biopsy are mandatory before accepting
geal connective tissue sheath and subcutaneous fat.90 An inflammatory cell that the patient has only cutaneous lesions.15,16 Only 5% or less of cases of
infiltrate composed of lymphocytes, histiocytes, plasma cells, and variable dermatomyositis can be classified as the amyopathic variant after long-term
numbers of eosinophils is present in the dermis, subcutaneous fat, and fas- follow-up.14 For the diagnosis of amyopathic dermatomyositis to be made,
cia.91,92 Mast cells are sometimes conspicuous.92 Late stages are characterized it has been suggested that there should be absence of clinical or laboratory
by hyaline sclerosis involving the dermis through to the subcutaneous fat.92 signs of muscle disease for at least 2 years after the onset of skin disease.17
Additional features that have been documented include dermal edema with The clinical cutaneous signs of amyopathic dermatomyositis are identical to
lymphangiectasia and heavy mucin deposition in both the dermis and fascia.90 those seen in classic dermatomyositis. Patients with amyopathic dermato-
The histological features overlap between morphea/systemic sclerosis and myositis, like those with dermatomyositis/polymyositis, are at increased
eosinophilic fasciitis. risk of developing severe interstitial fibrosis of the lung and associated
malignancies.16
Polymyositis/dermatomyositis Dermatomyositis/polymyositis is associated with severe morbidity and
high mortality, the latter particularly reflecting cardiac and pulmonary
Clinical features involvement.
The cutaneous features are usually quite distinctive.18 Commonly, the
Polymyositis is a rare inflammatory disorder of muscle, the etiology of which
patient presents with periorbital edema and a reddish–violet discoloration,
is unknown.1,2 If certain cutaneous lesions are also present, the term ‘dermat-
often termed heliotrope erythema (heliotrope flower) (Figs 17.125, 17.126).
omyositis’ is applied. The overall incidence is approximately five new hospi-
The upper eyelids are most often affected and the eruption is typically sym-
tal cases per million of the population per year.1 As many diseases may include
metrical.19 This is usually associated with a lupus-like erythema, which
features of muscle weakness and elevated muscle enzyme activities, strict cri-
involves the rest of the face and spreads to the neck, upper trunk, and extensor
teria must be applied to the diagnosis of these two diseases (Table 17.9).
surfaces of the limbs and dorsal aspects of the hands and fingers (Fig. 17.127).
Either of these conditions may be confidently diagnosed if a patient fulfills the
It is associated with a slight scale. Exceptionally, generalized subcutaneous
first four criteria (polymyositis) or three of the four plus the typical rash
edema may develop.20
(dermatomyositis).3,4
Other cutaneous features include erythematous papules over the
Five variants of the disease are recognized (Table 17.10). With respect to
metacarpophalangeal joints (Gottron's sign), periungual erythema,
type V, dermatomyositis most commonly coexists with scleroderma (sclero-
telangiectasia, and splinter hemorrhages ( Figs 17.128 , 17.129 ).
dermatomyositis), but it may also develop in association with SLE, rheuma-
toid arthritis, and Sjögren's syndrome.4,5 To diagnose an overlap syndrome
the appropriate diagnostic criteria must be fulfilled for each disease and not
just a few common manifestations. Overlap syndromes occur more frequently
in polymyositis than in dermatomyositis and show a marked female predomi-
nance (9:1).6,7
Dermatomyositis not uncommonly presents solely with cutaneous mani-
festations. The quoted frequency of this type of presentation is variable and
it is not that rare for the skin eruption to precede the onset of muscle
involvement by more than 2 years.8,9 The proposed concept of amyopathic
Table 17.9
Diagnostic criteria for polymyositis/dermatomyositis
Symmetrical weakness of proximal limb muscles and anterior neck flexors
plus esophageal and respiratory muscle involvement
Positive muscle biopsy features
Elevated skeletal muscle enzymes
Appropriate electromyographic features
A typical rash
Fig. 17.125
After Bohan, A. and Peter, J.B. (1975) Parts 1 and 2. New England Journal of Medicine,
Dermatomyositis: note the characteristic red–mauve discoloration around the eyes.
292, 344–347, 403–407. There is also spread onto the cheeks. From the collection of the late N.P. Smith, MD,
Fig. 17.126 Fig. 17.128

Dermatomyositis: the upper eyelids are particularly affected. From the collection of Dermatomyositis: characteristic purple papules on the knuckles (Gottron's sign).
the late N.P. Smith, MD, the Institute of Dermatology, London, UK. By courtesy of Dr J.C. Pascual, Alicante, Spain.
Fig. 17.127 Fig. 17.129

Dermatomyositis: note the erythema and slight scale on this patient's chest. By Dermatomyositis: Gottron's papules, periungual erythema and telangiectatic
courtesy of the Institute of Dermatology, London, UK. capillary loops. By courtesy of Dr J.C. Pascual, Alicante, Spain.
Gottron's papules are typically found on the knuckles, but knees, elbows, been linked to internal malignancy.26,48,49 A rare case with acute onset
and malleoli may also be affected.21 The toes are characteristically vesiculobullous lesions and massive mucosal necrosis of the intestine has
spared. The nail fold capillaries may be enlarged, dilated, and distorted. been documented. 50 Bullous pemphigoid may also rarely be associated
Avascular areas are also often present.18 Cuticular overgrowth is some- with dermatomyositis. 51 Eruptive dermatofibromas have been reported
times evident, and occasionally there is a cutaneous vasculitis presenting in a single patient with dermatomyositis who was treated with predniso-
as digital ulceration, periungual infarcts, and mouth ulcers, though more lone and methotrexate.52
often in the childhood variant.18 With time, the skin may become more Symmetrical proximal (limb girdle) muscle weakness is the most common
atrophic and show the features of poikiloderma, which particularly presenting feature of polymyositis.6 The legs are almost always the initial site
affects the extensor surfaces and upper back, but may be more wide- of involvement. The patient experiences difficulty in getting out of a chair,
spread ( Fig. 17.130 ). 6,7 Scalp involvement, which presents with scaling walking up the stairs, combing his hair or raising his head from a pillow.
and erythema, is not uncommon and is frequently pruritic.18 Interestingly, the facial muscles are almost never involved.53 Although the
Photosensitivity has occasionally been reported. 6,19 Other rare or unusual muscles may be painful, this is not usually severe, and tenderness is not often
features include gingival telangiectases, follicular papules resembling present. Muscle atrophy develops later in the course of the disease when
pityriasis rubra pilaris, erythroderma, erythema confined to seborrheic fibrosis and troublesome contractures may supervene.
areas, dermographism, lesions resembling malignant atrophic papulosis Esophageal involvement manifests as dysphagia, which correlates with the
(Degos' disease), a vesicobullous rash, a pustular eruption, Sweet-like presence of an associated malignancy.4 Symptoms may also indicate pre-
dermatosis, granuloma annulare, cutaneous amyloidosis, localized muci- esophageal involvement due to cricopharyngeal striated muscle weakness.6
nosis, panniculitis, and lipodystrophy. 21–45 Gingival telangiectases have Sequelae include nasal regurgitation and aspiration pneumonitis, the latter
also been found in association with anti-Jo-1 antibody.46 Some patients being associated with a high mortality. A change in voice is a not uncommon
present with a centripetal flagellate erythema affecting the trunk and manifestation. Juvenile dermatomyositis has also been associated with isch-
proximal extremities.47 Subepidermal blistering may occur and this has emic ulcerative colitis and celiac disease.54,55
Arthralgia is not uncommon, but frank arthritis is rare except in the over-
lap group of patients.4 Destructive arthropathy has been reported in a patient
with amyopathic dermatomyositis associated with anti-Jo-1 and anticyclic
citrullinated peptide antibodies.75 Aseptic bursitis of the olecranon has been
reported in a single patient.76
Laboratory investigations may reveal non-specific findings of a raised
ESR, hypergammaglobulinemia, and a false-positive Wassermann reaction.
Antinuclear factor may be found in a small percentage of patients with poly-
myositis/dermatomyositis. Anti-RNP and -SM antibodies are only seen in
‘overlap’ patients. In addition to anti-Jo-1 antibody, additional newly
described antibodies include PM-1, Ku, Mi-1, -2 and -3, and Pa-1.77 The sig-
nificance of these (except anti-Jo-1) is uncertain.78
Often stressed in polymyositis/dermatomyositis is the association with an
increased risk of developing malignancy.79 Although there has been a great
range in reported incidences from small studies, varying from 15% to 60% of
cases, recent investigations have suggested that the risk is less.56,80–85
Fig. 17.130 Polymyositis/dermatomyositis has been described in association with the fol-
Dermatomyositis: in this lowing malignancies: breast cancer, neuroendocrine carcinoma of the lung,
patient with longstanding small cell lung cancer, hepatocellular carcinoma, neuroendocrine carcinoma
disease, atrophy and of the liver, duodenal carcinoid, gallbladder carcinoma, carcinoma of the
variable pigmentary bladder, prostate cancer, renal cell carcinoma, clear cell ovarian carcinoma,
changes (poikiloderma) fallopian tube cancer, carcinosarcoma of the uterus, nasopharyngeal carci-
are present on the noma, esophageal cancer, Klatskin tumor (hilar cholangiocarcinoma), thy-
dorsum of the hand.
roid cancer, thymic carcinoma, cancer of the colon, primary gastric melanoma,
By courtesy of the
metastatic melanoma, diffuse large B-cell lymphoma, primary cutaneous
London, UK. B-cell lymphoma-leg type, follicular lymphoma, lymphoplasmocytoid lym-
phoma, acute myeloid leukemia, and Kaposi's sarcoma.86–120 Among the
reported associations, breast, stomach, and ovarian tumors are most often
Electromyographic features in polymyositis/dermatomyositis are said to cited. In a recent study analyzing patients with dermatomyositis in China,
be pathognomonic and include the triad of short, low amplitude, polyphasic nasopharyngeal cancer was the most frequent association, followed by lung
potentials, increased spontaneous activity including fibrillation potentials cancer.121 Patients should have a very thorough physical examination com-
with positive sharp waves at rest, irritability, and bizarre high-frequency bined with routine laboratory investigations, chest X-ray, CT scan of the
repetitive discharges.53,56 abdomen and pelvis, and (in female patients) mammography. Underlying
The serum usually contains raised levels of creatine kinase, aldolase, lac- malignancy should be suspected in patients who do not respond to therapy or
tate dehydrogenase, and transaminases; as not all these may be elevated in those who develop frequent episodes of myositis.81,122 A recent study suggests
any one patient it is usually recommended that all are estimated routinely.6 that patients requiring more extensive search for malignancy should include
Sequential muscle enzyme studies are particularly useful for monitoring prog- those with constitutional symptoms, with rapid onset of dermatomyositis or
ress and response to treatment. polymyositis, without Raynaud's phenomenon, with a high ESR, and with a
Involvement of cardiac muscle is not uncommon and patients may have very high creatine kinase level.85
tachycardia, sinus bradycardia, electrocardiographic abnormalities (e.g., There appears to be an increased risk of thyroid disease, particularly hypo-
bundle branch block), congestive heart failure, and cardiomegaly.57,58 thyroidism, especially in patients with interstitial lung disease.56 Juvenile der-
Restrictive cardiomyopathy has also been described in a patient with matomyositis, which has an annual incidence of about one new case per
dermatomyositis.59 million of the population per year, shows a female predominance (2:1) and
Pulmonary involvement, as determined by the radiological changes of presents most often in the first decade.72 In addition to the features described
interstitial fibrosis and/or clinical evidence of impaired respiratory function, above there is a high incidence of vasculopathic manifestations including gas-
may occur in as many as 40% of patients with polymyositis/ dermatomyosi- trointestinal ulceration with hemorrhage, which may be fatal.1 Multiorgan
tis.6 Patients are also at increased risk for development of pulmonary hyper- involvement is common. The condition is often preceded by an infection.123
tension.60 Pneumomediastinum and interstitial pneumonia are rare The prognosis is usually good, with up to 70% of children making a full
complications.61,62 Pulmonary hemosiderosis is an exceptional finding in juve- recovery.123 In severely affected patients, widespread cutaneous involvement
nile dermatomyositis.63 An important recently described association is that may be complicated by extensive scarring and diffuse calcification.124
between the anti-Jo-1 antibody, pulmonary fibrosis, and dermatomyositis.64–69 Scleroderma/polymyositis overlap (sclerodermatomyositis) is the most
More than 50% of patients with anti-Jo-1 antibody have interstitial lung dis- common overlap syndrome. Although the myositis component is usually
ease.65 Patients with this variant are not at risk of an increased incidence of identical to that seen in dermatomyositis/polymyositis, the heliotrope ery-
internal malignancy. Additional features of this variant may include Raynaud's thema and Gottron's papules are usually absent.125 The sclerodermatous cuta-
phenomenon, arthritis and tenosynovitis. Spread to the thoracic muscles can neous manifestations tend to be restricted to the peripheries. This overlap
result in severe respiratory difficulties; terminal bronchopneumonia is there- syndrome is associated with the Ku antibody and a case has been reported in
fore an important cause of death.70 association with Graves' disease and thrombocytopenic purpura.126
Cutaneous vasculitis is characteristic of the childhood variant, which may Autoimmune idiopathic thrombocytopenia with anti-Ku antibody has also
involve the viscera; it has also been described in adult patients and may be been associated with dermatomyositis.127
associated with an increased risk of malignancy. Digital ulcers, periungual
infarcts, and oral ulcers are associated manifestations.6 Deep cutaneous and
subcutaneous ulcers, not associated with vasculitis, have rarely been reported Pathogenesis and histological features
in adult-onset dermatomyositis, and are likely to be related to obliterative While the etiology and pathogenesis of polymyositis/dermatomyositis are
(micro)vasculopathy.71 Calcification of the skin, soft tissues, and muscle is unknown, it has been proposed that environmental factors (e.g., drugs, toxins
rare except in the childhood variant where it may be widespread and of help or viruses) acting in association with a genetic predisposition result in a pri-
diagnostically.72–74 Skin calcification has been demonstrated to correlate with marily immune-mediated disorder.56 There is evidence to suggest that both
autoantibodies to a 140-kD protein.74 humoral and cell-mediated components are important.
Antinuclear factor is commonly present. Antimyosin and antimyoglobin emphigus foliaceus, Duchenne muscular dystrophy carrier status, familial
p
antibodies have been described, but their significance is uncertain. It is not polyposis colli, ulcerative colitis, hemophagocytic syndrome, organic solvent,
clear whether they precede or follow the onset of the myositis, and their pres- and silicone gel-filled breast implants.166–175
ence does not explain the cutaneous manifestations. However, antimyosin Direct immunofluorescence of lesional skin reveals granular deposits of
antibodies accompany any inflammatory myositis and are therefore probably immunoglobulin (IgG, IgA, and IgM) and complement at the dermoepidermal
a consequence of muscle necrosis. junction in about 35% of patients.176,177 Site selection is of importance, positiv-
A further set of antibodies directed against nuclear antigens have been ity being most frequent with nail bed biopsies.176 A more recent study has dem-
described in 35–40% of patients with dermatomyositis/polymyositis:128 onstrated C5b–9 deposition in blood vessel walls and along the dermoepidermal
• PM-1 (PM-Scl) antibody correlates closely with polymyositis and junction in conjunction with a negative lupus band test.178,179 This finding has
polymyositis/scleroderma overlap. high specificity (93.5%) and sensitivity (78.5%). Epidermal keratinocytes may
• Ku antibody is a marker for sclerodermatomyositis. also be positive for C5b–9 and IgG.179 The finding of C5b–9 in the wall of small
• PA-1 antibody correlates with polymyositis, arthritis, and fibrosing alveolitis. blood vessels suggests that a complement-mediated microvascular injury may
• Mi-2 correlates with dermatomyositis.6,56,128 be of some importance in the pathogenesis of dermatomyositis.
The presence of antibodies to the RNP antigens, U1 and U2, although not The pathogenesis of childhood dermatomyositis has a predominantly isch-
specific, is certainly highly suggestive of dermatomyositis/systemic sclerosis emic basis (see below).123
overlap syndrome.125,129,130 Antisignal recognition particle (SRP) antibodies are The cutaneous findings are variable. The erythematous eruption shows
uncommon, but are usually associated with severe disease.126 Although these slight hyperkeratosis and epidermal atrophy, with effacement of the ridge pat-
antinuclear autoantibodies are of diagnostic value, they have not yet been tern (Fig. 17.131).123 Basal cell liquefactive degeneration is typical and cytoid
shown to be of pathogenetic significance. Anti-p155-kD protein antibody has bodies are sometimes present (Fig. 17.132). Basement membrane thickening
been detected in 22% of patients with polymyositis/dermatomyositis and 75% is occasionally prominent. There is upper dermal edema and melanophages
of patients with cancer-associated dermatomyositis.131 Anti-CADM-140 anti- may be evident. Rarely, the edema results in subepidermal vesiculation.180
body is more frequent in patients with amyopathic dermatomyositis and
correlates with interstitial lung disease in Japanese patients.132,133
Dermatomyositis and polymyositis may develop in patients with other
known autoimmune disorders, including autoimmune thyroid disease and
insulin-dependent diabetes mellitus.56,134 The precise role of humoral immu-
nity in dermatomyositis is unclear, but it is thought to be particularly related
to the capillary loss and ischemic damage.135
Cell-mediated immunity is important in the development of experimental
models of polymyositis. Lymphocytes taken from animals with allergic myo-
sitis (based upon sequential injections of heterologous muscle with Freund's
adjuvant) prove cytotoxic to skeletal muscle fibers in culture and may undergo
lymphoblastic transformation. Parallels do exist in the human disease, but
whether these represent initiating factors or develop as a consequence of mus-
cle damage is unknown.1 A variety of cellular immune abnormalities have
been documented, including the presence of activated mononuclear cells
within skeletal muscle, abnormal trafficking of mononuclears to skeletal
muscle, decreased autologous mixed lymphocyte responses, and mitotic and
proliferative responses to autologous muscle.56,136,137
There is some evidence to suggest an inherited predisposition with an
increased incidence of HLA-B8 and HLA-DR3 in both dermatomyositis and
polymyositis, particularly in patients who have anti-Jo-1 antibodies.56,138
Fig. 17.131
There are rare instances of familial disease.56 Dermatomyositis: there is hyperkeratosis and epidermal atrophy. Note the mild
A number of animal experimental models have shed some light on the telangiectasia.
possible pathogenesis of human myositis.56 Injection of muscle extracts into a
number of animals results in a mild, nonpersistent myositis.56
Several viruses – including Coxsackie B virus, simian acquired immunodefi-
ciency retrovirus, and murine encephalomyocarditis virus – have been shown
to induce a chronic myositis-like disease. Virus strain and host genetic factors
appear to be of particular importance.56 Although uncertain, it has been sug-
gested that some cases of dermatomyositis, particularly the juvenile variant,
may represent an abnormal immunological response to a viral infection.70
Picornaviruses, including the coxsackievirus group, have been particularly
implicated.1 The anti-Jo-1 antibody (an antiaminoacyl-tRNA synthetase) reacts
with histidyl-transfer RNA synthetase.135 This enzyme has been shown to be
capable of interacting with the RNA of a number of picornaviruses in addition
to its normal substrate tRNA.56 It has been suggested that the development of
the autoantibody may occur as a consequence of this aberrant interaction.56
It is interesting to note that an illness similar to dermatomyositis may be
induced by a number of infectious organisms including leishmania, parvovi-
rus (erythrovirus) B19, human immunodeficiency virus, and toxoplasma.139–143
Tuberculous myofasciitis has developed in a dermatomyositis patient.144
Dermatomyositis/polymyositis has been reported as an adverse reaction to a
number of drugs, such as hydroxyurea, cyclophosphamide, etoposide, fluvastatin,
simvastatin, pravastatin, omeprazole, minocycline, carbimazole, terbinafine, Fig. 17.132
and interferon beta-1a.145–165 Furthermore, polymyositis/dermatomyositis has Dermatomyositis: there is atrophy with effacement of the ridge pattern. In this
also been found in association with hepatitis B vaccination, psoriasis, example cytoid bodies are conspicuous. Note the pigmentary incontinence.
Fig. 17.133 Fig. 17.134

Dermatomyositis: focal, mild basal cell hydropic degeneration is seen on the right. Gottron's papule: note the hyperkeratosis, hypergranulosis, and irregular acanthosis
A chronic inflammatory cell infiltrate is present. simulating lichen planus. There is basal cell hydropic degeneration and cytoid bodies
are present in the superficial dermis. By courtesy of D. Whittemore, DO, MD
Anderson Cancer Center, Houston, Texas, USA.
A light chronic inflammatory cell infiltrate is usually present (Fig. 17.133). It

is commonly restricted to the superficial dermis and is not associated with the
cutaneous adnexae. The infiltrate consists of activated T lymphocytes and
macrophages with occasional dermal Langerhans cells.181 Helper T cells pre-
dominate. In some instances the presence of marked hyperkeratosis, follicular
plugging, dermal edema, and increased quantities of basement membrane-like
material results in considerable histological overlap with lupus erythematosus,
and clinicopathological correlation is essential. A recent study found the most
consistent histological parameters in dermatomyositis to be vacuolar changes
of basal keratinocytes, dermal mucin accumulation, and a mild to moderate
dermal mononuclear inflammatory cell infiltrate.182 Dermal sclerosis may
occasionally be present.183
Increased quantities of Alcian blue-positive glycosaminoglycans are fre-
quently present within the dermis.180 Sometimes there are foci of calcification
and panniculitis is occasionally evident.
The poikilodermatous lesions show hyperkeratosis, mild epidermal atro-
phy with loss of the epidermal ridge pattern, and basal cell liquefactive
degeneration.123 Additional features may include marked pigmentary incon-
tinence, cytoid body formation, and a patchy lymphocytic inflammatory
cell infiltrate. The dermis is edematous, often contains increased mucin, and Fig. 17.135
characteristically shows conspicuous dilated vascular channels. Nuclear Dermatomyositis: note the perivascular chronic inflammatory cell infiltrate.
atypia of the infiltrate as seen in poikilodermatous mycosis fungoides is not
a feature.
Gottron's papules are characterized by hyperkeratosis, mild papillomato-
sis, acanthosis or, less often, epidermal atrophy and the features of interface
dermatitis as described above (Fig. 17.134).184,185 The histology of the cen-
tripetal flagellate erythema shows the changes of interface dermatitis.47
Ultrastructural studies contribute little to our understanding of dermato-
myositis. Tubuloreticular inclusions as described in SLE have been documented
in endothelial cell and pericyte cytoplasm, but their significance is
uncertain.186
In the juvenile variant, the cutaneous features are similar to those described
above with the proviso that fibrosis is sometimes evident, calcification is more
common and occlusive vascular disease (as characterized by fibrous intimal
proliferation with fibrin thrombi) is often present.123,124
Skeletal muscle changes include both degenerative and regenerative fea-
tures in addition to a focal chronic inflammatory cell infiltrate (Figs 17.135,
17.136).123 The latter is composed predominantly of lymphocytes, but histio-
cytes, eosinophils, and plasma cells may also be evident.187 The lymphocytes
consist of substantial numbers of B cells, particularly in association with blood
vessels, in addition to T-cells, which are predominantly found in and around
the altered muscle fibers.188 As in cutaneous lesions, T-helper cells predomi- Fig. 17.136
nate. Up to 25% of muscle biopsies may, however, show no evidence of Dermatomyositis: the infiltrate consists predominantly of lymphocytes.
Fig. 17.137 Fig. 17.139

Dermatomyositis: the central fiber is intensely swollen, eosinophilic, and Dermatomyositis: the lower fiber is basophilic and shows excessive nuclei –
fragmented; there is a loss of striations. features of regeneration. Note the centralization of nuclei in the upper fiber.
is usually quite sparse, consists of lymphocytes, monocytes, and plasma cells

centered predominantly on the vasculature in the perifascicular connective
tissue.193 Muscle changes are variable and range from perifascicular atrophy
in milder disease through to focal necroses and infarction in the more seri-
ously affected patients, in whom fibrosis may also be a feature.193 The vascu-
lar lesions include endothelial cell swelling and necrosis with or without
occlusion, non-necrotizing lymphocytic vasculitis, and loss of the peripheral
fascicular capillary bed.193
Immunofluorescence of muscle biopsies in childhood dermatomyositis
commonly shows vascular intramural IgM and C3.193
Mixed connective tissue disease

Clinical features
As originally defined by Sharp et al., mixed connective tissue disease (MCTD)
represents a clinical condition in which patients have an overlap of signs and
symptoms of systemic sclerosis, systemic lupus erythematosus, and polymyo-
sitis/dermatomyositis.1,2
Fig. 17.138
Dermatomyositis: the fiber in the upper midfield is swollen, eosinophilic,
Although the concept of mixed connective tissue disease as a distinctive
vacuolated, and in places granular; beneath is a regenerating basophilic cell. entity separated from other connective tissue diseases has been controversial,
the disease has characteristic and reproducible clinical and serological fea-
tures.3,4 Some patients present with manifestations that are not entirely diag-
inflammation.4 The degenerative fibers are swollen and intensely eosinophilic nostic and may progress over time to develop typical features of MCTD or
and may show loss of striations (Fig. 17.137). Some fibers are vacuolated, but other connective tissue diseases, particularly SLE. These patients are desig-
others appear granular or fragmented (Fig. 17.138). Proliferation and central- nated as having an unclassified or undifferentiated connective tissue disease.5
ization of muscle nuclei is common, as is sarcoplasmic basophilia – features of MCTD is characterized by a marked female predominance (16:1) and
regeneration (Fig. 17.139). Histological changes identical to inclusion body shows no racial predilection.6,7 Presentation is usually in the second and third
myositis, namely rimmed vacuoles, have also recently been reported in patients decades, but children may also be affected.1,8–10 Clinical features include
with dermatomyositis.189,190 arthralgias and nondeforming arthritis, swollen hands with tapered or
If material from a longstanding ‘burned out’ lesion is biopsied, the muscle sausage-shaped fingers, Raynaud's phenomenon, abnormal esophageal motil-
fibers are atrophic and there is endomysial fibrosis. Perifascicular atrophy – the ity, myositis, lymphadenopathy, fever, hepatomegaly, serositis, and splenomeg-
presence of one or two rows of atrophic fibers at the edge of a fascicle – is said aly.1,11 Patients were initially thought not to show features of renal, pulmonary
to be characteristic of dermatomyositis.191 The muscle pathology in dermato- or neuropsychiatric involvement or vasculitis. In addition, their sera invariably
myositis and polymyositis is said to differ.56 In dermatomyositis the inflamma- contained high titers of antibody to a saline extractable nuclear antigen
tory cell infiltrate tends to be septal or perivascular whereas in polymyositis it is (ENA), U1-RNP, and speckled antinuclear antibody. Precipitating antibody
intrafascicular. Muscle necrosis in dermatomyositis tends to involve small groups to SM soluble nuclear antigen was absent. The disease responded to
of fibers, while in polymyositis the affected fibers tend to be single and sparse. corticosteroid therapy and had a favorable outcome.
Denervation neuropathic features are also occasionally present, presum- In the light of data from subsequent experience, the above, rather simplis-
ably due to involvement by the inflammatory process of small intramuscular tic, overview has had to be modified.6,12 Although a variety of diagnostic cri-
nerve fibers.123 Steroid atrophy of type II muscle fibers may be seen in biopsies teria have been proposed, that of Alarcón-Segovia and Cardiel has been
from treated patients. chosen, largely because of their simplicity.13 They suggest that if the criteria
In childhood dermatomyositis, vascular changes affecting the capillaries, used are restricted to certain key clinical manifestations then MCTD may be
venules, and arterioles are common.192 The inflammatory component, which accurately diagnosed (Table 17.11).7
Relapsing polychondritis 757
Table 17.11 systemic sclerosis. It is generally considered that, although mortality is low in
Diagnostic criteria for mixed connective tissue disease MCTD, there is a much greater morbidity due to internal involvement than
Serologic was originally appreciated.
high anti-RNP titer (> 1:1600 by hemagglutination or an equivalent by MCTD has also been associated with Hashimoto's thyroiditis, thymic car-
another method) cinoma, sarcoidosis, vitamin D deficiency, retinal vasculopathy, acute coro-
Clinical nary syndrome, Kikuchi-Fujimoto disease, mixed-type autoimmune hemolytic
edema of the hands anemia, autoimmune thrombocytopenia, thrombotic thrombocytopenic pur-
synovitis pura, panniculitis, hypertrophic obstructive cardiomyopathy, esophageal
myositis (biopsy proven or elevated CPK) motor dysfunction, interstitial lung disease, mucous membrane pemphigoid,
Raynaud's phenomenon (two or three phases) and sensorineural hearing loss, MPO-ANCA-positive polyangitis, cutaneous
acrosclerosis
polyarteritis nodosa, human T-lymphotropic virus type 1 carrier status, aseptic
Diagnosis of MCTD requires
positive serology plus three or more of the clinical criteria
meningitis, ANCA-positive glomerulonephritis, and nephrotic syndrome.33–54
CPK, creatinine phosphokinase; MCTD, mixed connective tissue disease; RNP, Pathogenesis and histological features
ribonucleoprotein. Reproduced with permission from Alarcón-Segovia, D. (1994)
Clinics in Dermatology, 12, 309–316. The etiology and pathogenesis of MCTD are unknown. MCTD has, however,
apparently followed vinyl chloride exposure.32 Immunoglobulin (Gm) allo-
type association and an increased frequency of HLA-DR4 in patients with
polyarthritis have been documented.16,55 Patients are frequently lymphopenic
Essential to the diagnosis is the presence of high titer anti-ENA antibodies
with diminished circulating T cells and increased B cells.16
(anti-U1-RNP). The U1-RNP is an RNA-protein complex, composed of U1
The histological features of the varying cutaneous manifestations have
snRNA and several proteins, of which U1-70K proteins are specific for the
been described in the appropriate sections (Figs 17.140, 17.141). Biopsies
complex.14 In MCTD, antibodies against the U1-70K proteins are the most
from cutaneous lesions with no typical features may show histological fea-
prominent, and those directed against the apoptotic form of U1-70K appear to
tures similar to those of subacute lupus.56
be particularly useful as serological markers of MCTD.15 Anti-ENA antibodies
Direct immunofluorescence may reveal epithelial speckled nuclear positiv-
are also present in the sera of patients with SLE. In MCTD, however, the anti-
ity, presumably representing in vivo binding of anti-U1-RNP antibodies.57
body–antigen interaction is sensitive to ribonuclease and trypsin and resistant
to deoxyribonuclease, the antigen in fact being ribonucleoprotein (U1-RNP).16
In SLE, the antibody activity is resistant to ribonuclease and deoxyribonu-
clease, but sensitive to trypsin, and the antigen is SM. Anti-ENA antibodies are Relapsing polychondritis
not seen in systemic sclerosis or dermatomyositis. Patients with MCTD do not
usually develop antibodies to native DNA.17 The presence of anti-Ro (SS-A) Clinical features
antibodies appears to identify a subgroup of patients frequently presenting Relapsing polychondritis is a rare disorder characterized by recurrent episodes of
with malar rash and photosensitivity.18 Nucleoporin p62 antibodies have been inflammation of cartilaginous tissue throughout the body and its subsequent
reported in a single patient with MCTD and were suggested to signify poor degeneration and replacement by fibrous tissue (Fig. 17.142).1,2 The ears (93%),
prognosis in patients with connective tissue disorders.19 Patients with active nose (56%), larynx, and trachea (30%) are predominantly affected.3–7 Skin mani-
MCTD have significantly higher serum levels of antiendothelial cell antibodies festations are the presenting features in approximately 50% of cases.6 There is a
than those with inactive MCTD, making antiendothelial cell antibodies a slight male predominance and the median age at diagnosis in one large study was
useful marker of clinical disease activity.20 Exceptionally, antineutrophil 46.6 years.8 Presentation in children is exceptional.9,10 Pediatric and adult-onset
cytoplasmic antibodies against proteinase-3 have been detected in MCTD, relapsing polychondritis patients share similar clinical features.10 However, chil-
and contributed to the development of systemic atherosclerosis.21 dren have a family history of autoimmune diseases more often than adults.
In addition to hand and finger changes and Raynaud's phenomenon, However, they infrequently present with associated autoimmune conditions.10
patients may develop alopecia, areas of hypo- and hyperpigmentation, and Clinical criteria for diagnosis have been established. Three of these, together with
sclerodermiform nail fold capillaropathy. Cutaneous lesions of DLE, SCLE, biopsy confirmation of chondritis, are required for diagnosis (Table 17.12).5
and SLE also occur.22 Occasionally, the cutaneous lesions of dermatomyositis Although it particularly affects Caucasians, cases have been recorded in
are evident. Livedoid vasculitis with ulcers has also been documented and Asians, blacks, Hispanics, and the Japanese.3 The sex incidence is equal. Most
was associated with poor prognosis in the single patient described.23 Other patients present in the fourth decade.4 There is no evidence of a hereditary
less common manifestations include alopecia and oral ulcers.24 Sicca symp- predisposition.6 Clinical signs may be subtle and can resemble those seen in
toms are present in up to one-third of patients.25 Behçet's disease or inflammatory bowel disease; the diagnosis is often diffi-
Systemic features that are more commonly documented in MCTD include cult.2,11 Familial cases are exceptional.12
deforming polyarthritis, which particularly affects the hands and feet (often Auricular chondritis is the commonest lesion and is frequently bilateral.3
in association with rheumatoid factor), juxta-articular and peritendinous Patients present with painful, tender, erythematous, sometimes blue–black,
nodules, and calcification involving the forearms, wrists, hands, and feet.6,26 and swollen ears.6 Chronicity leads to distortion and flabbiness. Arthritis
A distinctive mutilating arthropathy giving rise to a ‘main en lorgnette’ (seronegative) particularly affects the sternoclavicular, costochondral, and
appearance is said to be characteristic.16 sternomanubrial joints.3 One or more joints may be affected and lesions are
It is now known that if patients are followed for a sufficiently long period often migratory.6 Painful nasal chondritis may result in epistaxis, and saddle
there is a much greater risk of visceral lesions than was previously realized.22 nose is an occasional complication. Nasal involvement is seen in over 50% of
The majority develop asymptomatic respiratory involvement. Pulmonary patients.8 Oral aphthosis was present in 11% of patients in a large series.2 In
hypertension with a poor prognosis is, however, not rare27,28 and represents 6% of patients, oral and genital aphthae were seen.2 When the disease initially
the most severe clinical manifestation of MCTD.29 The presence of anti-β2- presents, inflammation of a single site may be confused with erysipelas.13
glycoprotein I antibodies has been demonstrated to correlate with develop- Ocular lesions include conjunctivitis, corneal ulceration, iridocyclitis, epis-
ment of pulmonary hypertension in patients with MCTD.30 Pulmonary cleritis, proptosis, cataract, chorioretinitis, scleromalacia perforans, scleritis,
veno-occlusive disease has also been implicated in the pathogenesis of pulmo- retinal detachment, blindness, edema of the eyelids and muscle palsies, and
nary hypertension in MCTD.31 Up to 10% of patients develop renal disease optic neuropathy.3,6,8,14–17 Chronic conjunctivitis due to obliterative micoran-
(albeit usually mild) and a significant proportion of patients develop neurop- giopathy has been reported in a single patient with relapsing polychondritis.18
sychiatric and cerebral manifestations, including trigeminal neuropathy and Central nervous system complications comprise aseptic meningitis and menin-
migrainous headaches.32 The mixed nature of the clinical manifestations later goencephalitis, encephalitis lethargica, Lewy bodies-like dementia is a rare
becomes less obvious with evolution towards a single disease process, usually complication.17,19–23 Trigeminal neuralgia has also been reported.24
Fig. 17.140 Fig.17.141 Fig. 17.142

Mixed connective tissue disease: morphea-like Mixed connective tissue disease: high-power view Relapsing polychondritis: the ear shows considerable
features. There is dense dermal sclerosis with showing dermal sclerosis. erythema and swelling. By courtesy of R.A. Marsden,
extension into the subcutaneous fat. MD, St George's Hospital, London, UK.
Table 17.12 arthritis, Sjögren's syndrome, dermatomyositis, MCTD, SLE, inflammatory

Diagnostic criteria for relapsing polychondritis bowel disease (both ulcerative colitis and Crohn's disease), and myeloprolif-
erative disorders.2,6,32,46–54 Rare associations of relapsing polychondritis
Recurrent articular chondritis
include ankylosing spondylitis, Behçet's disease, HIV, splenic abscess, chronic
Cochlear and vestibular damage
Ocular involvement hepatitis C, mixed cryoglobulinemia, sarcoidosis, common variable immuno-
Nasal involvement deficiency, familial Mediterranean fever, and amyloidosis.55–62
Tracheal/pharyngeal involvement An increased ESR and anemia are the commonest significant laboratory mani-
Nonerosive polyarthritis festations. Increased urinary glycosaminoglycans have also been documented.63
Relapsing polychondritis has a significant mortality. The 5-year survival rate
is approximately 74%.32 Infection, respiratory failure, systemic vasculitis, large
Respiratory lesions may affect the larynx, trachea, and major bronchi vessel aneurysm rupture, and renal failure are the commonest causes of
with obstructive symptoms, stenosis, collapse, pneumothorax, pneumoperi- death.1,32
toneum, and bronchopneumonia.3,7,8,25 Exceptionally, airway involvement A number of patients have been reported to have myelodysplastic syn-
may be the only manifestation of the disease.26 Cardiovascular lesions drome associated with relapsing polychondritis.41,64–68 This is of interest since
include valvular incompetence, conduction defects including complete heart myelodysplastic syndrome is known to be associated with autoimmune dis-
block, cystic medial necrosis of the aorta, aortitis, aortic valve regurgita- ease.69,70 In a large study of 200 patients, 11% had myelodysplastic syn-
tion, vasculitis and pericarditis, and pericardial effusions.3,8,17,27–30 drome.2 Other malignancies occurring with relapsing polychondritis include
Involvement of the heart valves occurs in up to 10% of patients and sys- splenic non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic
temic vasculitis, reminiscent of polyarteritis nodosa, has been described.31 myelomonocytic leukemia, and Kaposi's sarcoma.71–74 Association with epi-
Ear involvement includes external ear chondritis, otitis media, vertigo, and thelial malignancies is less frequent.75
deafness.32 Relapsing polychondritis has been associated with the luteinizing hor-
Dermatological manifestations are present in 35–50% and may even pre- mone-releasing hormone (LH-RH) analogue goserelin. As the disease may
cede the development of relapsing polychondritis in about 12% of cases.2 worsen during pregnancy and during chorionic gonadotropin therapy, it is
Skin lesions have included leukocytoclastic vasculitis, hypocomplementemic suggested that hormones may be a precipitating factor.76
urticarial vasculitis, cutaneous polyarteritis nodosa, erythema elevatum diuti-
num, livedo reticularis, alopecia, retarded nail growth, erythematous nod- Pathogenesis and histological features
ules, erythema annulare centrifugum, erythema multiforme-like lesions, The precise etiology of relapsing polychondritis is poorly understood. Several
urticarial plaques, erythema nodosum, thrombosis, pyoderma gangrenosum- studies have suggested an immunological mechanism.6 The association with
like lesions, Sweet's syndrome, postinflammatory hyperpigmentation, and autoimmune diseases in many patients lends support to this thesis. Antibodies
psoriasis.2,3,6,33–43 Exceptional associations with normolipemic plane xan- (predominantly IgG) to type II collagen, which accounts for over 50% of the
thomatosis and with panniculitis showing septal and lobular involvement proteins in cartilage, have been detected in a proportion of patients in titers of
accompanied by vasculitis have been documented.44,45 1:10 to 1:320.37,46,77,78 The antibodies are directed against both native and dena-
Significant disease associations that may be present in up to 30% of tured protein.46 Using ELISA, one study showed that 50% of patients have anti-
patients include leukocytoclastic vasculitis, systemic vasculitis (Takayasu and bodies against type II collagen.79 In this same study, 4% of control subjects and
temporal arteritis, Wegener's granulomatosis), Hashimoto's thyroiditis, 15% of rheumatoid arthritis patients also had antibodies in their sera. Those
Relapsing polychondritis 759
patients who have the autoantibody show evidence of active disease, whereas
those without it are either in remission or being treated.46 Rats immunized with
type II collagen develop auricular chondritis. Cartilage from these same ani-
mals had positive immunofluorescence for IgG and C3.80 In a single patient,
T-cell clones were found to be specific for the collagen II peptide 261–273.81
An association between the disease and HLA-DR4 has been reported but
there is no predominance of any DR4 subtype.82
Antifetal cartilage antibodies have been detected by indirect immunofluo-
rescence studies.78 Documentation of transplacental transfer of these antibod-
ies with neonatal involvement suggests that they are of pathogenetic
significance. One group of authors suggested that matrilin-1, a cartilage
matrix protein, is the target of autoreactivity.83,84 Another group found
autoantibodies to matrilin-1 in 13% of patients and antibody titers correlated
with symptomatology.85 Rats immunized with matrilin-1 develop nasorespi-
ratory abnormalities (but not ear or joint changes).86 Cartilage oligometric
matrix protein has also been suggested as a potential autoantigen.87
Circulating immune complexes have also been demonstrated in relapsing
polychondritis, together with deposits of immunoglobulin and complement
in inflamed cartilage, adding further support to a possible immune mecha-
nism in this disease.3,38,46 Granular deposits of immunoglobulin and comple- Fig. 17.143
Relapsing polychondritis: in this early lesion, the degenerate cartilage shows
ment (C3) have been described at the chondrofibrous junction in two
intense eosinophilia.
patients.87 The presence of antineutrophil cytoplasmic antibody (ANCA) has
been reported.88 Elevated serum levels of macrophage migration inhibitory
factor have also been documented.89 Increased serum levels of proinflamma-
tory cytokines, namely macrophage inflammatory protein 1β, monocyte
chemoattractant protein 1, and interleukin-8 have also been demonstrated in
patients with relapsing polychondritis.90
There is some evidence suggesting that cell-mediated immunity may also
be of importance in the pathogenesis. Patients display positive lymphoblast
transformation and macrophage migration inhibition to cartilage glycosamin-
oglycans.1 Responses correlate with episodes of disease activity. Dysregulation
of NKT cells has also been detected in relapsing polychondritis.91
Histological examination of the skin is unremarkable. The dermis contains
a mild focal lymphohistiocytic infiltrate. Examination of the fibrocartilagi-
nous tissues, however, shows degenerative and inflammatory changes affect-
ing the marginal chondrocytes, with loss of basophilia and poor Alcian blue
staining of the cartilaginous tissue (Figs 17.143, 17.144). The inflammatory
cell infiltrate, which includes lymphocytes, plasma cells, histiocytes, and occa-
sional polymorphs, infiltrates the degenerate cartilage. Eventually, there is
replacement by granulation and fibrous tissue.3 Atypical lymphoid infiltrates
mimicking a lymphoma have rarely been described.92
Chondrodermatitis nodularis helicis differs by the presence of characteristic lay-
ering of fibrin, granulation tissue, and cartilage with degenerative changes. Fig. 17.144
Clinically, chondrodermatitis helicis presents as a focal, punched-out ulcer. This Relapsing polychondritis: a mild chronic inflammatory cell infiltrate is present in the
differs from the diffuse involvement of the ear seen in relapsing polychondritis. perichondrium.
Infectious diseases of the skin
18
Chapter
See
for references and
Wayne Grayson additional material
Viral infections 761 Diseases caused by Bartonella Algal infections 850

species 803
Common wart 761 Protothecosis 850
Cat scratch disease 803
Plantar warts 763 Trench fever 803
Bartonellosis 804 Fungal infections 851
Plane warts 766 Bacillary angiomatosis 804
Tinea capitis 852
Condyloma acuminatum 767 Lyme disease 806 Infections caused by Microsporum canis and
Bowenoid papulosis 769 Endemic (nonvenereal) Microsporum audouinii 852
Epidermodysplasia verruciformis 769 treponematoses 808 Kerion 852
Endemic syphilis 808 Endothrix infections 853
Herpes simplex virus infections 771 Yaws 809 Favus 853
Pinta 811 Black piedra 854
Varicella and herpes zoster 776
White piedra 854
Cytomegalovirus infections 779 Tuberculosis 811
Tinea corporis 855
Exanthem subitum 780 Tuberculids 818
Tinea pedis and tinea cruris 856
Eruptive pseudoangiomatosis 780 Cutaneous complications of Bacille
Calmette-Guérin vaccination 819 Nodular granulomatous
Diseases caused by orthopox viruses 781 perifolliculitis 858
Nontuberculous environmental
Milker's nodule 783 mycobacterial infections 820 Diseases caused by Malassezia
species 858
Ecthyma contagiosum 783 Leprosy 825 Tinea versicolor 858
Molluscum contagiosum 785 Rhinoscleroma 831 Malassezia (Pityrosporum) folliculitis 859
Hand, foot, and mouth disease 787 Nocardiosis 834 Tinea nigra 861
Viral hemorrhagic fevers 788 Botryomycosis 835 Candidiasis 861
Virus-associated trichodysplasia Malakoplakia 836 Aspergillosis, fusariosis and
spinulosa 789 pseudallescheriosis 863
Actinomycosis 837
Whipple's disease 838 Blastomycosis 865
Bacterial infections 790
Erythrasma 839 Paracoccidioidomycosis 868
Impetigo 790
Trichomycosis 840 Coccidioidomycosis 869
Staphylococcal scalded skin
syndrome 791 Pitted keratolysis 840 Cryptococcosis 871
Erysipelas and cellulitis 794 Cutaneous diphtheria 841 Zygomycosis 874
Necrotizing fasciitis 796 Sago palm disease 841 Chromoblastomycosis 876
Infective folliculitis 797 Tularemia 842 Mycetoma 877
Folliculitis keloidalis nuchae 799 Infections caused by Rickettsiae 842 Phaeohyphomycosis 879
Pseudofolliculitis 799 Alternariosis 881
Protozoal infections 844
Meningococcal septicemia 799 Histoplasmosis 881
Leishmaniasis 844
Gonorrhea 800 Penicilliosis 883
Amebiasis cutis 848
Plague 800 Sporotrichosis 883
Infections caused by free-living
Cutaneous anthrax 801 amebae 848 Lobomycosis 885
Brucellosis 802 Toxoplasmosis 849 Pneumocystosis 886
Common wart 761
Diseases caused by Nematode infestation 891 Cestode infestation 894

Mesomycetozoea 887
Onchocerciasis 891 Cysticercosis 894
Rhinosporidiosis 887
Cutaneous larva migrans 893 Echinococcosis 894
Arthropod infestations 888

Trematode infestation 893
Scabies 888
Schistosomiasis 893
Tungiasis 890
Viral infections
Common wart
The common wart (verruca vulgaris) is caused by infection with human
papillomavirus (HPV) (Fig. 18.1). HPV is a DNA virus of the papovavi-
rus family. The number of known HPV genotypes currently stands at more
than 100, classified according to the extent of their DNA homology (DNA
hybridization) (Table 18.1).1–4 In order for an HPV type to be regarded
as ‘new’, sequences in selected genomic regions must exhibit more than
10% divergence compared to any of the known HPV types.4 Monoclonal
antibodies to intact viruses have been produced and can demonstrate
individual types of HPV; antibodies to viral components are only group
specific (Fig. 18.2). In recent years, advances in molecular pathology
have resulted in improved and more specific methods of HPV detection,
including in situ polymerase chain reaction (PCR) and nonisotopic in situ
hybridization (NISH).5
Papillomaviruses, which are small, nonenveloped, and show icosahedral
symmetry, contain circular double-stranded DNA composed of approxi- A
mately 8000 base pairs.4,6 The viral particle, which has a diameter of approx-
imately 55 nm, contains 72 capsomeres.1,2,4,6 The HPV genome is divided
into three functional regions: a late region, an early region, and a noncod-
ing 1000 base pair upstream regulatory region (URR). The URR is located
immediately upstream of the E6 open reading frame (ORF) and contains
sequences regulating expression of all ORFs, including promoter elements
and transcriptional enhancer sequences. In excess of 20 messenger RNAs
are expressed, usually in a differentiation-specific and cell-specific manner.4
Genes in the early region (E1, E2, E4, E5, E6, E7) are responsible for tran-
scription, replication, and cellular transformation. The E4 ORF is highly
expressed in differentiated HPV-infected epithelial cells. Some forms of E4
encode a protein capable of disrupting the cytokeratin network, resulting
in the phenomenon of koilocytosis.4 The E4 ORF represents a region of
maximal divergence between different HPV types.7 Each viral genotype is
most often detected in lesions at specific anatomical sites or shows distinct
histological characteristics.2,8–10
HPV infection in man results in a variety of lesions including verruca
vulgaris, filiform warts, verruca plana, plantar warts, anogenital warts, B
and bowenoid papulosis.6 Mucosal lesions include oral warts and con-
dylomata, focal epithelial hyperplasia or Heck's disease, nasal and con- Fig. 18.1
junctival papillomas, laryngeal papillomatosis, and cervical lesions.4,6 In Viral warts: (A) these are exceedingly common and may affect any site; (B) lesions
addition to its role in cervical cancer, HPV is increasingly recognized are frequently multiple. (A) By courtesy of the Institute of Dermatology, London,
as an important cause of a number of neoplasms including Bowen's UK; (B) By courtesy of J.C. Pascual, MD, Alicante, Spain.
disease and malignant lesions of the anus, external genitalia, and else-
where.2 Of equal importance is the recognition that HPV infection may
be asymptomatic or result in a carrier status. A recent study showed Clinical features
that cutaneous HPV infections commonly persist on healthy skin Common warts are caused by HPV types 1, 2, 4, 7, and 26–29.2,6 In immuno-
over several years, and that persistence does not appear to be associated suppressed patients, HPV subtypes 75, 76, and 77 may be pathogenetic.12
with age, sex, a history of warts, immunosuppressive therapy, or HPV A case with extensive, recalcitrant verrucae linked to infection with HPV type
type.11 57 has been reported.13 Rarely, HPV subtypes associated with genital warts
762 Infectious diseases of the skin
Table 18.1
Variants of human wart virus infection
HPV type Associated clinical lesions

1 Deep plantar warts, common warts
2 Common warts, flat warts
3 Flat warts
4 Common warts, plantar warts
5 Epidermodysplasia verruciformis (EV)
6 Genital warts, laryngeal papilloma
7 Butcher warts
8 EV
9 EV, keratoacanthoma
10 Flat warts
11 Laryngeal papillomas, genital warts
12 EV
Fig. 18.2
13 Focal epithelial hyperplasia Verruca vulgaris: note the positive labeling of the nuclei in this section stained with
14, 15 EV a peroxidase-labeled antiserum to papilloma virus.
16 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma, digital, squamous cell carcinoma, as an erroneous clinical or histological diagnosis of condylomata acuminata
nongenital Bowen's disease could lead to allegations of sexual abuse.16
17 EV Warts are very common lesions, particularly in children.17 Adults are also
frequently affected. In a survey of 2180 adults, 3.5% had warts.18 Butchers
and slaughterhouse workers have an increased risk.19,20 Common warts may
cervical carcinoma
occur anywhere on the skin and in people of any age, but are most common
19–25 EV, keratoacanthoma on the backs of the hands and the fingers and on the knees of young children,
26–29 Common warts, flat warts where they appear as firm keratotic papules 1–10 mm across (Figs 18.3,
18.4).17 Koebnerization is common (hence kissing lesions on fingers).6
30 Laryngeal carcinoma, genital warts
31–32 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma
33 Cervical carcinoma
34 Bowenoid papulosis, Bowen's disease Fig. 18.3
35 Cervical dysplasia, cervical carcinoma Verruca vulgaris: there is
a raised, discrete scaly
36 EV plaque on the dorsal
37 EV, keratoacanthoma aspect of the hand. From
the collection of the
38 EV late N.P. Smith, MD, the
39 Bowenoid papulosis, cervical carcinoma Institute of Dermatology,
London, UK.
41 Flat warts
cervical carcinoma
43, 44 Genital warts, laryngeal papillomas
46, 47 EV
48 Bowenoid papulosis, Bowen's disease
49, 50 EV
51–54 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma
55 Genital warts, laryngeal papillomas
Reproduced with permission from Melton, J.L. and Rasmussen, J.E. (1991)
Dermatologic Clinics, 9, 219–233.
such as 6 and 11 have been found in common warts in children.14 HPV-16,

a common genital HPV type with oncogenic potential, was detected in 6.6%
of lesions in a recent series of 45 immunocompetent patients with nongenital
cutaneous warts.15 Conversely, verrucae vulgaris may sometimes occur on the Fig. 18.4
vulva. HPV type 2 has been detected in such cases. It is important to note that Verruca vulgaris: verrucae are most commonly seen on the hands and fingers. From
these ‘nonvenereal’ genital lesions may occur in girls less than 5 years of age, the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Plantar warts 763
In other sites they may appear more filiform and less firm (Fig. 18.5). The Pathogenesis and histological features
latter are particularly seen on the lips, nostrils, and eyelids.3 Giant periungual
In situ hybridization studies of HPV lesions have shown that viral DNA syn-
lesions have been described.21 Warts may also present as a cutaneous horn.
thesis in the epidermis occurs in the superficial prickle cell layer and full virus
They persist for a few months up to several years and often regress spontane- assembly with capsid production occurs in the granular cell layer.6 HPV DNA
ously, particularly in children.
has been demonstrated in apparently normal skin up to 15 mm from a virus-
Chronically immunosuppressed patients (e.g,. following renal trans-
associated lesion.29 The requirement for growth in very well-differentiated
plantation) often have a large number of warts (Fig. 18.6).22,23 Chronicity
epithelia may explain the difficulty of culturing HPV and why host destruc-
is associated with increasing numbers of lesions. Epidermodysplasia
tion of the lesions may be protracted. Immune mechanisms are presumed to be
verruciformis-like lesions due to HPV-5 have also been described in
less effective against organisms or altered cells that are situated superficially
HIV-positive patients and following renal transplantation.24 Numerous
with no direct blood supply.
warts may be seen in other immunosuppressed patients (e.g., with
Regression of HPV lesions is usually spontaneous, but may not occur for
lymphoma, leukemia, Hodgkin's lymphoma, and HIV infection).6,25–27 In
several years.30 Cell-mediated immunity seems to be important in effecting
patients with AIDS, warts may regress following highly active antiretroviral the regression since lymphocytes are seen infiltrating the wart epithelium at
therapy (HAART).28 this stage. Other features of regression include liquefactive basal cell degen-
eration, epidermal degeneration, and vascular thrombosis.30,31 Recently, Toll-
like receptors (TLRs) have been identified as important role players in viral
recognition and the initiation of an antiviral host immune response. TLR3,
TLR9, IFN-β and TNF-α appear to play an important role in the skin's innate
immune response to HPV infection.32 Langerhans cells and Langerhans-
like dendritic cells may exert direct antiviral activity. This is facilitated via
the expression of TLRs such as TLR3, which may in turn trigger the release
of IFN-inducible chemokines, including CXCL9, a monokine induced by
IFN-γ.33
Following regression of the wart(s), an individual is usually immune to
further HPV infection. Patients with a deficiency in cell-mediated immunity –
whether primary or acquired, iatrogenic or virally induced (HIV/AIDS) – are
particularly susceptible to the development of warts, which tend not to invo-
lute spontaneously and can be a particularly refractory therapeutic problem.
Transmission of HPV is by inoculation of infected desquamated cells
through close contact at points of minor trauma; hence common warts are
seen most often on the hands. Periungual warts are particularly associated
with nail biting and plantar warts are especially related to prolonged immer-
sion in water.18
Common warts show filiform acanthosis with vertical tiers of parakerato-
sis over the tips of the exophytic component (Fig. 18.7). There is also marked
Fig. 18.5
Filiform wart: this variant
orthokeratosis. A downward extension of the acanthosis produces a curvi-
occurs most often on linear deep margin and curved distortion of the adjacent rete ridges in the
the face and around the uninvolved epidermis. There is a prominent granular cell layer within which
axillae. From the collection are enlarged clumps of irregular basophilic keratohyalin (Fig. 18.8).3 These
of the late N.P. Smith, MD, are seen best in the concavities between the papillomatotic epithelial papil-
the Institute of lae. Large cells with prominent vacuolated cytoplasm and a small pyknotic
Dermatology, London, UK. nucleus are seen in the upper layers of the epidermis (koilocytes) (Fig. 18.9).
Koilocytes are, however, more frequently observed in genital warts (see
below). Connective tissue and tortuous small blood vessels may invade the fil-
iform projections (Fig. 18.10). In some cases, involvement of the superficial
portion of the hair follicles by HPV results in focal changes identical to a
trichilemmoma or an inverted follicular keratosis.34 However, not all of these
lesions are induced by HPV as has been suggested.35
Ordinary common warts are only exceptionally associated with in situ
or invasive squamous cell carcinoma.36,37 HPV-16 has been associated with
periungual Bowen's disease and squamous carcinoma.38–40 The role of HPV
in cutaneous neoplasia is discussed further in Chapter 22. Recent molecular
studies have implicated cutaneous HPV infection as a carcinogenic cofactor in
association with solar ultraviolet radiation in the evolution of nonmelanoma
skin cancer.41
Plantar warts
Clinical features
Plantar warts occur on the sole of the foot; they are only slightly elevated
and appear as a horny plug surrounded by a ring of hyperkeratotic skin (Fig.
18.11). Often they are covered with black dots representing thrombosed
Fig. 18.6 capillaries (Fig. 18.12).1 They are most common in children and are fre-
Verruca vulgaris: presentation with such large numbers of lesions raises the possibility quently seen over pressure points. Most plantar warts are caused by HPV-1
of immunosuppression. By courtesy of the Institute of Dermatology, London, UK. and are painful; however, HPV-4 may produce a confluent or mosaic pattern
A B
Fig. 18.7
Verruca vulgaris: (A) note the hyperkeratosis and papillomatosis; (B) there is often marked parakeratosis typically arranged as a vertical tier. Koilocytes are conspicuous.
Fig. 18.8 Fig. 18.10

Verruca vulgaris: large vacuolated cells with enlarged and irregular keratohyalin Verruca vulgaris: the core of the papillary projection contains conspicuous dilated
granules are characteristic. capillary loops.
of similar small warts (‘mosaic plantar warts’) and these are painless (Fig.
18.13).2,3 They may also be seen on the palms and in the periungual region.
There have been reports from Japan of unusual plantar warts produced by
HPV-60.4–6
The lesions may be nodular, ridged or pigmented. A cystic variant has also
been described.4–10 The cystic variant has the features of an epidermoid cyst
and may rarely be multiple.11 Most are associated with HPV-60 but an asso-
ciation with HPV-57 has also been reported.12–14 Epidermoid cysts induced by
HPV may also be seen outside acral locations.15,16 Pigmented warts are caused
by HPV-4, 60 or 6517 and may contain fibrillar intracytoplasmic inclusion
bodies.18 A case of a large plantar wart caused by HPV-66 has been docu-
mented.19 A further subtype of HPV associated with palmoplantar warts is
HPV-63.8,20
Plantar warts usually regress within a few months in children, but may
persist longer in adults. Rarely, chronic plantar warts may be associated
with the development of verrucous carcinoma (carcinoma cuniculatum) (see
Ch. 22).21,22
Fig. 18.9 Plantar warts are almost entirely endophytic, with a central parakeratotic plug
Verruca vulgaris: high-power view of koilocytes. surrounded by multiple deep extensions of acanthotic epidermis (Fig. 18.14).
Plantar warts 765
Fig. 18.11 Fig. 18.13

Plantar wart: the lesion Mosaic warts: here there are a large number of small warts. They are particularly
is flat and shows very resistant to therapy. By courtesy of the Institute of Dermatology, London, UK.
marked hyperkeratosis.
By courtesy of
R.A. Marsden, MD,
London, UK.
Fig. 18.14
Plantar wart: typical depressed, crateriform lesion containing a parakeratotic plug.
Fig. 18.12
Plantar wart: vascular thromboses as seen in these two lesions are common
manifestations of involution. By courtesy of R.A. Marsden, MD, St George's
The depth and complexity of these downgrowths have been likened to an

anthill, giving rise to the term ‘myrmecia’. Vacuolation is more prominent in
the plantar wart and, in the active growing phase, large eosinophilic (and to
a lesser extent basophilic) cytoplasmic inclusions are present, which repre-
sent disordered growth of giant keratohyalin granules (Fig. 18.15). The large
eosinophilic cytoplasmic inclusions are usually seen in infections caused by
HPV-1 and to a lesser extent in those caused by HPV-60 and 65.7 In warts
induced by HPV-4, the infected keratinocytes show prominent cytoplasmic
vacuolar change with almost no keratohyalin granules. Intranuclear inclu-
sions may also be evident (Fig. 18.16). HPV can be demonstrated in the
nuclei of these cells by electron microscopy (Fig. 18.17). Melanin granules
are discernible within the cytoplasm of HPV-60-induced pigmented plantar Fig. 18.15
warts. Plantar wart: these eosinophilic keratohyalin granules are characteristic.
Fig. 18.16 Fig. 18.18

Plantar wart: note the conspicuous intranuclear eosinophilic inclusions. Plane wart: note the typical flat, flesh-colored papules, which have extended in a
linear distribution due to scratching (Koebner phenomenon). By courtesy of
B Al-Mahmoud, MD, Qatar, Oman.
Fig. 18.17 Fig. 18.19

Plantar wart: this honeycomb arrangement of HPV is characteristic. By courtesy of Plane wart: there is hyperkeratosis and slight regular acanthosis; papillomatosis is
I. Chrystie, FIMLS, St Thomas' Hospital, London, UK only mild. Note the prominent cytoplasmic vacuolation.
few weeks or months, or may persist for years. Signs of regression include
Regressive changes are the same as those described in common warts pruritus, an erythematous, edematous appearance, depigmented haloes, and
and consist of thrombosis of superficial blood vessels, necrosis, and a mixed an eruption of multiple tiny plane warts.2,6,7 Cell-mediated immunity plays
inflammatory cell infiltrate.23 A recently described multiplexed PCR-based a key role in the spontaneous regression of plane warts in immunocompe-
assay may have merit in both HPV genotyping and in monitoring treatment tent individuals.8 Multiple plane warts may evolve as a cutaneous manifesta-
efficacy.24 tion of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected
patients receiving highly active antiretroviral therapy.9 Exacerbation of lesions
has been reported following facial laser resurfacing.10
Plane warts
Clinical features Plane warts are acanthotic and show orthokeratosis with an open pattern remi-
Plane warts (verrucae plana), usually caused by HPV-2, 3 or 10, are flat, niscent of ‘chicken wire’ (‘basket weave’ hyperkeratosis). Parakeratosis is not a
smooth, and a few millimeters in diameter with typically little change in color feature and there is little papillary configuration to the acanthosis (Fig. 18.19).
from the adjacent skin, although they may appear gray-yellow or pale brown Keratinocytes of the upper part of the stratum spinosum show striking cytoplasmic
(Fig. 18.18).1–3 HPV-5 is rarely implicated in HIV-infected patients.4 Plane vacuolation with margination of the keratohyalin granules and tonofilaments.4
warts may also result from HPV types 26–29 and 41 infection.5 They affect Regression is characterized by keratinocyte necrosis (apoptosis), individual cell
the face, backs of the hands, and the shins. There may be only a few present, keratinization, parakeratosis, lymphocytic exocytosis with spongiosis, and a
but occasionally they are very numerous and become confluent in areas of superficial perivascular chronic inflammatory cell infiltrate.2,11–13 The lympho-
scratching (koebnerization).6 Plane warts are common in children and may cytes encountered in regressing lesions have been found to express the cytotoxic
be seen in women, but are not usually found in males after puberty except granule granzyme-B.14 Extravasation of erythrocytes may be a feature and
in association with HIV infection. They may regress spontaneously after a edema of the papillary dermis is frequently present.15
Condyloma acuminatum 767
Anal squamous carcinoma has also been shown to contain HPV-6, 16, and
Condyloma acuminatum 18 in a significant proportion of cases (Fig. 18.25).6 The rate of local recur-
rence is about 30%.15 The lesions are uncommon in children (when they
Clinical features may be a sign of sexual abuse) and are seen most often in young adults
Condylomata acuminata are particularly caused by HPV types 2, 6, 11, 16, (second and third decades), frequently in association with other genital
18, 30–33, 35, 39, 41–45, 51–56, and 59 and develop as a consequence of the infections.4,9,16 Childhood condylomata regress spontaneously in more than
trauma accompanying sexual intercourse.1–13 HPV-6 and 11 alone account 50% of cases.17
for more than 90% of these lesions, with HPV-6 present in about two-thirds It is important to note that a significant proportion of genital HPV
of cases and the remaining one-third caused by HPV-11.4,5 The incubation infections are asymptomatic.3,18 The female partners of male patients with
period is variable (usually between 2 and 3 months).14 Condylomata acumi- condyloma acuminata have been shown to have an increased risk of cervi-
nata occur on the glans penis and prepuce or shaft as soft, fleshy, sometimes cal HPV infection and intraepithelial neoplasia (SIL/CIN).19 Cervical neo-
filiform plaques and may extend into the meatus (Figs 18.20, 18.21). On plasia associated with pre-existent condylomata acuminata has also been
the shaft they are less exophytic. Vulval lesions may be bulky and macer- related to a background of immunosuppression, at least in some patients.20
ated, and may extend into the introitus (Fig. 18.22). Similar fleshy and fili- The worldwide HPV prevalence in cervical carcinomas is reported to be
form soft masses occur perianally, more often in males (Figs 18.23, 18.24). 99.7%.21 HPV-16, 18, 31–33, 35, 39, 42, and 51–54 are most commonly
associated with cancers of the cervix, vulva, and penis.7–9,22,23 According to
a recent study, patients with condylomata acuminata are at increased risk
for developing not only carcinomas of the vulva, vagina, penis, and anus,
but also certain nonanogenital squamous cell carcinomas.24 It is antici-
pated that routine vaccination with a quadrivalent vaccine against HPV
types 6, 11, 16, and 18 will lead to a significant reduction in the burden
of vulval and cervical carcinomas, genital warts, and genital intraepithelial
neoplasia.25
A large, exuberant, and locally destructive variant of condyloma (Buschke-
Löwenstein tumor) may rarely be encountered (Fig. 18.26).26,27 This is associ-
ated with HPV types 6, 11 or 16. It is likely that this giant variant represents
Fig. 18.20 a variant of verrucous carcinoma but the issue has been controversial
(see Ch. 22).26–30 Juvenile laryngeal papillomas containing HPV-6 and 11 can
note the typical filiform
appearance. By courtesy
be seen in children born to mothers with condylomata acuminata.3 They may
of the Department of show malignant progression if irradiated.
Genitourinary Medicine, Malignant transformation of condyloma acuminatum is uncommon but
St Thomas' Hospital, it is seen more often than in other lesions associated with HPV except for
London, UK. epidermodysplasia verruciformis.
Fig. 18.21 Fig. 18.22 Fig. 18.23

Condyloma acuminatum: there are multiple lesions Condyloma acuminatum: in this patient there is very Condyloma acuminatum: multiple perianal lesions are
on the shaft of the penis and scrotum. By courtesy of widespread involvement of the vulva and perineum. present. By courtesy of N.C. Dlova, MD, Nelson R.
the Department of Genitourinary Medicine, This patient is likely to have cervical HPV infection. Mandela School of Medicine, University of KwaZulu-
St Thomas' Hospital, London, UK. By courtesy of R.A. Marsden, MD, St George's Natal, South Africa.
Hospital London, UK.
Fig. 18.24 Fig. 18.26

Condyloma acuminatum: Buschke-Löwenstein tumor: there is massive infiltration of the buttocks and
there is very extensive perineum with numerous sinuses. HPV type 6 was identified by DNA in situ
involvement of the hybridization and Southern blot analysis. By courtesy of A. Grassegger, MD,
perineum. From the University of Innsbruk, Austria.
Smith, MD, the Institute of
Condylomata acuminata are characterized by marked acanthosis with a
solid or trabecular pattern and a broad rounded exophytic growth (Fig.
18.27). There is a sharp, fairly regular, deep margin. The surface of the
lesion is hyperkeratotic and parakeratotic. Superficial vacuolated keratino-
cytes (koilocytes) are characteristic (Fig. 18.28) and coarse keratohyaline
granules may be present. The vacuolated epithelium is often most marked
in the declivities. Condylomata that are treated with podophyllin prior to
removal demonstrate marked epidermal pallor and increased mitoses and
necrotic keratinocytes in the lower half of the epidermis.31 These changes
may lead to a misdiagnosis of malignancy. Giant condyloma acuminatum
(anogenital verrucous carcinoma, Buschke-Löwenstein tumor) occurs most
frequently on the genitalia, and is larger and more cauliflower-like.26–28 It
shows some tendency to endophytic growth, but without any suggestion
of frank infiltration. It can recur locally, but metastasizes very rarely. Most
experts regard this lesion as a variant of verrucous carcinoma. Anal condy-
lomata may develop bowenoid features, and occasionally invasive tumor
supervenes.6–8
A
Fig. 18.25 Fig. 18.27

(A, B) Condyloma acuminatum: in addition to multiple condylomata, there was Condyloma acuminatum: note the keratotic acanthotic epidermis with rounded
histological evidence of in situ squamous cell carcinoma. By courtesy of P. Ngheim, lateral borders. Koilocytes are present in the declivities of the papillomatous
MD, Dana Farber Cancer Institute and Harvard Medical School, Boston, USA. epithelium.
Epidermodysplasia verruciformis 769
A bowenoid papulosis lesion consists of a well-circumscribed area of acan-
thosis producing a raised plaque or dome, which is hyperkeratotic and
sometimes shows superficial epithelial vacuolation.20,21 The keratinocytes
may show nuclear hyperchromatism and pleomorphism. There is variable
dyskeratosis.
These histological features of atypia, associated with numerous mitoses,
including atypical forms, are similar to those of true Bowen's disease. The
distinction rests in the circumscribed elevated plaquelike pattern, the age of
the patient, and the size and multiplicity of lesions.
Epidermodysplasia verruciformis
Clinical features
Epidermodysplasia verruciformis (EV) is a rare inherited condition characterized
by selective susceptibility to skin infection with certain HPV types, defects in cell-
mediated immunity, and an increased risk for the development of cutaneous malig-
Fig. 18.28 nancies, especially squamous cell carcinomas.1,2 Affected individuals present with
Condyloma acuminatum: note the parakeratosis and vacuolation of the superficial a wide range of HPV subtypes including 3, 5, 8–10, 12, 14, 15, 17, 19–25, 28, 29,
keratinocytes. 36–38, 46, 47, 49, 50, 51, and 59.1,3–5 The more common flat warts, caused by
Bowenoid papulosis
Clinical features
Bowenoid papulosis (koilocytosis with intraepithelial neoplasia) is a clinico-
pathological entity that bears marked histological similarity to koilocytosis,
SIL/CIN, and Bowen's disease. Although the term is no longer used by The
International Society for Study of Vulval Disease (ISSVD), many clinicians
believe that it represents a distinctive clinicopathological entity and we have
decided to describe it in this chapter. Clinically, it is quite different from geni-
tal Bowen's disease in that multiple small papules develop over a short time
scale in young people. Prognosis is uncertain; many patients do not show evi-
dence of progression, but a small proportion may develop invasive tumor and,
on occasion, this may have metastatic potential. It is usually associated with
HPV-16 or 18, but occasionally HPV types 31–35, 39, 42, 49, and 51–54 are
detected.1–6 Although uncommon, some cases may be associated with mixed
infection by different HPV types.6,7 A unique HIV-associated case with geni-
Fig. 18.29
tal and extragenital (lip) lesions caused by two separate HPV types (HPV-16
Epidermodysplasia
and HPV-32, respectively) has been described.8 E6 and E7 viral oncoproteins verruciformis: (A)
of high-risk HPV types induce overexpression of p16 and human telomerase innumerable small flat
reverse transcriptase.9 warts are present; (B)
Bowenoid papulosis most often presents as multiple reddish-brown, some- the dorsum of the hand
times lichenoid, discrete papules, but occasionally these become a conflu- is a commonly affected
ent plaque. Papules, on average 4 mm in diameter, are found on the penis, site. By courtesy of the
vulva, perianal region, and perineum. Extragenital sites of occurrence include A Institute of Dermatology,
the face, neck, and fingers.10–12 An isolated case of oral bowenoid papulosis London, UK.
in an HIV-infected male has been reported.13 Bowenoid papulosis manifests
in young, sexually active adults in contrast to true Bowen's disease, which
occurs in an older age group. Genital Bowen's disease is, however, also often
associated with HPV-16.14 The occurrence in childhood should raise suspi-
cion of sexual abuse.3 Genital bowenoid papulosis has been associated with
periungual bowenoid dysplasia.15
Spontaneous regression is uncommon.16 As progression to frank inva-
sive carcinoma in bowenoid papulosis is rare, these lesions are best managed
conservatively. However, bowenoid papulosis may be resistant to treat-
ment and may be characterized by a prolonged course in immunosuppressed
patients.2 Bowenoid papulosis has also been associated with oral warts and
lingual carcinoma.4 It has recently been shown that patients with bowenoid
papulosis and HPV infection may be primarily immunosuppressed due to
diminished T-helper cell levels (non-HIV-associated).2,14 The condition may
also occur in organ transplant recipients.17 Penile bowenoid papulosis is
associated with a high risk of the consort developing cervical dysplasia.18,19
Consequently, female patients and consorts should regularly have cervical B
smears.
Fig. 18.30 Fig. 18.32

Epidermodysplasia verruciformis: these plane warts are due to HPV-3 and HPV-10 Epidermodysplasia verruciformis: these scaly macules on the chest and axilla
infection. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK. resemble pityriasis versicolor.
lupus erythematosus, Hodgkin's lymphoma, and HIV infection and in rare

patients following renal transplantation or peripheral blood stem cell trans-
plantation.13–17 An EV-like eruption has been documented in association with
idiopathic CD4 lymphopenia and even with CD8 lymphopenia.18,19
EV therefore represents an unusual condition in which HPV infection,
inherited predisposition (possibly a defect in cell-mediated immunity), and
exposure to the sun all play a role (co-carcinogens).1,2,11

The pathogenesis of epidermodysplasia verruciformis is not yet fully under-
stood. The EV-related HPV may be present in the general population, but the
characteristic lesions only occur in predisposed individuals (Fig. 18.33).1,11 It
has recently been established that invalidating mutations in either of two adja-
cent novel genes termed EVER1 and EVER2 are responsible for most cases
of EV.20 This susceptibility locus for EV has been mapped to the long arm of
chromosome 17 (17q25).20,21 The EVER1 and EVER2 transmembrane proteins
encoded by these genes are located in the endoplasmic reticulum.22 One group
of investigators has shown that the proteins form a complex that interacts with
zinc transporter 1 (ZnT-1), resulting in altered intracellular zinc distribution in
Fig. 18.31
Epidermodysplasia verruciformis: note the numerous flat warts on the dorsum
keratinocytes.23 It has been proposed that EVER proteins in keratinocytes may
of the hand. From the collection of the late N.P. Smith, MD, the Institute of serve as restriction factors for EV-specific HPV types.22 There have, however,
Dermatology, London, UK. been reports of cases lacking EVER1 and EVER2 mutations.24,25
HPV-3 and HPV-10, may also occur in these patients but have an extensive distri-
bution pattern; they may form plaques and can be persistent.6 These are seen most
often on the arms, legs, face, and the dorsum of the hands (Figs 18.29–18.31).4
The specific EV subtypes of HPV cause reddish, or pigmented or depigmented,
scaly flat macular plane warts, mainly on the trunk, but also on the face, neck, and
arms.2 Clinically they resemble pityriasis versicolor (Fig. 18.32). Some patients,
especially those who are dark-skinned, may present with seborrheic keratosis-like
changes.7,8 Spiny hyperkeratosis of the fingers is a rare manifestation.9
Susceptibility to EV is usually inherited in an autosomal recessive manner
although X-linked recessive inheritance has been reported in one family.10 The
lesions persist throughout life, and after some years (usually more than 20) they
may show nuclear atypia resembling Bowen's disease, and frank carcinoma
sometimes develops. Basal cell carcinoma can also occur.11 The tumors develop
particularly on sun-exposed skin and are most often associated with HPV-5 or
8.4,12 Patients who develop invasive squamous carcinoma in association with
EV do so at a younger age than those who develop this tumor not in association
with EV (27 years compared with 67 years in one study).1,12 Such tumors, which
are often multiple, are usually associated with a good prognosis unless they are
treated with radiotherapy when they may be associated with metastatic dis- Fig. 18.33
ease, which has a high mortality.3 EV-like disease has been reported in patients Epidermodysplasia verruciformis: electron micrograph showing the characteristic
with a background of immunosuppression in such conditions as systemic lattice structure.
Herpes simplex virus infections 771
There appears to be a specific abnormal T-cell response to HPV-infected

keratinocytes. The immune defect most often associated is a reduction in the
number and function of T-helper cells, but patients with EV do not show general
immunodeficiency or susceptibility to other infections. There have nevertheless
been rare reports of EV in association with common variable immunodefi-
ciency syndrome.26 EV is not usually seen in patients with iatrogenic immuno-
suppression. Humoral immunity is characteristically normal, although a case
with isolated IgM deficiency has been documented.27 EV has been described in
association with severe immunodeficiency, lymphoma, and disseminated mol-
luscum contagiosum infection.28 EV has also been reported in a patient with
malignant thymoma.29 EV-associated HPVs have been detected in the amniotic
fluid, placenta, and cervical scrapes of a pregnant patient with EV, thereby sug-
gesting that vertical transmission of EV HPVs may play a role.30
Histologically, EV is characterized by hyperkeratosis, hypergranulosis,
and acanthosis (Figs 18.34, 18.35). The keratinocytes are vacuolated and
show a striking blue-gray pallor on staining with hematoxylin and eosin.
They are arranged in clusters or columns, the pallor being most conspicuous
in the superficial granular cell layer. Identical focal changes may be occasion-
ally seen in samples removed for other reasons in patients without the disease.
As the lesions progress to atypicality, the nuclei of the keratinocytes become Fig. 18.35
Epidermodysplasia verruciformis: the superficial keratinocytes are swollen and have
larger and hyperchromatic, and cellular maturation is more disorderly.3,31 The
basophilic cytoplasm.
dysplastic changes may also affect appendigeal epithelium, particularly that
of sweat ducts. The atypia eventually amounts to carcinoma in situ and in
30–50% of patients the lesions progress to invasive carcinoma. Cutaneous of the TGF-β1 signaling pathway.32 Most carcinomas are squamous in type,
neoplasia in EV is largely associated with HPV-5 and 8. The E6 oncoprotein of but some show features reminiscent of sweat gland differentiation. The sweat
HPV-5 inhibits transactivation of SMAD3, which is an important component ducts may show markedly disordered growth and atypia. These stages in the
progression to frank carcinoma only occur on sun-exposed skin. In contrast
to cervical cancer where the viral genome is integrated into the host DNA, in
EV it remains extrachromosomal (episomal). Ultraviolet-B radiation has been
shown to modulate the noncoding region promotor activity of HPV-5 and 8
in infected keratinocytes.33
Swollen keratinocytes, as described above as a diagnostic feature of EV, have
been recorded as a manifestation of immunosuppression, particularly HIV
infection.34 Focal histological features of EV have rarely been documented
as an incidental finding in a variety of benign skin lesions in the absence
of clinical evidence of underlying EV, including an intradermal nevus, a
pigmented seborrheic keratosis, and an acantholytic acanthoma. The term
‘EV acanthoma’ has been proposed for these isolated, incidental cutaneous
lesions.35
Herpes simplex virus infections

A
Herpes simplex virus (HSV) has two subtypes: HSV-1 and HSV-2.1 There is
considerable homology between the two genomes, about 50% of sequences
being highly conserved.2 Humans are the natural hosts for HSV-1 and
HSV-2 and therefore also represent the viral reservoir.3 Herpes viruses are
double-stranded DNA viruses with a complex capsid and glycoprotein
envelope (Fig. 18.36).
Clinical features
HSV-1 usually causes herpes labialis (90%), whereas HSV-2 most often causes
herpes genitalis. Although HSV-2 previously accounted for approximately
90% of herpes genitalis cases, more recent epidemiological evidence reflects
an increase in the proportion of cases attributable to HSV-1 (22–29%) and a
diminished number of HSV-2 positive cases (68–71%).4,5 In some European
cohort studies, HSV-1 infection has been a more common cause of genital
herpes than HSV-2 infection. This trend may be attributable to the practice of
oral sex.4 Both HSV-1 and HSV-2 are transmitted through mucosal surfaces
or traumatized skin by exposure to contaminated secretions.3,6–8
B A first-episode infection – i.e., in someone who is seronegative (first-episode
primary infection) or who has serum antibodies to the heterologous HSV type
Fig. 18.34 (first-episode, nonprimary infection) – may be associated with constitutional
Epidermodysplasia verruciformis: (A) there is hyperkeratosis and acanthosis; symptoms of fever and malaise.9,10 These symptoms are often worse in women
(B) note the characteristic, swollen, paler-staining cells showing nuclear vacuolation. with genital herpes, perhaps because of the wider area of epithelium involved
Fig. 18.36
Herpes virus: all members
of the herpes virus
group have identical
ultrastructural morphology.
Note the outer membrane
surrounding the virus
core. The herpes virus
is an icosahedron with
162 capsomeres on its
surface. By courtesy of
I. Chrystie, FIMLS, St
Thomas' Hospital, London, Fig. 18.38
UK. Herpes simplex: this patient shows a particularly severe infection. By courtesy of
and the greater viral load. The lesions may be found in the mouth, pharynx,
lips, penis, vulva, vagina, or cervix (Figs 18.37–18.41). HSV infections are
also being seen more frequently in perianal and anorectal sites. Involvement
of a finger in the form of a herpetic whitlow is most often seen in healthcare
workers, especially dental practitioners (Fig. 18.42).11 Primary HSV-1 infec-
tion, however, is asymptomatic in about 90% of patients, and primary HSV-2
in about 75%.12 It is important to remember that infection is for life. Herpes
compunctorum is a rare form of HSV infection acquired as a result of tattoo-
ing.13 HSV may also be transmitted during close contact sports such as wres-
tling and rugby (herpes gladiatorum).14
At the original inoculation site there is no detectable change for 3–5
days. The lesions that develop vary with site, but all are associated with the
development of small grouped vesicles, often on an erythematous base. On
mucosal surfaces the vesicles rupture early and are superseded by grayish-
yellow plaques or ulcers. In skin, grouped vesicles are seen on an erythema-
tous base and then evolve into grouped pustules, which rupture and result
in a crusted ulcer.15,16 The lesions are typically painful and sting or itch. The
distribution of the lesions is characteristically wider than the initial site of
inoculation, involving the area of innervation by the sensory nerve to that
site. Occasionally, a separate area of lesions may develop away from the ini-
tial inoculation site, after transmission along a different branch of the same
Fig. 18.39
Herpes simplex 2: vulval
involvement showing
erythema and crusted
vesicles. By courtesy of
R.A. Marsden, St George's
nerve. These initial cutaneous lesions only develop after involvement of the
nerve and the ganglion and subsequent return of the virus to the epithelium.3
The lesions may then extend peripherally to involve adjacent skin or mucosa.
This first episode of infection lasts for around 15 days. The epithelial lesions
then resolve completely, but the virus persists, becoming latent within the
ganglia of the corresponding sensory nerve.17
Recurrent HSV lesions are usually less florid than the first infection and
are not usually associated with general symptoms. They may be precipitated
by sunlight, fever, menstruation, pregnancy, HIV infection, emotional stress
or local trauma.12 The incidence of recurrent orofacial herpes varies from
16% to 45%, while that of recurrent genital herpetic infection varies from
about 50% to 65% of patients.3 Repeated recurrence is usual with genital
Fig. 18.37 HSV-2 and common with orofacial HSV-1, but with gradually decreasing
Herpes simplex 1: primary infection showing grouped vesicles on an erythematous frequency. ‘Reinfection’ with the heterologous type resembles a less severe
base. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. first-episode primary infection.
Fig. 18.40
Herpes simplex 2: in this patient there is very severe ulceration. By courtesy of J.C. Fig. 18.43
Pascual, MD, Alicante, Spain. Eczema herpeticum: this
variant usually presents
in atopic children.
By courtesy of J.C. Salas,
MD, Azteca, Monterrey,
Mexico.
Antibodies to HSV-1 are found in about 70–90% of adults, suggesting

very wide contact with the virus, with a subclinical infection or an unrecog-
nized oropharyngitis in childhood.8 Worldwide, an estimated 16% of people
aged 15–49 years are infected with HSV-2.18 The seroprevalence of HSV-2
infection varies geographically.18,19 The seroprevalence in Asian countries
ranges from 10% to 30%, whereas more than 80% of female commer-
cial sex workers in parts of sub-Saharan Africa are infected.20 The United
States saw a 30% rise in the prevalence of HSV-2 infection between the
late 1970s and the early 1990s.18 Although HSV-1 occurs most commonly
above the waist and HSV-2 below, these are preferential rather than obliga-
tory sites. It has been noted that 10–15% of first-episode genital herpes
is associated with pharyngeal lesions, emphasizing not only the frequency
of orogenital contact, but that both viruses can affect either orofacial or
Fig. 18.41 genital epithelia.
Herpes simplex 2: there is intense erythema and multiple ulcers are present on both Occasionally, a first-episode primary infection in an atopic patient may
the glans and the shaft. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad. result in extensive vesicular crops, so-called Kaposi's varicelliform erup-
tion (eczema herpeticum) (Figs 18.43, 18.44).21 These lesions pustulate,
ulcerate, and crust, as in the usual herpetic infection, but involve more or
less the whole skin surface. Systemic symptoms may be severe, with fever
and dehydration. The condition may occasionally prove fatal. Recurrent
attacks may occur, but they are usually short and less severe. This man-
ifestation of herpetic infection may also complicate Darier's disease,
Hailey-Hailey disease, Grover's disease, pemphigus foliaceus, and other
bullous dermatoses.22 Historically, a similar clinical picture was occasion-
ally caused by vaccinia virus (eczema vaccinatum) as a complication of
vaccination against smallpox. Histologically, the lesions of Kaposi's vari-
celliform eruption are the same as those of the more localized form of
herpetic infection. Disseminated disease may be seen in the immunosup-
pressed (Fig. 18.45).
HSV infection in pregnancy may be associated with both severe maternal
illness and fetal involvement via transplacental spread.20,23 Congenital infec-
tion is rare, but neonatal herpes simplex infection is seen in 10% of babies
born to women with an active herpetic lesion after the thirty-second week
of pregnancy.20,24 Congenital HSV infection forms part of the TORCH com-
plex.25 Lesions in congenital herpes infection can be extensively bullous, with
Fig. 18.42 severe erythroderma and loss of body fluid through exudation. The reported
Herpetic whitlow: intact vesicles may be seen on the proximal phalanx. The medical mortality rate in infants with disseminated infection is approximately 57%.26
and dental professions are at particular risk from this mode of spread. By courtesy Neonatal infection usually presents as a relatively mild oropharyngitis and
of R.A. Marsden, MD, St George's Hospital, London, UK. many are probably undiagnosed.
The most characteristic feature in the pathogenesis of herpetic infections

is the early involvement of sensory nerves within which the virus, without its
lipid/glycoprotein envelope, is transported to the ganglia.30 Further replica-
tion (associated with cell lysis) occurs within the ganglia and the complete
virus then migrates to the skin around the site of inoculation via the periph-
eral sensory nerves. This process of viral migration also occurs at times of
recurrence. The state of the virus during the latent periods, which may last
for many months or years, is not clear. It may continue as a more or less
intact virus, but in virtually suspended animation without cell death, or it
may persist as episomes or be incorporated into the cell genome. Immune
mechanisms are responsible for both latency and reactivation of the virus.30
Although immune defects (particularly of cell-mediated immunity and
including HIV infection) are associated with a high incidence of severe and
extensive herpetic infections, a state of raised immunity (either humoral
or cellular) does not preclude recurrent lesions; indeed, recurrent lesions
are usually associated with very high titers of IgG antibody. It is thought
that humoral immunity may impede neuronal extension and reduce the
likelihood of encephalitis, but cell-mediated immunity is effective in lim-
iting the local cutaneous extension of the lesions and accelerates healing.
Fig. 18.44 Low levels of interferon-gamma (IFN-γ) may contribute to reactivation of
Eczema herpeticum: this infections.31
can be a very serious Histologically, the early change of HSV infection is increasing edema of
condition and affect the
the keratinocytes, which progresses to so-called ballooning degeneration.32
whole body. By courtesy
Some adjacent keratinocytes fuse so that they appear large and multinu
St George's Hospital, cleate. A number of cells show acantholysis, while others rupture as a result
London, UK. of extreme balloon degeneration (reticular degeneration). The result of
acantholysis and balloon degeneration is an irregular intraepidermal vesicle
containing groups of keratinocytes, many of which may be multinucleate
(Figs 18.46–18.50). The nuclei of keratinocytes may contain basophilic
and/or pale ground-glass inclusions. As a vesicle expands it involves the
full thickness of the epidermis and may not be so clearly intraepidermal.
HSV infection of the hair follicle epithelium can result in herpes folliculitis.33
Involvement of hair follicles is, in fact, very common in most infections.
In cases with very prominent superficial secondary changes, the distinctive
findings of the infection are sometimes only evident in the infundibular por-
tion of the hair follicle.
The underlying dermis is usually intensely infiltrated by mixed inflammatory
cells. The infiltrate shows perineural accentuation and occasionally a super-
ficial leukocytoclastic vasculitis is present (Fig. 18.51).32 Dermal nerve twigs
may exhibit a perineural inflammatory infiltrate composed of lymphocytes
and neutrophils, sometimes associated with intraneural involvement. Schwann
cell hypertrophy and frank neuronal necrosis are occasionally encountered.34
Infection is sometimes associated with a prominent lymphoid infiltrate with
frequent CD30-positive cells resulting in a pseudolymphoma.35
Fig. 18.45
Disseminated herpes infection: widespread lesions may be seen in immuno
suppressed patients. By courtesy of the Institute of Dermatology, London, UK.

The double-stranded DNA of herpes virus is enclosed in an icosahedral protein
shell (capsid) which in turn is invested by a complex envelope of lipid and gly-
coproteins. The latter are important in the attachment and penetration of cells.
The complete virus measures about 150–1200 nm in diameter.12 Viral replica-
tion occurs within the nucleus where a basophilic Feulgen-positive inclusion
body, including viral DNA, may be found as well as an eosinophilic inclusion
body, which represents a focal deficiency of viral DNA, a so-called ‘scar’ of
viral infection.2 Heparan sulfate moieties act as receptors to which HSV-1
and HSV-2 bind.27,28 HSV-1 encodes a complement-interacting glycoprotein
(gC) and an IgG Fc binding glycoprotein (gE). These glycoproteins mediate
immune evasion.29 Glycoproteins C and D (gC and gD) play an important
role in the attachment of HSV-1 to host cell surface heparan sulfate receptors, Fig. 18.46
whereas glycoprotein B (gB) is responsible for HSV-2 cellular attachment, Herpes simplex: intraepidermal vesicle in which there is intracellular edema
entry, and cell-to-cell spread.27,28 (ballooning degeneration) and acantholysis.
Fig. 18.47
Herpes simplex: scanning view of intact intraepidermal blister.
Fig. 18.50
Herpes simplex: high-
power view of blister.
The features of an ulcerated herpetic lesion are not diagnostic unless the
epithelial margins retain the characteristic features of intracellular edema,
multinucleate epithelial cells, and inclusion bodies. Careful scrutiny of the
surface exudate may nevertheless reveal isolated degenerate epithelial cells
whose nuclei contain ghost outlines of herpetic viral inclusions. This should
prompt examination of the adjacent intact epidermis for more characteristic
features of HSV infection.36 The viable multinucleate cells are the diagnos-
tic feature of the Tzanck test, a Giemsa-stained smear of vesicle contents.
Biopsies of anogenital HSV-related ulcers in HIV-infected patients may show
evidence of concomitant cytomegalovirus infection.36,37 In the past, labora-
tory diagnosis of herpes infection was confirmed by growth in tissue cul-
ture, electron microscopy, immunofluorescent demonstration of viral-specific
protein or viral DNA hybridization.38 Nowadays, the diagnosis of HSV-1 or
Fig. 18.48 HSV-2 infection can also be confirmed by PCR or immunohistochemistry
Herpes simplex: the roof shows acantholysis and scattered characteristic (Fig. 18.52).39
intranuclear inclusions.
A B
Fig. 18.49
(A, B) Herpes simplex: note the numerous multinucleate giant cells and conspicuous pale-staining inclusions (B).
Fig. 18.53
Varicella (chickenpox):
(A) note the widespread
distribution of vesicles
Fig. 18.51 on the face, upper
Herpes simplex: multiple vessels show intense fibrinoid necrosis. chest, arms, and legs;
(B) close-up view. (A) By
London, UK; (B) by
A courtesy of the Institute of
Fig. 18.52
Herpes simplex: positive immunohistochemistry.
B
Varicella and herpes zoster

Clinical features Complications include pneumonitis, meningitis, encephalitis, myelitis, and
Varicella-zoster virus (VZV), also referred to as herpes varicella virus, is purpura fulminans. In the last, symmetrical hemorrhagic and necrotic lesions
similar morphologically to herpes simplex virus (HSV), and is the causative are seen on the legs following typical chickenpox, and the condition is asso-
agent of varicella and zoster.1–3 ciated with disseminated intravascular coagulation. Acquired deficiencies in
Varicella, or chickenpox, which is highly contagious, is most often an protein S or protein C has been implicated in the pathogenesis of varicella-
infection of children and is characterized by a disseminated vesicular erup- associated purpura fulminans.6,7 Less common complications include orchitis,
tion in crops. The major route of dissemination is by airborne droplets from hepatitis, glomerulonephritis, arthritis, myocarditis, and rhabdomyolysis.4,8,9
the respiratory tract.4,5 In the immunocompetent, spread via the cutaneous Necrotizing fasciitis is a potentially life-threatening complication of child-
lesions seems to be of little importance. Varicella is endemic in the temperate hood varicella.10
climates and manifests predominantly in winter and spring.4,5 Varicella occurring in pregnancy may have serious consequences for
The incubation period is around 2 weeks and is followed by a rash, which is both mother and fetus.11 Varicella pneumonia may lead to maternal death.
most pronounced on the trunk. The rash starts as red macules 2–4 mm across, Congenital varicella syndrome occurs in approximately 2% of neonates
which progress rapidly to fragile vesicles said to resemble ‘dew drops on rose born to mothers who acquire chickenpox during the first two trimesters.
petals’; these become pustular and rapidly show crusting (Fig. 18.53). Lesions in Manifestations of this syndrome include dermatomal cutaneous lesions, ocu-
varying stages are present at any one time. There is often considerable pruritus and lar involvement, neurological complications, and skeletal abnormalities.5,11
the associated scratching may result in secondary infection with Staphylococcus Generalized neonatal varicella, which carries a mortality of around 20% if
aureus or Streptococcus pyogenes.5 Mucosal lesions are frequently also present. untreated, is the result of a maternal varicella rash appearing in a mother
Systemic effects in children are mild whereas they are almost invariably severe without antibodies between the last 4 or 5 days of pregnancy and the first
in adults, neonates, and immunocompromised patients. 2 days following delivery of the baby.5,11
Varicella and herpes zoster 777
A B
Fig. 18.54
(A, B) Herpes zoster (shingles): intact vesicles in a characteristic dermatomal distribution. From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
Herpes zoster, or shingles, occurs particularly in adults, usually the

elderly, and most often presents as a girdle-like vesicular eruption in the tho-
racic or lumbar region, or with facial lesions as a result of trigeminal nerve
involvement (Figs 18.54, 18.55).3,4,12 It is analogous to a recurrent episode
of herpes simplex where the virus remains latent in the ganglia of sensory
nerves. It is, however, worth noting that although rare, coinfection with VZV
and HSV has been reported.13 Herpes zoster is thought to develop as a con-
sequence of partial immunity.4 The eruption is preceded by paresthesia or
pain in the dermatome supplied by a sensory nerve. This is followed, usually
after 2–4 days, by the development of an edematous erythematous plaque
on which groups of vesicles arise. As in chickenpox, these rapidly become
pustules, which may coalesce to form bullae, occasionally hemorrhagic
(Fig. 18.56). The areas become crusted and this may very occasionally be
followed by scarring and keloid formation. The lesions are usually painful and
this may persist for months or years as postherpetic neuralgia. Involvement of
Fig. 18.56
Herpes zoster (shingles): older lesion in which the rash has a hemorrhagic
component. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
the ophthalmic division of the trigeminal nerve (herpes zoster ophthalmicus)

is an important manifestation in the elderly, which can have serious compli-
cations (Fig. 18.57).12 Involvement of the mucocutaneous division of the sev-
enth cranial nerve or the eighth cranial nerve leads to Ramsay Hunt syndrome,
which is characterized by lesions in the auricular canal, facial paralysis, and
auditory and vestibular symptoms.12 Rarely, noncontiguous multidermato-
mal cutaneous involvement (zoster multiplex) may occur.14 Although uncom-
mon, herpes zoster may occur in children who have received varicella vaccine,
a live attenuated virus. Cervical and sacral dermatomes are most commonly
affected in these children and potential complications include secondary bac-
terial infection, scarring, and depigmentation.15
Reactivation of latent VZV may be associated with a deficiency in cell-
mediated immunity, as immunity to chickenpox per se is normally lifelong.
Patients with Hodgkin's lymphoma, non-Hodgkin's lymphoma or systemic
Fig. 18.55 lupus erythematosus, and those treated with irradiation or chemotherapy, are
Herpes zoster (shingles):
particularly at risk and often develop a more serious illness.4,5 In more severe
there is intense erythema,
intact vesicles, and crusted cell-mediated immunodeficiency the zoster may become widely disseminated
lesions. By courtesy and sometimes proves fatal. Disseminated cutaneous lesions most often
of R.A. Marsden, MD, present as vesicles, pustules, hemorrhagic bullae, ulcers, and black eschars
St George's Hospital, although occasionally patients may develop verrucous, hyperkeratotic lesions
London, UK. (Fig. 18.58).16 Visceral involvement is most often seen in the lung, liver, and
Herpes zoster is a well-recognized cutaneous manifestation of the immune

reconstitution inflammatory syndrome occurring in HIV-infected patients
(including c hildren) receiving highly active antiretroviral therapy.22,23

Although inhalation of viral particles is the usual route of infection, direct
cutaneous inoculation may occur. Initial contact is followed by viremia
before the cutaneous lesions develop. During the viremic stage VZV is trans-
ported to the skin by T cells. Cell-free viral replication takes place in the
skin and facilitates person-to-person spread. Even when the resolution of
the lesions is clinically complete, the virus may remain latent in the ganglia
of sensory nerves.24 IgG, IgM, and IgA antibodies develop soon after the
vesicles; some IgG antibody is detectable thereafter throughout life, but the
other antibodies disappear. It has been noted that cell-mediated immunity is
depressed during an episode of chickenpox and for at least the first few days
of zoster.
VZV has the ability to interfere with the expression of major histocom-
patibility complex (MHC) class I and class II proteins required for CD4 and
CD8 T-cell recognition, leading to delayed clearance of virus-infected cells.25
Fig. 18.57 VZV glycoprotein E (gE) is essential for viral replication and also plays a
Herpes zoster (shingles): role in spread of the virus from cell to cell, secondary envelopment, and viral
ophthalmic involvement entry.26,27 Open reading frame 66 (ORF66) of VZV encodes a protein kinase
is particularly seen in
which modulates apoptosis and interferon pathways, down-regulates MHC
the elderly. By courtesy
class I protein expression on cell surfaces, and facilitates tropism of VZV
St George's Hospital, for T cells.28 These are just some of many aspects of the complex pathogen-
London, UK. esis and immunobiology of VZV infection.3,25,29,30 A more detailed account
is beyond the remit of this text, and the reader is thus referred to reference
numbers 3, 25, 29, and 30.
Histologically, the cutaneous lesions of VZV, whether in varicella or zoster
form, are generally indistinguishable from those of herpes simplex although it
has been suggested that inflammation is more profound in the latter. Follicular
epithelial involvement may also serve as a further point of distinction (see
below).31 The intraepidermal blisters associated with intracellular edema and
multinucleate epithelial cells with inclusion bodies are characteristic. The der-
mal infiltrate and fibrinopurulent exudate are seen regularly, but are not diag-
nostic. There is often more intraepidermal and dermal hemorrhage than in
herpes simplex infection.
The wart-like cutaneous lesions encountered in patients with AIDS show
hyperkeratosis, verruciform acanthosis, and virally induced cytopathic alter-
ations, often with minimal or absent cytolysis of the infected epidermal
keratinocytes, and little by way of a dermal inflammatory infiltrate.17,19,20
Immunosuppressed individuals with VZV infection may have a protracted
clinical course during which biopsies reveal a lichenoid inflammatory reac-
tion pattern rather than cytolysis of keratinocytes.32
Biopsies from early herpes zoster lesions may exhibit VZV-infected cells
Fig. 18.58
Herpes zoster:
in the hair follicles, suggesting that VZV spreads from dorsal root ganglia
disseminated lesions or trigeminal ganglia to an area of skin innervated by myelinated nerves, the
may be seen in latter terminating at the level of the follicular isthmus.31,33 Exclusive involve-
immunosuppressed ment of folliculosebaceous units in this manner may predate the evolution
patients. By courtesy of of more characteristic vesicular lesions, and serves as a point of distinction
N.C. Dlova, MD, Nelson R. from recurrent herpes simplex. In the latter, there is axonal transport of
Mandela School of the virus from sensory ganglia to the skin via terminal nonmyelinated nerve
Medicine, University of twigs.31 Very rarely, VZV infection may manifest with dermal vasculitis in
KwaZulu-Natal, South the absence of associated epidermal involvement.34 Another rare occurrence
Africa.
is exclusive involvement of epithelium of the eccrine apparatus (herpetic
syringitis), manifesting with isolated nodular skin lesions in the absence of
epidermal viropathic changes.35 A number of cutaneous reactions have been
brain.4 Cerebral disease most often presents as progressive leukoencephalitis. described at the sites of healed herpes zoster scars. These include pseudo-
A nonimmune individual may contract chickenpox from a person with herpes lymphomatous cutaneous lymphoid hyperplasia, granulomatous vasculitis,
zoster. Herpes zoster occurs in as many as 40–50% of patients in the first year granulomatous folliculitis, granuloma annulare, lichen planus, reactive per-
following bone marrow transplantation, but the lesions increasingly resemble forating collagenosis, lichen sclerosus, and cutaneous Rosai-Dorfman dis-
varicella as the time after transplantation increases. This suggests that T cells ease.36,37 Active lesions may also harbor a pseudolymphomatous dermal
specific for VZV are less well represented as time goes by. lymphoid infiltrate.38
VZV infection in patients with AIDS may present with unusual mani- As with HSV, the presence of multinucleate cells is valuable in the Tzanck
festations, including verrucous skin lesions resembling viral warts and dis- test. In shingles, the spinal ganglia may show necrosis with inflammation, and
seminated varicella in the absence of skin lesions.17–20 Verrucous VZV intranuclear inclusions are sometimes evident.39 Otherwise, diagnosis is usu-
infection, however, has also been reported in a renal transplant recipient.21 ally based on clinical criteria, but can be confirmed by electron microscopy,
Cytomegalovirus infections 779
simplex, bacillary angiomatosis, Mycobacterium avium complex, and even

mucormycosis.26–30 CMV infection is said to occur in 20–60% of organ
transplant recipients, with cutaneous manifestations occurring in 10–20%
of patients with systemic infection.24 Skin lesions in AIDS- and non-AIDS-
associated immunocompromised patients do not appear to differ clinically
or histologically.25
Reported cutaneous manifestations include ulcers on the genitalia, anus,
perineum, buttocks and thighs, purpuric eruptions, petechiae, erythema
nodosum, cutaneous vasculitis, hyperpigmented nodules and plaques, lesions
resembling prurigo nodularis, erythema multiforme (including the persistent
form of the latter), nodular auricular lesions, epidermolysis, urticaria, pus-
tules, vesiculobullous lesions and a generalized, pruritic erythematous macu-
lopapular eruption.23–25,31–45 Cutaneous CMV infection has also been detected
in a patient with febrile ulceronecrotic Mucha-Habermann disease.46 There
are isolated reports of CMV infection in association with eruptive pseudoan-
giomatosis and reactive perforating collagenosis.47,48 A possible link to sclero-
derma has also been suggested.49,50 In one study, graft-versus-host disease-like
histological changes were observed in biopsies of clinically normal skin from
allogeneic bone marrow transplant recipients who had peaks of CMV antigen
Fig. 18.59 in the blood within 100 days of transplantation.51
Herpes zoster: positive immunohistochemistry.
immunofluorescence of blister contents, growth in tissue culture, PCR, in situ In addition to maternally derived infections, there is also some evidence to
hybridization or immunohistochemistry (Fig. 18.59).5,20,40 Serological tests suggest a venereal mode of spread.52 In the immunocompromised patient,
are less useful than rapid antigen-detection methods and are only of value CMV infections represent an acquired phenomenon or reactivation of a
later, when a rising titer can be demonstrated.5 latent focus.40 In immunosuppressed transplant recipients, infection occurs
predominantly after the first month post-transplantation and is the result of
either primary infection, reinfection or reactivation of latent disease.42 A high
Cytomegalovirus infections antigen-specific T-cell response to CMV is responsible for chemokine-mediated
endothelial cell damage.53
Clinical features The histological hallmark is the presence of large, often purple-staining,
Antibody studies suggest that most people have been exposed to cytomega- intranuclear inclusions surrounded by a clear halo (Figs 18.60, 18.61).
lovirus (CMV).1 Generally, an asymptomatic infection ensues. CMV infec- Smaller basophilic, periodic acid-Schiff (PAS)-positive intracytoplasmic
tion, however, may result in clinical features under a variety of circumstances. inclusions may also be evident. These have been described within enlarged
These include neonatal lesions, an infectious mononucleosis-like disease in endothelial cells of dermal blood vessels, sometimes accompanied by the fea-
adults, or a manifestation of disseminated disease in immunocompromised tures of leukocytoclastic vasculitis.21,25,34,35 Inclusions may sometimes be iden-
patients.2,3 A recent in-depth review of the literature revealed that severe tified in dermal fibrocytes, macrophages, and eccrine ductal epithelial cells,
visceral CMV infection in apparently immunocompetent individuals might the last rarely associated with syringosquamous metaplasia.25,54,55 They have
not be as uncommon as previously considered.4 Clinical lesions in the skin, also been identified within the endothelial cells of blood vessels and histio-
however, are distinctly uncommon. cytes in the inflammatory bed deep to cutaneous ulcers (Figs 18.60, 18.61).31
CMV is the most frequently transmitted viral infection in utero.5,6 The Cutaneous nerve involvement (CMV neuritis) has been reported in perineal
incidence of reported infection ranges from 0.2% to 2.2% of live births.7,8
Less than 10% of affected infants and neonates will actually develop clini-
cal lesions.5,9 Clinical manifestations have been grouped with other neonatal
infections under the rubric ‘TORCH syndrome’ which includes toxoplas-
mosis, other infections (e.g., syphilis), rubella, cytomegalovirus, and herpes
simplex.10
Affected newborn babies and neonates may develop a wide range of lesions
including jaundice, hepatosplenomegaly, microcephaly, sensorineural deaf-
ness, chorioretinitis, pneumonia, direct hyperbilirubinemia, thrombocytope-
nia with petechiae, purpura, and ‘blueberry muffin’ lesions.2 The last consist
of blue-red or violaceous papules and nodules and represent foci of dermal
erythropoiesis.11 The mortality in this syndrome is of the order of 20–30%.5
Other reported pediatric manifestations of CMV infections include sclere-
dema, the Gianotti-Crosti syndrome, perineal ulceration, the juvenile variant
of papular-purpuric gloves and socks syndrome, acute hemorrhagic edema of
infancy, and the fetal inflammatory response syndrome (FIRS).12–18
Adults, particularly females, most often in the third decade, may develop
a heterophil agglutinin-negative infectious mononucleosis-like syndrome in
which a short-lived rubelliform eruption has been described.2,19,20 Patients
are also at risk of developing an ampicillin-related allergic dermatosis
Fig. 18.60
(cf., infectious mononucleosis).2,20–22
Cytomegalovirus: this
CMV infection may also be a feature of immunosuppression.3,23–25 specimen comes from
Generalized CMV infection is a not uncommon finding at autopsy in a patient with HIV/AIDS.
AIDS patients. CMV is frequently detected in association with toxoplas- Note the hemorrhage and
mosis and Pneumocystis jiroveci (formerly Pneumocystis carinii) infection, intense inflammatory cell
and has also been described in patients with concomitant cutaneous herpes infiltrate.
as an important pathogen in transplant recipients.3,8 Other reported clini-

cal associations and cutaneous manifestations of HHV-6 infection include
papular-purpuric ‘gloves and socks’ syndrome, erythema elevatum diutinum,
an infectious mononucleosis-like syndrome, the Gianotti-Crosti syndrome,
drug hypersensitivity syndrome, and more recently, pityriasis rosea.10–16
HHV-6 DNA has also been detected in lesions of Langerhans cell histio-
cytosis.17 HHV-7 has been implicated in pityriasis rosea and drug-induced
hypersensitivity syndrome.16,18
The histopathological findings in exanthem subitum are rather non-specific
and include papillary dermal edema and a superficial perivascular mononu-
clear inflammatory cell infiltrate. Rare cases with a vesicular presentation
may show mononuclear inflammatory cell exocytosis into the epidermis, with
microscopic intraepidermal spongiotic vesiculation. Intranuclear inclusions
(as seen in herpes simplex virus infection or varicella-zoster virus infection) are
absent. The diagnosis can be confirmed by immunofluorescence microscopy,
using an antibody to HHV-6.6
Fig. 18.61
Cytomegalovirus: high-power view showing the typical eosinophilic intranuclear Eruptive pseudoangiomatosis
inclusions.
Clinical features
In 1969, Cherry et al. reported a series of four infants who developed an
eruption of small hemangioma-like papules, which blanched on pressure. The
lesions had an abrupt onset and apparently evolved in association with an
acute echovirus infection, resolving spontaneously within a few days.1 This
uncommon condition was later referred to as eruptive pseudoangiomatosis
(EPA), and was initially regarded as an exanthem unique to infants and chil-
dren.2,3 A recent review of the literature, however, revealed that more than
half of all cases recorded thus far have occurred in adults, often as small
outbreaks, in the Mediterranean region during the summer months.4–6 The
condition is similar to or synonymous with the entity referred to in Japan
as erythema punctatum Higuchi, which has been linked to mosquito bites.6,7
In children the eruption is frequently preceded by an upper respiratory tract
infection or, less commonly, gastroenteritis.3,5 Prodromal constitutional symp-
toms such as malaise, fever, headache, vomiting or diarrhea are encountered
more frequently in pediatric patients than in adults.5 Rare cases have occurred
in iatrogenically immunosuppressed individuals.4,8
The acute eruption comprises numerous small, asymptomatic, bright red
angiomatoid papules. The individual lesions, which measure between 2 mm
and 5 mm in diameter, are surrounded by a distinctive pale halo and charac-
teristically blanch on pressure.9,10 The face, trunk, and limbs are sites of pre-
Fig. 18.62
Cytomegalovirus: positive immunohistochemistry.
dilection. Spontaneous resolution usually takes place within 3 to 10 days.3
Relapse, however, has been reported in around 70% of cases in some series.6
Exceptionally, EPA may persist for months.3
ulcers.56 In histological specimens from immunocompromised hosts, care
should be taken to rule out CMV infection in association with other infective Pathogenesis and histological features
disorders, such as herpes simplex virus infection or bacillary angiomatosis. Although there is often strong circumstantial evidence to suggest that the erup-
Vesiculobullous lesions are characterized by spongiosis and reticular degen- tion is precipitated by a viral infection, further investigation seldom leads to
eration, accompanied by epidermal multinucleate giant cells which may contain the identification of a specific pathogen.3,6 Isolated cases, however, have been
viral inclusion bodies.26 The diagnosis of CMV infection can be confirmed by linked to cytomegalovirus infection and infection with Epstein-Barr virus.11,12
immunohistochemistry, in situ hybridization or PCR (Fig. 18.62).57 Some cases have occurred following arthropod bites, especially those of mos-
quitos.6,13 A vector-borne infectious agent therefore seems probable in a sub-
set of patients.4 Since there is no true vascular proliferation, the authors who
Exanthem subitum initially described the condition proposed that the cutaneous lesions were the
result of either a direct viral effect on vascular endothelial cells or binding
Clinical features of antigen–antibody complexes to the endothelium.1 The latter is unlikely as
Exanthem subitum (roseola infantum) is a benign disease of infancy usually there is no evidence of vasculitis. The surrounding white ring observed clini-
caused by infection with human herpesvirus 6 (HHV-6).1,2 Infection with cally around each lesion has been ascribed to vasoconstriction peripheral to
human herpesvirus 7 (HHV-7), a closely related β-herpesvirus, however, may the central zone of vasodilatation.9 It seems likely that EPA represents an
also manifest as exanthem subitum.3,4 Usual clinical features include fever unusual reaction pattern in response to a number of different viruses.2
and a cutaneous eruption that resembles rubella or measles.3,5 A case with The histopathological picture predominantly shows dilated blood vessels in
vesicular lesions has been reported.6 the papillary dermis and upper reticular dermis. These vessels are lined by plump
A similar rash caused by HHV-6 infection has been reported in leuke- endothelial cells, which usually assume a hobnail-like appearance.2,10,14,15 A sparse
mic patients and bone marrow transplant recipients; a possible link to graft- perivascular lymphoid infiltrate is sometimes evident.8,9,12,15 Importantly, there is
versus-host disease has also been suggested.7–9 HHV-7 is also recognized no increase in dermal vascular density.9,10
Diseases caused by orthopox viruses 781
Although eruptive pyogenic granulomas, bacillary angiomatosis, bartonello-
sis and multiple glomeruloid hemangiomas may enter the clinical differential
diagnosis, each of the aforementioned conditions has distinctive histology
and is associated with a true angiomatous dermal vascular proliferation.
Furthermore, the individual lesions are not surrounded by a peripheral white
halo.
Hobnail hemangioma (targetoid hemosiderotic hemangioma) is charac-
terized clinically by a perilesional halo and histologically by hobnail-like
vascular endothelial cells. Unlike EPA, however, lesions are usually single,
the surrounding halo is pigmented rather than pale, and there is a true der-
mal vascular proliferation. Telangiectases lack protrusion of plump endothe-
lial cells into the dilated vessel lumina. Spider angiomas comprise centrally
located dilated dermal arterioles with thin branches; they too are devoid of
the prominent endothelium observed in EPA.1
A
Diseases caused by orthopox viruses
Clinical features
The orthopox viruses are DNA in type and cause variola, vaccinia, cowpox,
and monkeypox.
Variola
Variola, or smallpox, has not been diagnosed endemically since 1977 and
until recently appeared to be of historical interest only.1–4 In recent years,
however, there has been renewed interest in smallpox as a potential agent in
bioterrorism.5–7 It was endemic in parts of Africa, South America, and Asia,
with only occasional cases seen in Europe and North America. Transmission
of the virus, which is capable of retaining viability in dried exudate, is by
inhalation. The disease typically has an incubation period of 12 days, fol- Fig. 18.63
lowed by a prodromal phase of high fever, headache, and vomiting and 3–4 Variola (smallpox): (A)
days later by a transient erythematous and petechial rash. This is in turn fol- in contrast to those
lowed by the characteristic eruptive lesions (Fig. 18.63). These lesions are of chickenpox, the
most common on the face and limbs. They begin as papules, which become lesions are larger and
vesicular and then pustular and crusted. Healing is usually associated with a less superficial; (B)
pitted scar. Mortality varied from 2% to 50%, depending on the severity of note the widespread
hyperpigmented scars
the infection. Although death was previously attributed to secondary bacte-
in healed lesions. (A) By
rial sepsis, it has since come to light that it was probably the direct result of
courtesy of H.P. Lambert,
the cytopathic effects of the smallpox virus itself.8 It has been suggested that MD, St George's Hospital,
the scarring observed in survivors of the disease might have been the result of London, UK; (B) By
destruction of sebaceous glands, although other mechanisms have also been courtesy of R.A. Marsden,
proposed.9 B St George's Hospital,
London, UK.
Vaccinia
Vaccinia virus is closely related antigenically to variola virus, but is probably Although this rare zoonotic disease generally results in a self-limiting infec-
derived from cowpox virus. It was used for immunization against variola and tion, more severe illness may occur in immunocompromised individuals and
no doubt was effective because of its similar antigenicity. This skin inocula- those with eczema.20 The incubation period after inoculation is usually 5–7 days;
tion results in a single vesicle, which becomes pustular and crusts, like variola a papule then develops, which rapidly becomes pustular. The pustule is sur-
(Fig. 18.64). It also heals similarly, leaving a scar. Since it was accepted that rounded by a zone of erythema and edema. Eschars or necrotic ulcers may be
variola had been eradicated in the wild, for many years vaccination was no seen.16,21,22 The lesions are often multiple and can occur on the hands, arms or
longer thought necessary except in laboratory workers at special risk. Public face (Figs 18.65, 18.66).23 A severe generalized or varicelliform eruption in
fear of smallpox as a potential biological weapon or bioterrorism agent in the association with atopy has been reported.24,25 Sporotrichoid spread has been
United States of America, however, has led to the reintroduction of a small- documented.26 Lymphangitis, lymphadenitis, and fever are almost invariably
pox vaccination campaign in that country.7 The vaccination procedure is not present. Healing and recovery occur in 3–4 weeks. A fatal case of a cowpox-
without risk. Generalized vaccinia was occasionally seen and the vaccine was like illness has been recorded.27 One reported case developed facial cellulitis
responsible for some cases of Kaposi's varicelliform eruption (eczema vacci- and necrotizing lymphadenitis with abscess formation after inoculation of the
natum). Vaccinia necrosum and encephalitis were also rare complications.10 virus in the nasal respiratory epithelium.28
Occasional cases of generalized vaccinia following smallpox vaccination have
been recorded recently.11 Monkeypox
Monkeypox is an uncommon zoonosis attributable to monkeypox virus, a
Cowpox member of the orthopox virus group.29–31 The first recorded cases occurred
Despite the name, the reservoir for cowpox virus is not cattle, but wild ani- in the Democratic Republic of Congo (formerly Zaire) in 1970.29,32 Although
mals such as hedgehogs and badgers. Cattle and man are both infected acci- sporadic cases are encountered in remote villages in the tropical rain for-
dentally, although man may acquire the disease from cows. Cats, and more ests of West and Central Africa, an outbreak of the disease occurred in the
recently rats, have been identified as additional sources of infection.12–19 state of Wisconsin in the United States of America in 2003, spreading to
Fig. 18.64
Vaccinia: due to the
eradication of smallpox, Fig. 18.66
routine vaccination is no Cowpox: note the edema and surrounding erythema. By courtesy of M.S. Lewis
longer performed. Note Jones, MD, Wrexham Maelor Hospital, Wrexham, UK.
the eschar, edema, and
intense erythema.
By courtesy of the
London, UK.
Orthopox viruses are large and have a discrete DNA compartment (nucleoid)
and a complex capsid and lipoprotein coat containing characteristic tubu-
lar structures. They are brick-shaped and their outer tubular structures are
irregularly arranged. These viruses are all transmitted by inoculation except
variola, which usually gains entry by inhalation. The virus is able to resist
dehydration outside the host and therefore inhalation or inoculation of dust
or inoculation from shared facilities is quite possible, as well as direct inocu-
lation from an active lesion. Evidence has shown that these viruses secrete
interleukin (IL)-18 binding proteins, resulting in viral dissemination or per-
sistent infection.40 Variola virus encodes CrmB, a tumor necrosis factor recep-
tor homologue, which serves as a specific binding protein for a number of
chemokines that mediate recruitment of inflammatory cells to the skin and
mucosae, sites of viral entry, and viral replication. Binding of chemokines
is potentiated via the C-terminal domain of CrmB, referred to as smallpox
virus-encoded chemokine receptor (SECRET).41 In primate animal models,
multiorgan failure ensues in the presence of a high viral burden in the affected
tissues. A hemorrhagic diathesis and depletion of T-cell dependent zones in
lymphoid tissues may also be encountered. A cytokine storm arises due to
elaboration of cytokines such as IL-6 and IFN-γ.42 The vaccinia virus is able
to evade the host immune response by impairing dendritic cell maturation,
with subsequent inhibition of T-cell activation.43
Fig. 18.65 After inoculation the viruses proliferate within keratinocytes and basal
Cowpox: characteristic cells. This leads to severe intracellular edema with resultant ballooning degen-
umbilicated, ulcerated
eration and consequent reticular degeneration due to cell rupture, giving rise
nodules. Lesions are often
multiple. By courtesy of
to multilocular vesicles and subsequent infiltration by polymorphs. In variola,
M.S. Lewis Jones, MD, vaccinia, and monkeypox there is often extensive epidermal necrosis. Variable
Wrexham Maelor Hospital, degrees of hyperkeratosis and acanthosis are present. Cytoplasmic eosinophilic
Wrexham, UK. inclusion bodies may be seen in the keratinocytes of all four diseases. The
small inclusions of variola are called Guarnieri bodies. They are surrounded
by a clear halo and are located close to the nucleus (Fig. 18.67). Similar bod-
neighboring states.29,30,32–37 This outbreak was traced to a shipment of exotic ies are seen in vaccinia and monkeypox. Those of cowpox, however, are
animals from West Africa.31,36,37 Patients appeared to have come into direct slightly larger, but are still predominantly seen in the cytoplasm.44 A dermal
contact with ill prairie dogs that were being kept or sold as pets. It was estab- chronic inflammatory cell infiltrate consisting of lymphocytes is usually pres-
lished that these animals had been exposed to infected rodents imported from ent. CD30-positive cells may be very prominent and confusion with a CD30-
Ghana.31,37 Person-to-person spread may also occur.32 Prior smallpox vacci- positive lymphoproliferative disorder is possible if close attention is not paid
nation may confer some protection against monkeypox infection.29,35,38 The to the epidermal changes and the presence of inclusions.
condition presents with fever, rigors, and a skin rash, sometimes accompa- Diagnosis is based upon clinical information, but confirmation can be
nied by lymphadenopathy.30,34 The cutaneous lesions progress from papules obtained by electron microscopy, isolation of the viruses in tissue culture or,
to vesicopustules to resolving eschars.30 Encephalitis may also occur, and more recently, with the aid of PCR or in situ hybridization studies.22,30,35,45–47
fatalities have been recorded.29,35,39 Monkeypox may be confused clinically Variola virus is detectable in formalin-fixed, paraffin-embedded tissue after
with chickenpox.34 decades of prolonged archival storage.48
Ecthyma contagiosum 783
Milker's nodule virus measures 160–260 nm and is ellipsoid in shape.2 It is
characterized by spirally arranged tubules. The histological features are indis-
tinguishable from those seen in orf infection (see below).3,4 A CD30-positive
atypical dermal lymphoid infiltrate may sometimes be encountered and con-
fusion with a CD30-positive lymphoproliferative disease is possible.5 In the
latter, the CD30-positive cells are usually in clumps while in Milker's nod-
ule the CD30-positive cells are scattered between other inflammatory cells.
This is, however, not entirely consistent and in some cases clusters of CD30-
positive cells may be seen.
Ecthyma contagiosum
Clinical features
Ecthyma contagiosum (orf, contagious pustular dermatosis) is caused by an
epitheliotropic DNA parapoxvirus morphologically identical to that caus-
ing milker's nodule. The infection is endemic in sheep in which it causes
Fig. 18.67 crusted pustules of the lips and perioral area (Fig. 18.69).1–4 This underlies
Variola (smallpox): high-power view showing Guarneri bodies (arrowed). By courtesy the accurate descriptive term of ‘scabby mouth’ used by Australian farm-
of D. Wear MD, the Armed Forces Institute of Pathology, Washington, DC, USA., ers. It is transmitted by inoculation from sheep to sheep, though it is said
that the virus can persist in pastures. It is particularly likely to arise when
the pasture is dry and results in minor abrasions of the labial mucosa of the
sheep. Transmission to man, most often males and usually sheep-handlers,
Milker's nodule is usually by direct inoculation from infected lesions, but it may also result
from contact with contaminated objects such as fences and shears.5 Orf
Clinical features may also be seen in goats.3,4,6 In one English study, 23% of individuals
employed or living on a sheep farm reported having had the condition.7
Milker's nodule (or paravaccinia) is caused by a parapox virus, distinct from
Nonoccupational acquisition of the infection has been described following
that which causes cowpox.1,2 It occurs as a localized lesion on the udders
a sacrificial feast.8
of cows and causes little systemic disturbance. It may be recurrent in the
After an incubation period of 5–6 days, the lesion (usually a solitary, small,
same herd. It is usually acquired by man by inoculation, but since the virus
firm, red-blue papule) develops. It is most common on the hand or forearm
is viable in a dried state, indirect fomite infection is possible. Small out-
(Figs 18.70, 18.71).9 Less commonly, lesions may occur on the facial and
breaks involving several patients have been recorded.2 The incubation period
perianal regions.10–12 The papule becomes a flat-topped hemorrhagic blister
is around 5 days; some two to five red papules then develop, which gradu-
or pustule, later crusting over its depressed center. By this stage it may be
ally become bluish tender nodules.2 The overlying epidermis is at first tense
2–5 cm in diameter. Clinically, it may be mistaken for a pyogenic granuloma
and shiny, but becomes opaque and gray (Fig. 18.68). The center of the
or keratoacanthoma.6 The lesions are surrounded by a zone of erythema,
lesion is crusted and slightly depressed. The surrounding skin often shows
which may be associated with itching and tenderness. The main lesion usu-
lymphangitis, but despite this the lesion has the appearance of a tumor and
ally resolves without scarring in 3 weeks, although on rare occasions digital
is well circumscribed. There are few systemic symptoms, but there may be
deformity may occur.13 Lymphangitis, lymphadenitis, and mild fever occasion-
an associated short-lived papulovesicular eruption on the upper limbs and
ally develop.1 In addition, some patients develop a transient maculopapular
occasionally on the legs. The main nodular lesions resolve, without scarring,
eruption on the trunk or erythema multiforme-like lesions on the limbs.6,9,13
in 4–6 weeks.
Fig. 18.68 Fig. 18.69

Milker's nodule: the blister roof has an opaque appearance and there is surrounding Orf: the scabby mouth. By courtesy of B.J. Leppard, MD, Royal South Hants
erythema. By courtesy of the Institute of Dermatology, London, UK. Hospital, Southampton, UK.
Fig. 18.70
Orf: in this example there is a markedly hemorrhagic component. By courtesy of
M.M. Black, MD, Institute of Dermatology, London, UK.
Fig. 18.72
Orf: (A) the lesion is pedunculated and there is massive superficial dermal edema;
(B) the keratinocytes show ballooning degeneration.
Fig. 18.71
Orf: older lesion with a typical depressed center. By courtesy of A. Qureshi, MD,
Other potential complications include erysipelas, Pseudomonas aeruginosa

infection, a papulovesicular eruption, and a bullous pemphigoid-like bullous
eruption.13,14 Ocular involvement may be a rare manifestation.15 Giant lesions
are sometimes encountered.12,13,16,17 Giant orf lesions were reported recently
in an organ transplant recipient.16
The histological features are quite characteristic. The overall appearance of
the lesion is that of a symmetrical nodule. There is a parakeratotic crust and
acanthosis with thin epidermal strands extending quite deeply into the adja-
cent dermis.18 Viral cytopathic changes including cytoplasmic and nuclear
vacuolation are usually conspicuous.19 Reticular degeneration with intraepi-
dermal vesiculation is often evident (Fig. 18.72).
If the biopsy is taken from an early lesion, typical 3–5 μm intracytoplasmic
eosinophilic inclusions may be seen (Fig. 18.73).19 Sometimes intranuclear
inclusions may also be evident.5 They can be rendered more conspicuous with
Lendrum's phloxine tartazine (Fig. 18.74). Similar inclusions may also be
seen in the cytoplasm of the endothelial cells lining blood vessels, among the
underlying heavy chronic inflammatory cell infiltrate. The latter comprises
lymphocytes and histiocytes although neutrophils and occasional eosinophils Fig. 18.73
may be evident. The dermis is often very edematous, and characteristic of orf Orf: in the center of the field is an eosinophilic intracytoplasmic inclusion.
Molluscum contagiosum 785
Molluscum contagiosum
Clinical features
Molluscum contagiosum is a self-limiting epidermal papular condition caused
by a poxvirus of the Molluscipox virus genus (Fig. 18.76).1,2 The genome
encodes 163 proteins of which 103 are closely related to variola virus.3 It
occurs on the face, trunk, and limbs of young children, who are infected by
direct cutaneous contact or inoculation from fomites, and in young adults on
genitalia and surrounding skin after transmission by sexual contact.2,4 The
palms and soles are usually unaffected, but rare cases have been reported.5,6
Although the condition is worldwide it is more prevalent in tropical regions.1
The earlier literature indicated that lesions were particularly common in Fiji
and Papua New Guinea where 1 child in 10 had or had had the condition;
most infected children were under 5 years of age.7,8 More recent studies from
India and the United States have shown that around 80% of children with
molluscum contagiosum are younger than 8–10 years of age.9,10 There have
been rare reports of congenital infection.11
It has been suggested that molluscum contagiosum may be more common
Fig. 18.74
in people with atopic dermatitis.5 In the USA and UK the incidence in adults
Orf: the inclusions may be highlighted by Lendrum's phloxine tartazine.
attending STD clinics is in the range of 1 for every 40–60 cases of gonorrhea.
Transmission can also occur between wrestlers, between doctor and patient,
and through joint use of equipment and bathing facilities. The use of public
(and milker's nodule) is the presence of massive capillary proliferation and swimming pools appears of particular significance in children.12 The disease
dilatation.10,19 This is attributable to the production of virus-encoded homo- has an increased incidence in patients with impaired immunity. In the latter,
logues of ovine vascular endothelial growth factor.3,20 In addition, orf virus lesions tend to be more extensive, generalized, and persistent.5 Although man
encodes a homologue of interleukin-10, which appears to impair dendritic was initially thought to be the only host to the virus, there have been isolated
cell function and monocyte proliferation.21,22 A prominent, CD30-positive reports of molluscum contagiosum in animals such as certain bird species, the
reactive dermal lymphoid infiltrate may occur.23 chimpanzee, and possibly the red kangaroo.2
The immunobullous (bullous pemphigoid-like) lesions are subepidermal The incubation period ranges from 2 to 7 weeks but may be as long as
in location and contain a mixed inflammatory cell infiltrate, which includes 6 months.13 Individual lesions are smooth, shiny, pearly, firm, umbilicated
polymorphonuclear leukocytes and eosinophils. A recent study of two cases papules up to 5 mm across or occasionally larger (Figs 18.77–18.79). Mucous
showed that orf virus DNA was absent from the blistering lesions, while direct membrane involvement is seen occasionally.14 The lesions are usually quite
immunofluorescence microscopy revealed linear deposition of IgG and com- characteristic in appearance, but may be confused occasionally with a fibrous
plement C3 along the dermoepidermal junction in perilesional skin. Although histiocytoma, intradermal melanocytic nevus, keratoacanthoma, syringoma,
the precise autoantigen has yet to be identified, the condition appears to be basal cell carcinoma, common wart, and even cutaneous cryptococcosis. They
distinct from true bullous pemphigoid and other immunobullous conditions are often multiple, especially in patients with immune deficiency. Although
such as epidermolysis bullosa acquisita.14 uncommon, giant lesions may also occur, especially in immunocompromised
The diagnosis of orf may be confirmed immunocytochemically or by PCR, patients.15–17 HIV-infected individuals can manifest with exclusive involvement
including real-time PCR.24–27 The Tzanck test has also been used as a diag- of facial and perioral skin.18 Molluscum contagiosum may be a cutaneous
nostic aid.9 Ultrastructural studies reveal that the orf virus is best visualized manifestation of the immune reconstitution inflammatory syndrome in
in negatively stained preparations (Fig. 18.75).6 HIV-infected patients receiving highly active antiretroviral therapy.19,20
Fig. 18.76
Fig. 18.75 Molluscum contagiosum: electron micrographic examination shows that the
Orf: on electron micrographic examination the parapoxvirus has a cylindrical molluscum virus body is composed of virions, which are indistinguishable from
appearance and a typical criss-crossed internal structure. By courtesy of I. Chrystie, those in the other poxviruses. By courtesy of I. Chrystie, FIMLS, St Thomas'
FIMLS, St Thomas' Hospital, London, UK. Hospital, London, UK.
Symptoms of itching, tenderness, and pain are uncommon, but approxi-

mately 10% of patients develop an eczematous dermatitis around the mol-
luscum papule. The papule itself may become secondarily infected and then
resemble a furuncle. The individual lesion usually persists for 2 months, but
sometimes lasts much longer. Since the patient may have numerous lesions at
different stages of development, molluscum contagiosum can be present for
years in some patients. Pitted scarring sometimes occurs in atopic individu-
als.21 Systemic lesions have not been described.5
In molluscum contagiosum intracellular edema with reticular degeneration
and vesiculation are not features, in contrast to those caused by the other
pox viruses. The characteristic feature is the presence of lobulated, endo-
phytic hyperplasia, producing a circumscribed intradermal pseudotumor
(Fig. 18.80). The keratinocytes contain a very large intracytoplasmic inclu-
sion, which compresses the nucleus against the cell membrane. Although
initially eosinophilic in size, the inclusion gradually develops a marked baso-
philia (Fig. 18.81). The latter can be recognized in a cytological preparation
Fig. 18.77
Molluscum contagiosum: multiple umbilicated lesions are present. From the
Fig. 18.80
Molluscum contagiosum: characteristic scanning view showing the central
umbilication and epidermal hyperplasia.
Fig. 18.78
Molluscum contagiosum: central umbilication is a diagnostic clinical marker. From
Fig. 18.81
Molluscum contagiosum:
the intracytoplasmic
Fig. 18.79 inclusions almost
Molluscum contagiosum: this often develops as a result of sexual contact in young completely fill the cell and
adults. By courtesy of R.A. Marsden, St George's Hospital, London, UK. compress the nucleus.
Hand, foot, and mouth disease 787
Fig. 18.84
Molluscum contagiosum: there is an intense lymphohistiocytic infiltrate. Numerous
Fig. 18.82 infected keratinocytes are present.
Molluscum contagiosum:
note the tinctorial change
in this section stained
with Lendrum's phloxine Hand, foot, and mouth disease
tartrazine.
Clinical features
from the surface of the lesion; this may serve as a quick diagnostic test. Their This is a viral illness caused most often by coxsackievirus A16 and less often
presence may be rendered more conspicuous by the use of Lendrum's phloxine by enterovirus 71.1–11 It usually affects young children, shows seasonal varia-
tartrazine reaction (Fig. 18.82). tion (being more common in summer and autumn), and presents as small
Usually there is no dermal infiltrate, but when it does occur, allegedly in epidemics. A number of outbreaks have been documented in the East, especially
response to virus or inclusion bodies entering the dermis, the lymphocytic Taiwan.1,3–6,9,10 Outbreaks have also occurred in Malaysia, Singapore, and
infiltrate is so intense that lymphoma may enter the differential diagnosis if India.7,8,11,12 Children in their first four years of life are most susceptible.4,9,11
the characteristic inclusion bodies are not obvious (Figs 18.83, 18.84). This Other viruses implicated include echovirus 19, and very rarely, echovirus 4.13,14
dermal lymphoid infiltrate may harbor large, atypical CD30-positive lym- Recently, molecular phylogenetic analysis has shown that two distinct geno-
phoid cells, potentially mimicking a CD30-positive cutaneous lymphoprolif- groups of coxsackievirus A16 exist, namely, A and B.15 Phylogenetic evidence
erative disorder.22 This is particularly seen in regressing lesions containing few has also revealed that intertypic recombination between enterovirus 71 and
inclusion bodies, and the histologic diagnosis may be very difficult. coxsackievirus A16 may play a role in the emergence of subgenotypes of
enterovirus 71.16
The presence of metaplastic bone formation in otherwise typical lesions
of molluscum contagiosum has been reported.16,23 Molluscum contagio- Hand, foot, and mouth disease has an incubation period of 3–7 days.
sum has also been noted in association with epidermal cysts, melanocytic Following a prodrome of headache, fever, malaise, abdominal pain, and some-
nevi, melanoma, sebaceous hyperplasia, soft fibromas, lupus erythematosus, times diarrhea, patients develop oral ulcers and blisters, most commonly on
leukemia cutis, and eosinophilic cellulitis.16,24–27 the inner cheeks and lips, accompanied by small erythematous papules, which
soon evolve into grayish vesicles on the soles, palms, and ventral surfaces and
sides of the fingers and toes (Figs 18.85–18.88).1 Lesions are less commonly
found on the perineum, buttocks, trunk, and extremities. The eruption is self-
limiting. Complications only occur in approximately 6% of cases attributable
to coxsackievirus A16, notably aseptic meningitis.3
Hand, foot, and mouth disease due to enterovirus 71 is a more serious
illness, with complications occurring in approximately one-third of patients.
These include central nervous system lesions predominantly affecting the
cerebellum. Encephalitis, aseptic meningitis, and a poliomyelitis-like condition
can also occur.1,3,9–12 Concomitant infections may sometimes be seen.12 A mor-
tality rate of around 8% has been recorded. Death is usually attributable to
cardiopulmonary decompensation and acute pulmonary edema.3 The mecha-
nism of pulmonary edema is unclear, since it does not appear to be the direct
result of viral myocarditis in most cases; it has been postulated that increased
pulmonary vascular permeability secondary to brainstem lesions or a systemic
inflammatory response to encephalitis may play a role.5,17 In one outbreak in
Singapore, however, most fatalities were the result of interstitial pneumonitis,
either alone or in association with myocarditis or encephalitis.12

Fig. 18.83 The virus is transmitted by direct contact with nasal and pharyngeal secretions,
Molluscum contagiosum: rupture of an epidermal nodule has released inclusions feces, and blood. Histologically, the blister is intraepidermal and develops as
into the dermis with a resultant intense chronic inflammatory cell response. a consequence of marked inter- and intracellular edema (Figs 18.89, 18.90).
Fig, 18.85 Fig. 18.88

Hand, foot, and mouth disease: multiple oral ulcers are present. By courtesy of the Hand, foot, and mouth disease: there are numerous erosions on the sole of the
Institute of Dermatology, London, UK. foot. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 18.86 Fig. 18.89

Hand, foot, and mouth disease: there are numerous erosions with surrounding Hand, foot, and mouth disease: this low-power view of the finger shows gross
erythema. By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK. reticular degeneration with intraepidermal vesiculation. Degenerative changes
have resulted in epidermodermal separation. By courtesy of E. Wilson Jones, MD,
There may be associated papillary dermal edema. Viral inclusions and giant
cells are not a feature. Enterovirus 71 may induce apoptosis of infected host
cells via a virus-encoded protein.18
A real-time reverse transcriptase PCR method that allows for the dif-
ferentiation of enterovirus 71 from coxsackievirus A16 was described
recently.19
Viral hemorrhagic fevers

Clinical features
The hemorrhagic fever (HF) viruses are a special group of highly infectious
viruses transmitted to humans by arthropods (mosquitoes, ticks) or rodents,
resulting in systemic illness and a generalized bleeding diathesis.1–4 The viral
etiologic agents may be grouped according to family:
• Flaviviridae, which are responsible for infections such as yellow fever,
Fig. 18.87 dengue fever, Omsk HF, and Kyasanur Forest disease,
Hand, foot, and mouth disease: note the small vesicles with surrounding erythema. • Bunyaviridae, which cause Rift Valley fever, Crimean–Congo HF, and
By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK. hantavirus infections (e.g., hemorrhagic fever with renal syndrome),
Virus-associated trichodysplasia spinulosa 789
from these infected cells, resulting in increased vascular permeability, shock,

tissue necrosis, hemorrhage, and coagulopathy.1,9 Many of these viruses are
capable of suppressing innate and adaptive immune responses in the infected
host, leading to rapid local and systemic dissemination.1,10
The dermatopathological manifestations of this group of infections are
poorly documented, largely because of the infectious and hemorrhagic risks
associated with biopsy. In most cases the findings are relatively non-specific.
Consequently, skin biopsy is of questionable diagnostic or prognostic value
The cutaneous histological features of dengue HF are perhaps the best stud-
ied among the HFs.11–13 In general, HF cases with a maculopapular erup-
tion show mild lymphocytic vasculitis, with a mild perivascular mononuclear
inflammatory cell infiltrate, endothelial swelling, and minor perivascular
erythrocytic extravasation.2,4,11–14 Viral antigens may be demonstrated by
immunohistochemistry if specific antibodies are employed.14 Extensive der-
mal hemorrhage is seen in ecchymotic lesions. Intravascular fibrin-platelet
thrombi characterize cases complicated by DIC.
It is important to remember that the HF viruses are not the only infective agents
Fig. 18.90
that may be associated with pyrexia and hemorrhage. Other viruses such as
Hand, foot, and mouth disease: the epithelium shows necrosis and dyskeratosis.
A chronic inflammatory infiltrate is evident. By courtesy of E. Wilson Jones, MD, smallpox virus and herpes simplex also may produce a hemorrhagic fever pic-
Institute of Dermatology, London, UK. ture (e.g., hemorrhagic smallpox). Additional infective agents that may cause
hemorrhagic fever are rickettsiae (e.g., Rickettsia rickettsii), chlamydiae (e.g.,
Chlamydia psittaci), bacteria (e.g., Neisseria meningitidis, Yersinia pestis),
• Arenaviridae, which are responsible for Lassa fever, Argentine HF, fungi (e.g., Aspergillus), spirochetes (e.g., Leptospira icterohaemorrhagiae,
Bolivian HF, Venezuelan HF, Brazilian HF, etcetera, Borrelia recurrentis) and protozoa (e.g., Plasmodium falciparum).8
• Filoviridae, which cause Marburg virus disease and Ebola virus HF.1–3
There is marked diversity in the severity of illness and the mortality within Virus-associated trichodysplasia spinulosa
this group of diseases; dengue fever, for example, has a mortality of around
5% whereas the purported mortality associated with Ebola is 50–90%.4 Most Virus-associated trichodysplasia spinulosa (VATS) also known as viral-
viral HFs manifest as an acute febrile illness, often with myalgias. Conjunctival associated trichodysplasia is a rare, recently recognized, and novel viral infec-
injection and periorbital edema may occur.2,4 Although some earlier classification of the hair follicle in immunocompromised patients.1–3 It is mainly seen
tions of viral HF included chikungunya (caused by chikungunya fever virus, a in solid organ transplant patients, mainly renal transplant, but may also occur
member of the Togaviridae), hemorrhagic manifestations are relatively rare and in patients with chemotherapy-associated immunosuppression.4 It is likely
the disease has thus been omitted from more recent HF classifications.1,2,5 that VATS is the same entity as pilomatrix dysplasia and cyclosporin-induced
A detailed discussion of all of the conditions listed above is not possible, folliculodystrophy.3,5,6 Both conditions were attributed to cyclosporin therapy
and the reader is referred to references 1 and 2 for excellent overviews on the but the clinical and histologic features are remarkably similar.
subject. The further discussion here will focus on the potential mucocutane-
ous manifestations of viral HFs. Clinical features
A conspicuous, diffuse, nonpruritic maculopapular skin rash is typically Virus-associated trichodysplasia spinulosa is characterized by multiple small,
encountered in filovirus infections such as Marburg virus disease and Ebola skin-colored to erythematous spiky follicular papules which are asymptom-
HF. Desquamation may take place during the recovery phase in nonfatal atic or mildly pruritic and have predilection for the face and ears.1–3 Lesions
cases.3 A similar although less prominent eruption may be seen on the trunk can also occur on the trunk and limbs, although they tend to be more sparse
and limbs of patients with Rift Valley fever.2 Dengue HF is frequently associ- in these locations, and may coalesce. Focal alopecia can occur. When the
ated with a morbilliform rash, often with islands of spared skin.3,6 Omsk HF, immunosuppression is reduced the condition improves or regresses.
Kyasanur Forest disease, Argentine HF, and Bolivian HF are associated with a
papulovesicular eruption involving the palate.3 Around 30% of patients with Pathogenesis and histological features
dengue HF have mucosal involvement, most often of the conjunctiva.6 Virus-associated trichodysplasia spinulosa is induced by viral infection of
Thrombocytopenia is a characteristic sequel in the majority of viral HFs the hair follicle. Electron microscopy studies have demonstrated intranuclear
and manifests as petechial hemorrhages on the skin and in relation to the viral particles of variable size, from 30 to 46 nm with features that suggest a
mucous membranes. Ecchymoses may develop in severe infections and are polyoma virus.1–4 Cultures so far have been unsuccessful.
usually located over pressure points. There may also be bleeding from veni- Histologically, anagen hair follicles appear distended with dilatation and
puncture sites. Disseminated intravascular coagulation (DIC) is known to hyperkeratosis of the infundibula and abnormal maturation with marked inner
complicate the clinical course of some infections, especially Rift Valley fever.2–4 root sheath differentiation.3 The process has been described ‘as if the hair fol-
Jaundice is a typical feature of yellow fever but may also be encountered in licles were entirely devoted to producing inner root sheath’.2 Prominent cells
Rift Valley fever, Crimean–Congo HF, and the filoviral HFs.2,4 with eosinophilic cytoplasm and numerous trichohyaline granules are seen. The
Although Sindbis fever is not strictly one of the viral HFs, this relatively outer root sheath persists beyond the isthmus and the bulbs are abnormal, lack-
mild, self-limiting togavirus infection may rarely be associated with hemor- ing fully formed papillae. Often there are only few matrical-cells as they are
rhagic skin lesions, and has been included here for the sake of completeness.7 replaced by large numbers of cells with eosinophilic cytoplasm. There is usually
In usual cases of Sindbis fever the exanthem is papular or vesicular, occurring no transition between the inner root sheath and a fully cornified hair shaft.
in crops lasting up to 10 days. Lesions tend to be concentrated over the but-
tocks, legs, palms, and soles.8 Differential diagnosis
The differential diagnosis includes keratosis pilaris and lichen spinulosus.
Pathogenesis and histological features Keratosis pilaris mainly involves the proximal limbs, rarely involves the face,
Although the precise pathogenesis of all viral HFs has yet to be fully elucidated, and it has very subtle microscopic features, mainly hyperkeratosis and plug-
the general trend is to target dendritic reticulum cells, monocytes, lympho- ging of the infundibula. Lichen spinulosus mainly occurs in children, has pre-
cytes, hepatocytes, and vascular endothelial cells. The profound pathophysio- dilection for the proximal limbs, neck and buttocks, and it is characterized
logical effects are mediated via the release of a host of inflammatory cytokines histologically by hyperkeratosis in the infundibular part of the hair follicles.
Bacterial infections
Impetigo
The skin has a normal commensal population of bacteria in which
Staphylococcus epidermidis predominates.1 Other resident Gram-positive
bacteria include Micrococcus spp. and Corynebacterium spp.2 The free fatty
acids and other lipids derived from the stratum corneum and sebum have an
antibacterial role, yet 10–20% of the normal population are cutaneous car-
riers of S. aureus and approximately 10% are pharyngeal carriers of group
A β-hemolytic streptococci (Streptococcus pyogenes).1,3 This ‘carrier’ state
may precede infective lesions in the host or may be the origin of infections in
others. S. aureus and S. pyogenes are the most common agents in superficial
bacterial infections of the skin, but even organisms of low virulence, such as
S. epidermidis, can become pathogenic with a sufficiently large inoculum or
in an immunocompromised host.1 S. aureus toxin production is also respon-
sible for bullous impetigo, the staphylococcal scalded skin syndrome, and the
toxic shock syndrome.4,5
A
Clinical features
Impetigo is the most superficial pyogenic (pyoderma) bacterial skin infection
and is highly infectious. It is exceedingly common and occurs most often in
childhood, but may be seen in the elderly and in patients with immunodefi-
ciency states. It is typically subdivided into nonbullous (simple) impetigo and
bullous impetigo and follows the contamination of minor skin abrasions and
insect bites by S. aureus or S. pyogenes.6,7
In simple impetigo the lesions present as small superficial vesicles, which
rapidly burst and are replaced by a characteristic, adherent, thick yellow-
ish dirty crust with a margin of erythema (Figs 18.91–18.94). The mouth,
nose, and extremities are particularly affected. Regional lymphadenopathy
is sometimes present. Simple impetigo may occur in endemic or epidemic
form and often spreads to involve siblings and schoolmates. It is seen more
often in warm, humid conditions.8,9 S. aureus is the more frequent cause in
North America, whereas S. pyogenes is the more important etiological agent
of impetigo in developing countries.10 In some cases, however, the two bac-
teria appear to coexist. Streptococcal impetigo may occasionally progress to
cellulitis or precede acute glomerulonephritis, erythema nodosum or erythema B
multiforme.
Fig. 18.92
(A, B) Impetigo: note that the vesicles are covered by a golden crust. These perioral
lesions are at a characteristic site. By courtesy of R.A. Marsden, MD, St George's
Bullous impetigo is primarily a staphylococcal-mediated disease exclusively

due to phage group II S. aureus.8 Superficial blisters up to 2 cm across are
the initial features (Fig. 18.95). The contents are at first clear, but rapidly
become cloudy and then develop a thin seropurulent crust; erythema is not
marked. The lesions do not usually involve mucosae. There may be mild con-
stitutional symptoms, and the lesions resolve in 2–3 weeks.
Ecthyma is probably a variant of impetigo and occurs predominantly
on the lower limbs of children, but may occur in adults and at other sites
(Figs 18.96, 18.97).11,12 It presents with thick crusting, overlying punched-
out ulceration, and resultant scarring. S. pyogenes is the usual cause. It is
more common in tropical climates, where it occurs in all age groups. Minor
trauma or scabies infestation may determine the site of the lesions. It is pos-
sible that vasculitis and necrosis induced by bacterial toxins determine the
different presentation.
Ecthyma gangrenosum is usually a complication of Pseudomonas
aeruginosa septicemia that occurs in immunodeficient patients, particu-
Fig. 18.91
larly those with a neutropenia.13,14 It has also been reported in association
Impetigo: note the crusted
lesions on this patient's with hypogammaglobulinemia.15 There have been rare reports of ecthyma
forehead and cheeks. By gangrenosum occurring in the absence of neutropenia or septicemia.16–18
courtesy of R.A. Marsden, The condition has also been reported following toxic epidermal necrol-
MD, St George's Hospital, ysis.19 Lesions, which may be single or multiple, begin as painless ery-
London, UK. thematous macules that become indurated, bullous or pustular.13 Annular
Staphylococcal scalded skin syndrome 791
Fig. 18.95
Fig. 18.93 Bullous impetigo: there is a large raw erosion and a healed lesion distally. By courtesy
Impetigo: in this patient of the Institute of Dermatology, London, UK.
numerous vesicles are
evident. By courtesy
71 and produces exfoliative toxins A and B; the latter are also involved
London, UK.
in the staphylococcal scalded skin syndrome (see below).4,5,22,23 Impetigo
may be caused by community-acquired infection with methicillin-resistant
S. aureus.10,24
An early lesion of impetigo is characterized by a split in the epidermis just
beneath the stratum granulosum (Fig. 18.98). The resultant vesicle becomes
filled with neutrophils, Gram-positive cocci, and occasional acantholytic cells
(Fig. 18.99). The underlying dermis contains a mixed neutrophil and lym-
phocyte infiltrate. Neutrophils may be seen in the spongiotic stratum spino-
sum beneath the vesicle in the process of migrating from the dermis as a
chemotactic response to the causative bacteria. In conditions of impaired neu-
trophil function, impetigo may be common and more extensive.1
In echthyma, there is a sharply circumscribed area of ulceration with a
heavy neutrophil infiltrate and overlying adherent crust (Fig. 18.100).
Ecthyma gangrenosum is characterized by epidermal necrosis with hemor-
rhage and dermal infarction, usually accompanied by a mixed inflammatory
cell infiltrate of lymphocytes, histiocytes, and neutrophils.13 Less commonly,
a dearth of inflammatory cells is noted.13,25 Gram-negative bacilli may be seen
in the dermis and involving the media and adventitia of venules.13 Vasculitis
and thrombosis may be present.
The diagnosis is usually made on clinical grounds and supported by culture
Fig. 18.94
of the causative organisms. Rarely, a biopsy is necessary.
Impetigo: note the crusted healing lesions on the back. By courtesy of J Dayrit, MD,
Manila, The Philippines.
The lesion may be confused histologically with a superficial variant of
pemphigus, particularly as the latter can become secondarily infected and
there may be one or two acantholytic cells in impetigo. Antibodies in a
lesions have been described.20 The lesions soon become gangrenous and pemphigus-like pattern may be demonstrated in bullous impetigo and distinc-
covered by a characteristic gray-black eschar and erythematous halo. tion from pemphigus foliaceus may therefore be a problem.5,26,27 Generally,
Lesions are especially seen on the gluteal and perineal regions and on the the presence of numerous neutrophils and the recognition of Gram-positive
limbs.13 The mortality is high, particularly in those with multiple lesions. cocci is sufficiently characteristic to confirm impetigo, as acantholytic cells
Organisms other than P. aeruginosa have been implicated in the evolution are very scanty. Distinction from subcorneal pustular dermatosis and pustular
of the disease.21 psoriasis may be considered histologically, but the lack of acanthosis, although
not conclusive, should point towards impetigo.
The carrier state or inoculation by a contaminated object is a necessary
precondition to superficial infection of the skin. The organisms become Staphylococcal scalded skin syndrome
attached to the traumatized area, binding strongly to fibronectin and
possibly type IV collagen and laminin, which are abundant in the exudate.1,8 Clinical features
The innate virulence of the organisms and the host defense capability deter- Staphylococcal scalded skin syndrome (SSSS) is so named because of the pres-
mine the subsequent progress of the infection, but this is facilitated if the ence of staphylococcal toxin and the resemblance of the established lesion
bacteria produce coagulase, hyaluronidase or lipases.1 The form of S. aureus to a scald. It may present in epidemic form as well as sporadically. It occurs
responsible for bullous impetigo is of serotype II and mainly of phage type almost entirely in neonates and young children, who develop first a macular
Fig. 18.96
Ecthyma: (A) characteristic lesions in varying stages of
evolution; (B) a punched-out ulcer is shown in close-up.
A B By courtesy of M.M. Black, MD, Institute of Dermatology,
London, UK.
Fig. 18.97
Ecthyma: multiple lesions
are present. By courtesy
of N.C. Dlova, MD,
Nelson R. Mandela School
of Medicine, University
of KwaZulu-Natal, South
Africa.
scarlatiniform eruption in association with a staphylococcal infection. This

is often associated with fever, irritability, and skin tenderness.1–4 The erup-
tion then spreads from its usual original sites on the face, axillae, and groins
to involve large areas of the skin surface. Conjunctivitis is often also present.
Mucous membranes, however, are not affected. At the same time, the skin
becomes edematous and the surface fragile so that it can be sheared off in thin
wrinkled sheets, likened to peeling wet wallpaper, leaving a glistening red sur- B
face, and the child becomes sick and feverish (Fig. 18.101). SSSS is therefore
associated with a positive Nikolsky sign.1,5 Fig. 18.98
Following blistering, desquamation occurs and the skin often returns Bullous impetigo: (A) the site of cleavage is immediately below the granular cell
to normal by 2–3 weeks.6 Scarring is not usually a feature. The associated layer; (B) Gram-positive cocci are present.
Staphylococcal scalded skin syndrome 793
Fig. 18.99 Fig. 18.101

Bullous impetigo: in addition to neutrophils, occasional acantholytic cells may be Staphylococcal scalded skin syndrome: note the very extensive blistering.
present causing diagnostic confusion with pemphigus foliaceus. By courtesy of A. du Vivier, MD, King's College Hospital, London, UK.
Fig. 18.102
Staphylococcal scalded skin syndrome: note the widespread denuded areas at
the edge of which the epithelium is being shed. This case developed in a patient
following wound infection after a coronary artery bypass. By courtesy of S. Parker,
MD, West Middlesex Hospital, London, UK.
source of infection may be an upper respiratory tract infection, conjunctivitis

or umbilical sepsis, or it may be more occult, such as in the middle ear, in the
pharynx or at the site of minor surgery. The condition is rarely seen at other
ages, such as the first day after birth or even at birth, indicating an infection
acquired in labor or in utero, and it may be seen in older children.7 More than
50 adult cases have been reported, although many of these patients were either
immunocompromised (including HIV infection) or in renal failure with a possi-
ble inability to excrete the toxin. The condition does occur rarely in previously
healthy adults or those with relatively minor conditions (Fig. 18.102).1,8–17
The disease in neonates (Ritter's disease) is usually self-limiting with rapid
B resolution of the skin blisters and complete recovery. However, there is a mor-
tality of 2–4% due to progression of the staphylococcal infection or the com-
Fig. 18.100 plications of exfoliation. In the adult this rare condition has shown a mortality
(A, B) Ecthyma: there is a sharply delineated ulcer. Artifact is an important of over 50%.1,15 Recovery is facilitated by antistaphylococcal antibiotics and
differential diagnosis. attention to fluid balance.
An abortive form, the scarlatiniform variant (staphylococcal scarlet fever)

in which the initial erythroderma evolves into the desquamative phase in the
absence of blistering, has been described.4,6 This may be particularly associated
with occult bone and joint infections or contaminated wounds.6

In SSSS the organism is of group II and usually phage type 71, but phage types
3A, 3B, 3C, and 55 have also been found.4,12 These bacteria all produce an
epidermolytic toxin (formerly referred to as exfoliatin) of which there are two
antigenic types: exfoliative toxin A (ETA) and exfoliative toxin B (ETB).18–21
ETA is associated with a chromosomal gene while ETB is plasmid encoded.4,22
They have indistinguishable activity and manifest exquisite pathological sen-
sitivity by inducing blistering only at the level of the superficial epidermis.19,20
The effect of the toxins is determined by their site of production:
• Toxins produced by the appropriate staphylococcal infection of mucosae
or surgical wounds enter the circulation (toxemia) and produce a
generalized change in the skin, the SSSS. The intensity is determined by
the rapidity with which the toxins are metabolized and excreted renally
and by the presence of antibodies against the toxins.23
Fig. 18.104
• If the same staphylococcus infects the skin directly, local release of toxin Staphylococcal scalded skin syndrome: there is quite marked acantholysis in this
results in bullous impetigo. example.
Staphylococcal strains also produce toxic shock syndrome toxin (TSST-1)
and a variety of enterotoxins (A–E). These are more frequently associated
with staphylococcal scarlet fever and the toxic shock syndrome.19,24 Differential diagnosis
The toxin in both SSSS and bullous impetigo causes a split in the epidermis
The main clinical differential diagnosis is from toxic epidermal necrolysis
at the level of the granular layer (Fig. 18.103). Ultrastructurally, the level of
(TEN), a severe variant of erythema multiforme usually due to a drug reac-
separation is in the midgranular layer.25 It is associated with separation of the
tion. This, however, is uncommon in children. In TEN the skin changes are
cell membranes at the desmosomes, and the interdesmosomal regions appear
very widespread and mucosal involvement is common, whereas SSSS extends
less dense.26 The cells on either side of the cleft appear normal. It has been
from the face and flexures and does not involve mucosae. The contrasting
shown that the epidermolytic toxins (ETA and/or ETB) act as serine proteases
histology of the two conditions can be used with a frozen section technique
and bind desmoglein 1, a desmosomal adhesion molecule.20,21 The cleavage
to give a rapid diagnosis:4,5
and subsequent inactivation thereof induces blistering.21,24
• TEN is characterized by a subepidermal blister with a necrotic epidermal
Histologically, the clefts through the granular layer of the epidermis in
roof and a moderately intense lymphocytic infiltrate in the dermis.
SSSS are associated with only a scanty inflammatory infiltrate in the epider-
• SSSS is characterized by separation through the granular cell layer.
mis or dermis and there may be some dermal edema and dilatation of the
Alternatively, a Tzanck smear can be used, which reveals necrotic kerati-
superficial vascular plexus. The adjacent epidermis does not show necrosis.
nocytes with inflammatory cells in TEN and viable acantholytic keratinocytes
Acantholysis is variably present (Fig. 18.104).
without inflammatory cells in SSSS.
Erysipelas and cellulitis

Clinical features
Erysipelas
Erysipelas is classically a S. pyogenes (group A β-hemolytic streptococcal)
infection of the skin of the face, characterized by a sharply outlined edema-
tous, erythematous, tender, and painful plaque (Fig. 18.105). The outer mar-
gin is elevated and contrasts with the adjacent normal skin. Towards the edge
of the lesion there may be vesicles and hemorrhagic bullae. Other sites com-
monly affected include the feet and hands. Although S. pyogenes is the most
common organism, it is not always possible to culture it, and other strepto-
cocci (group C or G) or S. aureus may occasionally be isolated.1–4
The classical presentation of erysipelas is most often on the face, but it
has been suggested recently that the features of this condition are chang-
ing because it is becoming more common and is predominantly affecting the
lower limbs.4 A seasonal variation in incidence is not uniformly found.
The superficial infection of erysipelas is associated with a fever and mal-
aise. It is similar in its presentation, etiology and associated symptoms to
cellulitis, a spreading infection affecting deeper tissues. This lesion is again
clearly demarcated, hot, red, and painful, but without the elevated margin
Fig. 18.103
Staphylococcal scalded
of erysipelas. An associated lymphangitis and lymphadenitis are common.
skin syndrome: The lesions may progress to pustulation, ulceration, and necrosis; the last
vesiculation occurs at the may involve underlying fascia and muscle, resulting in necrotizing fasciitis.5
level of the granular cell Osteoarticular complications such as bursitis, arthritis, tendinitis, and osteitis
layer. have been reported.6
Erysipelas and cellulitis 795
Cellulitis more aggressive forms of cellulitis it is likely that other organisms (certainly
Cellulitis is similar to erysipelas, but tends to involve the deeper tissues and S. aureus and some anaerobes) may be causative or synergistic.14 A syner-
is seen most often on the legs, where it complicates tinea pedis or chronic gistic role for Staphylococcus aureus (especially methicillin-resistant strains)
lymphedema (Fig. 18.106).7,8 Other potential risk factors include diabe- and S. pyogenes has been implicated in the development of bullous erysipe-
tes mellitus, leukemia, postsaphenous venectomy, and peripheral vascular las.15 Group G streptococci predominated over group A β-hemolytic strepto-
disease. Patients with dry skin may also be susceptible.9 Cellulitis is char- cocci in a recent Finish series of 90 patients with acute cellulitis.16 There have
acterized by an expanding area of erythema. Involvement of lymphatics in been rare reports of severe cellulitis due to organisms such as S. pneumoniae,
both erysipelas and cellulitis is characteristic, resulting in the edema which Haemophilus influenza, and Nocardia otitidiscaviarum.17–19 In those forms of
is sometimes associated with vesiculation (Fig. 18.107); infective damage cellulitis in which necrosis is a more prominent feature bacterial toxins are an
to lymphatics in cellulitis may be the reason this condition can become important mechanism.
recurrent. Histologically, the conspicuous features of erysipelas and cellulitis are der-
The term hemorrhagic cellulitis has been applied to an uncommon mal edema and lymphatic dilatation. There is also a diffuse, heavy neutrophil
clinical syndrome caused by Gram-positive or Gram-negative organisms infiltration with a limited localization around blood vessels. Vascular and
of noncutaneous origin. Patients manifest with the abrupt onset of pain- lymphatic dilatation and red cell extravasation are variable features. In later
ful erythema on the lower extremities, followed by dermal hemorrhage stages some lymphocytes and histiocytes are also seen and granulation tis-
and sloughing of the overlying epidermis.10 There is usually a satisfac- sue may be present deep to the zone of subepidermal edema. When clinical
tory response to a combination of antibiotics and corticosteroid therapy. vesicles or bullae are noted, there is a corresponding severe papillary edema
Virulent marine bacteria such as Vibrio vulnificus may result in this form merging with subepidermal vesiculation.20
of bullous and hemorrhagic cellulitis; the disease carries an estimated mor- In hemorrhagic cellulitis the bacterial lipopolysaccharide-induced or bac-
tality of 15%.11 terial mitogen-induced release of tumor necrosis factor alpha (TNF-α) is
thought to result in injury to endothelial cells and epidermal keratinocytes.
Pathogenesis and histological features DNA fragmentation and cell lysis may be the consequence of neutrophil
Minor trauma to the skin is important in the development of both erysipe- degranulation and anti-DNase activation.10 Digestion of vascular basement
las and cellulitis, but peripheral vascular disease, diabetes, lymphedema, and membrane as a result of V. vulnificus metalloprotease production leads to the
alcohol abuse are additional predisposing factors. formation of hemorrhagic bullae.21 Histologically, there is necrosis of epider-
In both erysipelas and cellulitis, S. pyogenes is the most common organ- mal keratinocytes, necrotizing vasculitis affecting dermal blood vessels, and
ism and the lesions are initiated by inoculation of minor abrasions or splits in large numbers of bacteria.22
the epidermis.12 Proliferation of the organisms is associated with the produc- It is important to remember that not all cases of cellulitis are bacte-
tion of enzymes (streptolysins, deoxyribonuclease B, hyaluronidase) which rial in origin; deep fungal infections such as cryptococcosis and aspergil-
may be detected in rising titers and may therefore be useful diagnostically.13 lus may present with cellulitis in immunocompromised hosts.23 Appropriate
These enzymes are also important in facilitating the extension of the bacte- histochemical stains and the referral of additional specimens for microbio-
ria in the skin. Lymphatic involvement with obstruction is common, result- logical examination should facilitate correct identification of the etiological
ing in edema, and is associated with lymphangitis and lymphadenitis. In the agent.
Fig. 18.105 Fig. 18.106 Fig. 18.107

Erysipelas: characteristic sharply demarcated Cellulitis: note the widespread erythema. The lower leg Cellulitis: marked edema has resulted in vesiculation.
erythematous and edematous plaque. By courtesy of is a characteristic site. By courtesy of R.A. Marsden, By courtesy of R.A. Marsden, MD, St George's
J.C. Pascual, MD, Alicante, Spain. MD, St George's Hospital, London, UK. Hospital, London, UK.
Necrotizing fasciitis
Clinical features
Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, and poten-
tially fatal bacterial infection of the subcutaneous soft tissues. In recent years
there has been a dramatic resurgence in the number of reported cases.1–3 NF
may evolve following a surgical procedure (e.g., esthetic liposuction, caesar-
ean section, laparoscopic appendicectomy, excision of a skin lesion or even
cardiac catheterization), minor trauma, seemingly insignificant scratches, in
the presence of a chronic wound, or even in apparently intact skin.4–9 NF
occurs predominantly in middle-aged individuals, although the pediatric pop-
ulation may also be affected.1,10–14 Patients with underlying diabetes mellitus
and iatrogenic immunosuppression are particularly susceptible.10,15–19 NF is
a well-recognized complication of childhood varicella.13,14,20 Many reported
cases have developed after intramuscular injection of nonsteroidal antiinflam-
matory drugs, which may in turn mask the symptoms of evolving NF.10,21–24
Rare cases have occurred following the bite of a spider.25 NF may be a rare
complication of fistulating Crohn's disease.26 Reported mortality ranges from
9.4% to 53%.2,3,10,13,18,19 An increased fatality rate may be encountered in the Fig. 18.108
elderly and in those with worsening symptoms and signs within the first 48 Necrotizing fasciitis: this
hours of hospital admission.15 example has resulted in
exposure of muscle and
Although group A β-hemolytic streptococci (so-called ‘flesh-eating’ bacte-
tendons. By courtesy
ria) were first recognized as a prime etiological agent, a number of other aero- of R.A. Marsden, MD,
bic and even anaerobic pathogens have been implicated.1,27,28 It has become St George's Hospital,
increasingly apparent that NF very often is a polymicrobial condition. In London, UK.
some series, Staphylococcus aureus is the most frequently cultured organ-
ism.28,29 Less often, other streptococci have been identified; these include
group B and group G β-hemolytic streptococci, Streptococcus pneumoniae
and anaerobic streptococci (Peptostreptococcus spp.).22,28,30–32 Other bacte-
ria implicated include marine organisms (Vibrio vulnificus, V. parahaemo-
lyticus, Photobacterium damsela), members of the family Enterobacteriaceae, Necrotizing fasciitis due to invasive group A β-hemolytic streptococcal infec-
Serratia marcescens, Pseudomonas spp., Clostridium spp. and Bacteroides tion is associated predominantly with M types 1 and 3, which produce either
spp.11,17,28,33–41 Meleney's postoperative progressive synergistic gangrene pyrogenic exotoxin A or B, or both.27 Tissue invasion is facilitated by CD44-
(Meleney's gangrene) is synonymous with polymicrobial NF arising as a com- mediated cell signaling with subsequent manipulation of the host cytoskel-
plication of surgical trauma.42 The latter condition may be clinically indistin- eton.59,60 Superantigens and Th1 cytokines appear to play a critical role in
guishable from postsurgical cutaneous amebiasis.42,43 severe group A invasive streptococcal infections.61 Streptococcal cysteine pro-
The clinical presentation may be fulminant, acute or subacute.10 NF com- tease SpeB inactivates the antimicrobial peptide cathelicidin LL-37 at the bac-
mences as an ill-defined area of erythema, accompanied by tenderness, swell- terial surface.62 Impaired recruitment of polymorphonuclear leukocytes to the
ing, and increased temperature.44 It is, therefore, not uncommon for evolving site of the infection has been linked to the streptococcal peptidase ScpC which
NF to be mistaken for cellulitis or an insignificant wound infection, especially degrades IL-8.63 Protein S deficiency may be responsible for the necrosis.64
when the hallmark cutaneous necrosis is not established. This may result in Staphylococcus aureus may potentiate the β-hemolytic streptococcal infec-
a potentially life-threatening delay in diagnosis and aggressive surgical deb- tion in NF.43
ridement.45 The clinical features of established NF include severe pain, indu- An adequately sized specimen including subcutaneous soft tissue is essential
rated edema, skin necrosis, cyanosis, bullae (which may be hemorrhagic, for diagnosis. The histological appearances are those of a severe necrotizing
especially in cases caused by Vibrio spp.), crepitation, muscle weakness, and process with edema, necrosis, and inflammation involving skin and subcuta-
malodorous exudates (Fig. 18.108).19,23,35,44 Anesthesia may be a late sign.44 neous tissue, including fascial planes (Figs 18.109, 18.110).65 Deep biopsies
Patients often have other systemic manifestations of severe sepsis, including or debridement specimens containing underlying skeletal muscle may exhibit
hypotension, tachycardia, tachypnea, oliguria, and mental confusion.23,46 In concomitant myonecrosis.1 Vascular thrombosis is encountered at all levels,
NF caused by streptococcal species, the latter signs are usually attributable and secondary vasculitic alterations are not uncommon. Hyaline necrosis of
to streptococcal toxic shock syndrome.21 Radiographs may reveal gas in the sweat glands has been described.65 The presence of large numbers of bacteria
affected soft tissues.46 NF occurs mainly on the extremities, although almost often results in diffuse basophilia of the tissue on low-power examination.
any site may be affected, including the abdominal wall, chest wall, eyelids A Gram or Brown-Hopps' stain confirms the latter (Fig. 18.111).
and periorbital region, and the head and neck region.15,47–50 Periumbilical NF Although the histological picture is sufficiently distinctive to facilitate
may occur in newborn infants.12,14 The Waterhouse-Friderichsen syndrome is a diagnosis of NF, microbiological examination (including aerobic and
a potential complication of NF.51 anaerobic tissue culture) is of paramount importance in the identification
Fournier's gangrene is a clinical variant of NF which involves the penis, of the specific infective etiological agent(s). Intraoperative frozen section
scrotum, perineum, and abdominal wall in men and (less often) the vulva in has a particularly useful role to play, not only in early diagnosis but also
women.52–55 An obliterative endarteritic process affecting the small branches in assessing the viability of surgical margins at the time of debridement.66
of the superficial branch of the internal pudendal artery may play a key PCR detection of streptococcal pyrogenic exotoxin B may be useful in
pathogenetic role.56 Because of a response to corticosteroids, Fournier's gan- confirming group A streptococcal infection when cultures are negative or
grene may be perceived as a localized vasculitis.57 In addition to the usual unavailable.67
risk factors such as diabetes mellitus or immunosuppression, rare associa-
tions include vasectomy or unhygienic ritual circumcision.54 The reported Differential diagnosis
mortality of this polymicrobial synergistic necrotizing infection is in the Necrotizing (gangrenous) cellulitis has a similar etiopathogenesis to NF but
order of 16–20%.52,54,58 Extent of infection is a significant predictor of clinical shows no extension of the necrotizing inflammatory process into subcutane-
outcome.58 ous tissue planes. This diagnosis should be made with caution and only when
Infective folliculitis 797
Fig. 18.109 Fig. 18.111

Necrotizing fasciitis: there is intense acute inflammation of the dermis and Necrotizing fasciitis: innumerable Gram-positive cocci are present.
subcutaneous fat.
there is a complete absence of subcutaneous involvement in a specimen that

is of sufficient depth. NF is invariably associated with necrotizing inflamma-
tion of the dermis. Furthermore, necrotizing cellulitis may be a harbinger of
impending NF.
Tissue autolysis with bacterial overgrowth may closely mimic NF, espe-
cially if tissue is obtained from a patient with a relatively minor cutaneous
infection and the specimen was not placed in the appropriate formalin fixa-
tive prior to submission to the laboratory.
NF is distinguished from pyoderma gangrenosum and Sweet's syndrome
by the absence of true tissue necrosis and demonstrable bacterial organisms
by culture or appropriate stains in the latter two conditions. Although there
is frequent dermal infiltration by polymorphonuclear leukocytes in pyoderma
gangrenosum and invariable neutrophilic dermatosis in Sweet's syndrome,
the acute inflammatory changes in both conditions are centered on the dermis
rather than the subcutis. Vasculitic alterations may occur in both pyoderma
gangrenosum and NF but are usually absent in Sweet's syndrome.
Infective folliculitis
A
Clinical features
Infection of hair follicles is probably the commonest form of skin infection.
It is usually due to S. aureus (impetigo of Bockhart) and, although disfig-
uring, is self-limiting.1–7 Pustular folliculitis usually implies infection of the
ostium and upper part of the follicle. It presents as numerous small red and
tender pustules, which discharge pus and quickly resolve without scarring
(Fig. 18.112). Staphylococcal carriers tend to have recurrent infections.8
The role of community-acquired methicillin-resistant S. aureus in cutaneous
infections, including folliculitis, has been emphasized in the recent literature.9
Pseudomonas aeruginosa is a well-recognized cause of epidemics of fol-
liculitis associated with swimming pools, whirlpools or spa baths.10–12 These
shared facilities can be infected by Pseudomonas if they became alkaline and
if the chlorine content drops. Nevertheless, moisture and occlusion are neces-
sary to affect normal skin. For this reason lesions of this type are found only
under the area covered by bathing costumes. Other Gram-negative bacteria
such as Klebsiella spp., Escherichia coli, Enterobacter spp., and Proteus spp.
have been implicated in the pathogenesis of folliculitis in patients receiving
B long-term antibiotic therapy for treatment of acne or rosacea.13 Extensive
folliculitis may be an early manifestation of HIV infection.1 Micrococcus
Fig. 18.110 spp., which are considered to be commensal organisms, may be a cause of
(A, B) Necrotizing fasciitis: there is an almost pure neutrophil infiltrate with folliculitis in patients with HIV infection.14 Folliculitis due to Acinetobacter
necrosis. baumanii has been reported in a patient with AIDS.15
Fig. 18.114
Furuncle: multiple
Fig. 18.112 erythematous nodules
Folliculitis: characteristic small pustules with surrounding erythema. By courtesy of in the axilla, which is a
R.A. Marsden, MD, St George's Hospital, London, UK. commonly affected site.
The lesions are exquisitely
painful. By courtesy
London, UK.
Fig. 18.113
Furuncle: early lesion characterized by edema and erythema. By courtesy of the
Fig. 18.115
Furuncle: note the large swelling on the thigh. This patient was HIV positive.
A furuncle or boil is a more exuberant form of suppurative folliculitis. It By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
is common in young adults and usually affects the skin of the face, neck, but-
tocks, and axillae (Figs 18.113–18.115).1 Lesions can be up to 2 cm across
and the inflammation is not confined within the follicle, but is associated with
much surrounding erythema and often systemic symptoms. After discharge of Pathogenesis and histological features
the pustular necrotic core the lesion heals rapidly, but with scarring. A deep fol- Many cases of superficial suppurative folliculitis are associated with S. aureus.
liculitis due to S. aureus may affect the beard area; this form is termed sycosis The infection is not due to a break in the epithelium, but growth occurs with
or folliculitis barbae. the ostium of the follicle and may progress more deeply around the hair shaft.
A carbuncle is a variant of a furuncle with multiple tracks and routes of There is an associated accumulation of neutrophils, forming an abscess asso-
discharge. It is most commonly seen in older men and may be associated with ciated with spongiosis and infiltration of the adjacent follicular epithelium.
systemic symptoms.1,5 The superficial suppurative folliculitis may discharge through the ostium
Acute paronychia is comparable to a folliculitis in that it is a painful suppu- and rapidly resolve. Alternatively, it may progress more deeply and rupture
rative infection of the nail fold, most commonly caused by S. aureus; it heals through the follicular epithelium; the abscess then extends into perifollicular
rapidly on release of the pus (Fig. 18.116). A rare scarring alopecia in which dermis and surrounds the whole follicle. The follicular epithelium and hair
S. aureus has been implicated is termed folliculitis decalvans.16 Although the shaft with pus then form the purulent necrotic core of the furuncle or boil.
scalp is predominantly affected, lesions may also be found in the axillae and Healing is preceded by a lymphohistiocytic or even granulomatous phase and
pubic region (Fig. 18.117). is followed by scarring and loss of hair in the involved area. A carbuncle is
Meningococcal septicemia 799
c ommonly in black than in white men. Although it was initially thought

not to develop in females, rare cases have been reported.1–3 It presents in the
early stages with inflamed papules and pustules, but no consistent organisms
are found. Patients may complain of itching, burning or pain and advanced
lesions may be foul smelling.1 Each lesion is complicated by dense scarring,
producing a keloid-like appearance. Scarring alopecia is a complication.2 The
condition has recently been reported in Caucasian organ transplant recipi-
ents on cyclosporin therapy.4 Isolated cases occurring in association with
keratosis follicularis spinulosa decalvans have been documented in recent
publications.5,6

The pathogenesis is unknown. Any bacteria identified probably represent a
secondary phenomenon. It is doubtful whether poor hygiene is a factor. There
may be an element of pseudofolliculitis (see below) since the condition is
common in Afro-Caribbeans and Africans and is worsened by close shaving
of the neck.1,7–9 The use of pomades and wearing tight collars is said to exac-
erbate the condition.1 The term acne keloidalis is a misnomer, as the disorder
has nothing to do with acne vulgaris or its variants.
The follicle, which may contain pus extending through the epithelium, is
Fig. 18.116 initially surrounded by a lymphocytic and neutrophil infiltrate; later there are
Acute paronychia:
large numbers of plasma cells. The perifollicular inflammation is maximal at
pus and erythema are
present. By courtesy the level of the isthmus and lower infundibulum.2,10 The condition is more often
of E.E. Gluckman, MD, seen at a later stage, however, when there is marked fibrosis accompanying
King's College Hospital, free, broken hair shafts, many of which are surrounded by a foreign body giant
London, UK. cell reaction. Hyalinization as seen in a true keloid is only very occasionally a
feature. Complete loss of the sebaceous glands is a frequent occurrence.2,10
Pseudofolliculitis
Clinical features
Pseudofolliculitis (pseudofolliculitis barbae) presents with an acneiform pap-
ular and pustular eruption on the beard area. Comedones are not a feature. It
develops as a consequence of the reentry of a terminal hair shaft through the
epidermis and occurs most often in males with curly hair, but is also seen in
women in the pubic region following cosmetic shaving.1–4 Pseudofolliculitis
occurs predominantly in patients of African, African-American, and Hispanic
origin.2 The pathogenesis appears to be multifactorial, and seems to relate
to the shape of the hair follicle, the hair cuticle, and the direction of hair
growth.2 The penetration is facilitated by the sharp ends produced on hairs
by shaving and the curliness of the hair bringing the cut end back into con-
tact with the skin surface.4 Alternatively, the penetration may occur laterally
through the superficial part of the follicular infundibulum following partial
retraction of the hair after close shaving. A single-nucleotide polymorphism
in the keratin K6hf gene has been implicated in the pathogenesis of pseudo-
folliculitis.5 A hypertrophic form of the disease has been described in renal
Fig. 18.117 transplant recipients.6
Folliculitis decalvans: there is severe scarring with alopecia. Erosions, crusting,
and pustules are seen at the hairline. By courtesy of M.M. Black, MD, Institute of
The process is not a true folliculitis, and is not usually associated with infec-
tion. The reentry of the hair shaft provokes a foreign body granulomatous
associated with more persistent suppuration, much more fibrosis and granu- reaction with accompanying fibrosis. The inflammation is predominantly his-
lation tissue. Panton-Valentine leukocidin-producing strains of S. aureus have tiocytic with occasional multinucleate giant cells. Secondary infection may
been linked to the evolution of deep-seated, often multiple furuncles.17 result in superimposed suppuration. Resolution occurs rapidly, with slight
Although most of the suppurative forms of folliculitis are due to S. aureus, scarring, once the hair shaft is removed.
other causal conditions include dermatophytosis, herpes simplex, and syphilis;
the features of these infections are described under the appropriate headings
elsewhere in this chapter. Meningococcal septicemia
Clinical features
Folliculitis keloidalis nuchae Meningococcal septicemia is due to the Gram-positive diplococcus Neisseria
meningitidis.1–4 In its acute form this is a very serious condition with a high
Clinical features mortality, which affects children in seasonal epidemics. It is spread via drop-
This deep and scarring folliculitis and perifolliculitis (sometimes known let inhalation from upper respiratory tract infections. Meningitis is the most
as acne keloidalis or acne keloidalis nuchae) occurs on the back of the frequently encountered manifestation of meningococcal infection. Children
neck (lower occipital/nuchal region) of postpubertal males. It occurs more with acute meningococcal septicemia develop widespread purpura that shows
a predilection for the trunk and limbs. Ecchymoses may also be a feature. In ustulation, and eventually necrosis.4 In the dermis the histological features
p
the more chronic variant (chronic meningococcemia), patients present with are essentially those of a neutrophil-mediated acute vasculitis, often accom-
vasculitis-like lesions, particularly nodules, and palpable purpura.5 panied by thrombosis.10 Very occasionally Gram-negative diplococci may be
identified.
The histological features are essentially those of a leukocytoclastic vasculitis.6
Superimposed DIC may also be present. The hemorrhagic skin lesions and
Plague
vascular thromboses are attributable to upregulation of tissue factor lead-
ing to coagulation, and by inhibition of fibrinolysis by plasminogen activator
Clinical features
inhibitor.7 Impairment of the protein C anticoagulation pathway also plays Plague is an acute, febrile infectious disease caused by Yersinia pestis, a non-
an important role.8 motile, bipolar Gram-negative aerobic bacillus and one of the most deadly
Diplococci may be demonstrable in Gram-stained sections, especially pathogens known to man.1–5 The disease has a high incidence in South
in biopsies obtained from purpuric lesions.6 Culture or Gram staining Africa, Madagascar, the Far East, and parts of India. Foci of plague have
of aspirates or biopsies of skin lesions may facilitate early diagnosis. 9 also been reported from southwestern states of the USA and in parts of South
Diagnosis can also be confirmed on skin biopsy with the aid of a PCR- America.1,2,6–8 Rodents act as the reservoir, and the infection is usually trans-
based method.10 mitted to humans via the bite of a flea; aerosol spread may also occur, leading
to pneumonic plague.1,3–5 Y. pestis is well recognized as a potential bioweapon
and bioterrorism agent.5 There are three distinct clinicopathological forms
Gonorrhea of the disease: bubonic plague, primary pneumonic plague, and primary
septicemic plague.1–4
Clinical features
This common venereal disease is due to infection with the Gram-negative Bubonic plague
intracellular diplococcus Neisseria gonorrhoeae, which especially affects Bubonic plague accounts for the vast majority of cases. After a short incuba-
the mucous membranes. In males this results particularly in purulent ure- tion period of approximately 2–4 days, the disease manifests abruptly with
thritis, although gonococcal proctitis and oropharyngitis may also be seen. pyrexia, chills, tachycardia, and tachypnea, and the formation of a so-called
Females most often develop endocervicitis. Urethritis and proctitis can also bubo – a painful, pathologically enlarged unilateral group of infected lymph
be features.1 nodes, usually in the groin or axilla (Fig. 18.119).1 Cervical and axillary
Systemic gonococcal infection most commonly affects the skin, but may buboes are more common in children than in adults.7 Septicemia and second-
also result in arthritis and less often endocarditis or meningitis.1–3 Patients ary pneumonic plague may follow in untreated cases. Minor (‘ambulatory’)
present with small numbers of erythematous macules that progress to forms of bubonic plague also exist.1
painful papular, petechial or pustular lesions that particularly affect the
distal limbs (Fig. 18.118).2,4 They measure from 1 to 2 mm up to 2 cm Primary pneumonic and primary septicemic plague
in diameter. Lesions may appear frankly vasculitic.5 Cutaneous lesions Primary pneumonic plague is acquired by inhalation of the organisms,
can be a presenting feature of disseminated infection during pregnancy.3,6 whereas primary septicemic plague tends to occur after the bite of an infected
Rarely, however, patients present with primary cutaneous (genital and flea on the head and neck region. Untreated, both of these forms of plague
extragenital) involvement.2,4 Cellulitis, pustules, ulcers, and furuncle-like carry a mortality of around 90%.2
lesions have been documented.7,8 Pyogenic granuloma-like lesions of the
penile shaft have also been described.9 Primary digital gonorrhea has been Cutaneous manifestations
recorded.7
Cutaneous manifestations of Y. pestis infection are seen predominantly in
bubonic plague. A small vesicle, pustule, papule or necrotic lesion may
Pathogenesis and histological features develop at the site of the flea bite. The skin overlying the bubo is ery-
Disseminated lesions show variable epidermal changes ranging from edema thematous and edematous and may undergo hemorrhage and necrosis,
accompanied by a neutrophil infiltrate with purpura, to vesiculation,
Fig. 18.119
Bubonic plague: note the
inguinal lymphadenopathy
(bubo). By courtesy
of J. Frean, MD, and
the late M. Isaäcson,
MD, University of
Fig. 18.118 Witwatersrand,
Gonococcemia: pustules are commonly found on the hands and feet. By courtesy Johannesburg, South
of R.N. Thin, MD, St Thomas' Hospital, London, UK. Africa.
Cutaneous anthrax 801
resulting in the formation of fistulae.1,2 Roseolar, scarlatiniform, vesico-

pustular, and erythema multiforme-like eruptions may occur elsewhere
on the body.1 Petechial hemorrhages and ecchymoses characterize severe
cases. Cutaneous ulceration and necrosis may ensue, hence the term ‘black
death’.2
The lymph nodes comprising the buboes show severe acute hemorrhagic
lymphadenitis in the presence of large amphophilic or ‘ground-glass’ aggre-
gates of bacilli. Their characteristic ‘safety-pin’ appearance is discernible on
sections stained with the Gram's or Giemsa methods.1,2 Extranodal extension
results in ulceration of the overlying skin. Subsequent septicemic illness may
be complicated by DIC. In the skin the latter manifests with intradermal hem-
orrhage, thrombotic vascular occlusion, and multiple cutaneous infarcts.2 The
diagnosis may be confirmed by microscopy, culture, immunofluorescence,
enzyme-linked immunosorbent assay or PCR.1–4,7 An immunohistochemical
method for detection of the organism in formalin-fixed, paraffin-embedded
tissue has been described.9
Fig. 18.121
Cutaneous anthrax Anthrax: multiple lesions on the forearm. By courtesy of J. Frean, MD, and the late
M. Isaäcson, MD, University of Witwatersrand, Johannesburg, South Africa.
Clinical features
Anthrax is a zoonotic infection caused by Bacillus anthracis, an encapsu- is often pronounced edema of the surrounding skin, sometimes accompanied
lated, spore-forming, Gram-positive bacillus.1,2 Although the condition is by the formation of bullae.1 Lymphadenitis is sometimes seen. Septicemia may
relatively uncommon in humans, epidemic outbreaks still occur in tropical arise in untreated cases; this carries a mortality of 10–20%.1,2 A rare form of
and subtropical regions of the world (including Africa and South America), the disease termed malignant edema presents with severe, rapidly spreading
southern Europe, the Middle East, and India.1–5 Anthrax is very rarely seen edema, lymphangitis, lymphadenitis, and systemic symptoms. Hemorrhagic
in developed countries.6–8 Cutaneous anthrax accounts for more than 95% and necrotic vesicles may evolve in these cases.1
of cases; pulmonary and gastrointestinal forms account for the remainder,
and are associated with a high mortality.1 The condition is usually acquired
after contact with infected animals (herbivores) or contaminated animal Pathogenesis and histological features
products.4 It has also been described in rural Turkish children who were sub- B. anthracis is associated with potent virulence factors, namely a poly-D
jected to the ritual smearing of cow's blood on their foreheads.9 Under ideal glutamic acid capsule and a plasmid-encoded protein exotoxin consisting of
conditions, spores may survive in the soil or in animal products for many three components: edema factor, protective antigenic factor, and lethal fac-
years.1 Recently there has been renewed interest in the organism as an agent tor.2,11 Edema factor leads to increased vascular permeability via the produc-
of bioterrorism.8,10 tion or release of inflammatory mediators, including neurokinins, prostanoids
Cutaneous anthrax occurs after inoculation of B. anthracis into abraded and histamine.12
skin. An erythematous macule or papule develops after an incubation period The histological picture is dominated by massive subepidermal edema
of 2–3 weeks. This later evolves into a pruritic vesicle. A characteristic black (Fig. 18.122).6,13 Intraepidermal edema results in coalescent intercellular
eschar develops after breakdown of the blister (Figs 18.120, 18.121).1 There vacuoles.1 The epidermis is often attenuated. The dermis is expanded by a
Fig. 18.120 Fig. 18.122

Anthrax: cutaneous disease is the commonest manifestation in humans. This black Anthrax: there is massive subepidermal edema with subepidermal vesiculation.
crusted lesion is typical. By courtesy of J. Frean, MD, and the late M. Isaäcson, MD, Reproduced with permission from Mallon E, McKee PH. Extraordinary case report:
University of Witwatersrand, Johannesburg, South Africa. cutaneous anthrax. American Journal of Dermatopathology. 1977; 19: 79–82.
dense inflammatory infiltrate consisting of large numbers of polymorpho-

nuclear leukocytes, admixed with lymphocytes and histiocytes. The process
often extends into subcutaneous fat.6 Vasodilatation may be prominent.
Hemorrhage and fibrin deposition occur in the deep dermis and subcutis
(Fig. 18.123). Thrombotic vascular occlusion and fibrinoid necrosis of blood
vessel walls may be encountered in the deep dermis and subcutaneous fat (Fig.
18.124). Gram stain will reveal considerable numbers of large Gram-positive
bacilli in the superficial dermis (Fig. 18.125).6 The diagnosis is confirmed by
culture. Serological investigations are also available. Immunohistochemical
methods of detection may be employed on tissue specimens.2
Brucellosis
Clinical features
Brucellosis is a zoonotic infection by Brucella spp. such as B. meliten-
sis, B. abortus, B. canis, and B. suis.1–3 The organism is a Gram-negative
bacillus and infection is acquired either by ingesting contaminated,
Fig. 18.125
Anthrax: numerous elongated Gram-positive bacilli are present. Reproduced with
permission from Mallon E, McKee PH. Extraordinary case report: cutaneous
anthrax. American Journal of Dermatopathology. 1977; 19: 79–82.
unpasteurized milk/milk products, or by handling infected animal prod-

ucts (contact brucellosis). Human-to-human transmission does not occur.
Brucellosis results in either an acute febrile illness or a chronic systemic
disease characterized by fever, malaise, sweats, arthralgia, myalgia, and/
or hepatosplenomegaly.1–3 The mortality is low and most patients recover
within 3 months.3
Cutaneous manifestations occur in approximately 6% or less of cases;
however, this figure approached 14% in a recent series from Turkey.4–7
A number of cutaneous manifestations have been recorded, including a
disseminated papulonodular eruption, a diffuse maculopapular rash,
erythema nodosum-like subcutaneous nodules, purpura, leukocytoclastic
vasculitis, erythema multiforme, urticaria-like papules and plaques, multi-
ple abscesses, cutaneous ulcers, ecchymoses and (rarely) livedo reticularis,
Fig. 18.123 palmar erythema or a even a large mass mimicking a soft tissue tumor.3–6,8–12
Anthrax: marked fibrin deposition is evident. Reproduced with permission from Vasculitic skin lesions may form part of an infection-induced systemic
Mallon E, McKee PH. Extraordinary case report: cutaneous anthrax. American thrombotic microangiopathy mimicking Henoch-Schönlein purpura.13,14
Journal of Dermatopathology. 1977; 19: 79–82. There is a single case report of Brucella-associated Stevens-Johnson syn-
drome.15 Contact brucellosis manifests with erythema or pruritus, usually
on the forearm or hand. In some cases this may progress to a follicular,
vesicular or pustular eruption.3 A rare case of contiguous skin involve-
ment secondary to underlying Brucella chronic osteomyelitis was recorded
recently.16 A factitious case of brucellosis caused by autoinoculation has
also been reported; the patient developed bacteremia and ulcerating
cutaneous abscesses.17
The histological features vary according to the type of cutaneous lesion
biopsied. Biopsies obtained from the erythematous papular lesions show
a perivascular and periadnexal infiltrate of lymphocytes and histiocytes,
sometimes accompanied by epithelioid histiocytes and multinucleated
giant cells.4 Erythrocyte extravasation is sometimes seen, and inflamma-
tory cells may infiltrate the overlying epidermis.8 Erythema nodosum-like
nodules are characterized by a perivascular lymphohistiocytic infiltrate
centered on the deep dermis and superficial subcutis.4,9 There is associ-
ated vascular endothelial swelling and luminal thrombosis, sometimes
with foci of necrosis. Accompanying granulomatous inflammation is not
uncommon.8 Erythema multiforme lesions and leukocytoclastic vascu-
Fig. 18.124 litic lesions exhibit the usual histological changes associated with these
Anthrax: thrombosed vessels are present. Reproduced with permission from conditions.
Mallon E, McKee PH. Extraordinary case report: cutaneous anthrax. American Brucella organisms are rarely visualized in histological material. The diag-
Journal of Dermatopathology. 1977; 19: 79–82. nosis is therefore confirmed by culture, serology or PCR.1,3,4,8,18
Diseases caused by Bartonella species 803
Diseases caused by Bartonella species

Cat scratch disease
Clinical features
Cat scratch disease is a not uncommon, usually self-limiting illness which,
as its name implies, usually follows (after 3–5 days) a scratch or bite by a
cat (usually a kitten).1–7 On rare occasions, it has been reported following
a similar injury caused by a dog or even by a monkey.4 It occurs equally in
males and females, most often during the first two decades. Cat scratch dis-
ease shows seasonal variation, occurring usually in autumn and winter.1 The
causative agent is Bartonella henselae (formerly Rochalimaea henselae), a
weakly Gram-negative bacillus measuring 1–2 μm in length.5,6 The condition
was first described in 1950, yet the nature of the infective etiological agent
remained elusive until recently.6 In the past, a variety of infectious agents had
been suggested as responsible for cat scratch disease, including mycobacteria,
Chlamydia, herpes-like viruses and, more recently, Afipia felis.5,8 The cat rep-
resents the primary reservoir for the bacillus in addition to being its principal
Fig. 18.126
vector.9 Although transmission among cats is via the cat flea, the latter does
Cat scratch disease: an irregular ill-defined focus of necrobiosis is surrounded by a
not appear to play a direct role in transmission to humans.5,6 nodular lymphocytic infiltrate.
The primary skin lesion – a macule, papule, vesicle, pustule or nodule –
develops most commonly on the arm or hand, followed by the head, leg, con-
junctiva, trunk or neck, in decreasing order of frequency. Sometimes more
than one member of a family may be affected. The cutaneous lesions measure
1–5 mm or more in diameter and may sometimes resemble an insect bite.1
Other rare cutaneous manifestations include a nonpruritic macular or
maculopapular rash, erythema nodosum, urticaria, erythema marginatum,
erythema annulare, and thrombocytopenic purpura. A case with cutaneous
lesions resembling those of Sweet's syndrome has been reported.10 Fever and
malaise are occasional symptoms. Less common additional features include
headache, nausea, vomiting, arthralgia, and splenomegaly.
Patients invariably develop lymphadenopathy in the drainage region, usu-
ally within 1–3 weeks of the initial lesion. The enlarged nodes are tender
and often persistent, with lymphadenopathy lasting up to 2 months or more.
Suppuration is not uncommon. Conjunctival or eyelid lesions may be asso-
ciated with preauricular lymphadenopathy (Parinaud's syndrome).11 The
only consistently abnormal laboratory function test is a moderately raised
erythrocyte sedimentation rate (ESR). Purported cases of disseminated cat
scratch disease occurring as a manifestation of the acquired immunodefi-
ciency syndrome (AIDS) probably represent examples of advanced bacillary
angiomatosis (see below).12,13
Atypical manifestations of cat scratch disease may occur in as many as
25% of cases.5 These include nonthrombocytopenic purpura and bone, liver,
spleen, pulmonary, endocardial, and/or neurological involvement, presum- Fig. 18.127
ably due to bacteremia.1,5 A vasculitic pathogenesis has also been proposed.16 Cat scratch disease: close-up view of the necrobiosis in Figure 18.126.
Central nervous system lesions have significant morbidity and include coma,
encephalitis, convulsions, pareses, cerebellar signs, and abnormal tendon
jerks.14,15 Hepatosplenic infection results in peliosis.5,6
centers and associated with karyorrhexis. A peripheral rim of epithelioid cells
and occasional giant cells is characteristic. These features are not in them-
Histological features selves diagnostic because they may be seen in a variety of conditions including
The histopathological features are those of dermal necrobiosis.16 The necrobi- lymphogranuloma venereum, yersiniosis, and fungal infections.2
otic foci are round, triangular or stellate and are surrounded by a palisade of Previously, the diagnosis of cat scratch disease was confirmed by a posi-
histiocytes with occasional multinucleate giant cells (Figs 18.126, 18.127). tive delayed hypersensitivity reaction to the cat scratch disease antigen.1 Since
Around the periphery of the histiocytic zone is a lymphocytic infiltrate in B. henselae is difficult to culture, serology and PCR have been advocated as
which eosinophils may be conspicuous. Nuclear debris may sometimes be more reliable diagnostic modalities.5,6,23
prominent. The bacteria may often be identified using the Warthin-Starry
reaction or the Brown-Hopps modified Gram stain within histiocytes or lying Trench fever
free.17–20 Bacteria may also be detected immunocytochemically.1,21 In the adja-
cent dermis the blood vessels are surrounded by an infiltrate consisting of Clinical features
lymphocytes, plasma cells, and histiocytes. A granulomatous reaction has Although a major epidemic of trench fever was documented during the First
been described but this is an uncommon phenomenon.22 World War, more recent outbreaks of this condition have been described
In early lesions the lymph nodes show subcapsular foci of necrosis associ- among homeless people, in whom there is a high seroprevalence of this bac-
ated with a neutrophil polymorph infiltrate. An established infection is char- teremic illness.1,2 Outbreaks have also occurred in overpopulated Central
acterized by extensive necrotic lesions often involving the follicular germinal African refugee camps.3 Trench fever is caused by Bartonella quintana; human
body lice (Pediculus humanus var. corporis) are the known vectors.1,2 It is condition may be underreported in some endemic areas due to the existence
possible that head lice (P. humanus var. capitis) might also play a role in the of mild infection by less virulent strains of B. bacilliformis.2,7 The sand fly,
transmission of the disease.4 B. quintana may also cause chronic bacteremia, Lutzomyia (Phlebotomus) verrucarum is the suspected vector.6
endocarditis, and bacillary angiomatosis (see below).5
Patients present with non-specific symptoms and signs including head- Pathogenesis and histological features
ache, malaise, pyrexia, rigors, tachycardia, myalgia, arthralgia, and injected There is infection of endothelial cells and circulating erythrocytes following
conjunctivae. An erythematous macular or papular skin rash may occur. The introduction of B. bacilliformis via the bite of the suspected vector. In the
rash is often seen on the trunk and usually lasts no more than a day or two.6 cutaneous verruga peruana lesions, organisms are detectable in the extracel-
The disease is rarely fatal, except in some debilitated patients. Relapsing lular spaces, where they induce angiogenesis by producing putative microbial-
illness sometimes occurs, and the organism may remain latent in the host for encoded or microbial-induced angiogenic factors.1,8 Recent in vitro studies
a number of years following the acute infection.6 have shown that B. bacilliformis exercises a mitogenic effect on human vascu-
lar endothelial cells. GroEL produced by the organism regulates endothelial
Histological features cell growth.9,10 Others have observed that infection leads to the produc-
The histopathological features in the skin are non-specific. There is a perivas- tion of angiopoietin-2 by endothelial cells, and the production of vascular
cular lymphocytic infiltrate, without evidence of vascular thrombosis.6 endothelial growth factor (VEGF) by epidermal cells.11 The dermal angioma-
Organisms are not usually demonstrable in routinely stained skin biopsy tous proliferation appears to occur in concert with the reactivation of latent
specimens. Dermal vascular proliferation and neutrophilic infiltration (as B. bacilliformis organisms.1
seen in bacillary angiomatosis) are not features of trench fever. The diagnosis Histopathological examination of the verrucous lesions reveals an exu-
is confirmed by serology, culture or PCR.7 berant intradermal capillary proliferation lined by swollen endothelial cells,
often accompanied by a neutrophilic infiltrate. Some of the superficial and
peripheral vessels may be dilated, whereas deep dermal or subcutaneous
Bartonellosis nodules tend to have a more compact vascular and endothelial cell prolif-
eration.3,12 Occasional cases harbor a cytologically atypical endothelial pro-
Clinical features
liferation, resulting in potential confusion with malignant vascular tumors.13
Bartonellosis (Carrión's disease) is a biphasic disease caused by Bartonella There is a background mixed inflammatory cell infiltrate of variable intensity
bacilliformis, an organism that is closely related to B. henselae and comprising neutrophils, histiocytes, lymphocytes, and plasma cells. Careful
B. quintana.1–3 The initial stage of infection (hematic phase) is referred to examination of the endothelial cells in early lesions may reveal characteristic
as Oroya fever. Patients are acutely ill with pyrexia, rigors, myalgia, and intracytoplasmic aggregates of B. bacilliformis, referred to as Rocha-Lima
a severe hemolytic anemia. The last is attributable to infection of the cir- inclusions.3 These may be highlighted with the aid of a Giemsa preparation.
culating erythrocytes and can be confirmed with the aid of a blood smear. Ultrastructurally, the endothelial inclusions represent degraded bacteria and
Later, the disease enters an eruptive phase characterized by the evolution of extracellular matrix components contained within cell surface invaginations.3
numerous papular, nodular or verrucous vascular skin lesions, referred to as Bacteria are conspicuously absent from late lesions.
verruga peruana (Peruvian wart, cutaneous verrucous disease).2,4 These occur
predominantly on the face and extremities (Fig. 18.128). Atypical cases may
present with verrucous skin lesions as the sole manifestation.2 Most lesions
resolve spontaneously.3 Genital lesions and nasal mucosal involvement have Verruga peruana should be distinguished from Kaposi's sarcoma, bacillary
been recorded.5 angiomatosis, pyogenic granuloma, and true epithelioid vascular neoplasms
The condition is endemic in the higher altitude regions of Peru, where it (such as epithelioid hemangioma and epithelioid hemangioendothelioma).
was first decribed in the nineteenth century. Carrión's disease also occurs in
Ecuador and Colombia.6 Outbreaks have been recorded in nonendemic parts
of Peru, with a fatality rate of under 1%.7 It has also been suggested that the Bacillary angiomatosis
Clinical features
Bacillary angiomatosis is a vasoproliferative lesion that may be readily con-
fused with pyogenic granuloma or Kaposi's sarcoma and is seen predomi-
nantly (but not exclusively) in the skin.1–4 Lesions have also been described
in the bones, soft tissues, liver, lymph nodes, and spleen. Patients may have
systemic manifestations including fever, malaise, hepatosplenomegaly, and
lymphadenopathy.5 Although it was originally thought to be a disease specific
to AIDS, it has also been described in other immunocompromised states, and
even in apparently normal individuals.2,6–9 Patients present with widespread,
numerous (sometimes hundreds) of blood-red, smooth-surfaced, superfi-
cial papules and skin-colored or dusky subcutaneous nodules (Figs 18.129,
18.130).2 The condition may be caused either by Bartonella henselae (the
organism responsible for cat scratch disease) or less frequently by B. quintana
(the cause of trench fever).6

Bartonella henselae infection is acquired via a cat bite or scratch, or cat flea
bites, whereas B. quintana infection is transmitted by body lice. Patients with
bacillary angiomatosis, however, seldom seem able to corroborate this history.
A PCR-based study from Johannesburg revealed a 10% rate of Bartonella
bacteremia among 188 attendees at an HIV clinic, only one of whom exhib-
ited clinical features of bacillary angiomatosis.10 Vascular endothelial cells are
Fig. 18.128 the prime target of the organisms following initial intracellular colonization of
Verruga peruana: widespread papules are present. By courtesy of F. von Lichtenberg, erythrocytes.11 The VirB type IV secretion system of Bartonella plays a crucial
MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA. role in not only establishing intraerythrocytic infection but also in mediating
Diseases caused by Bartonella species 805
the organism's interaction with endothelial cells.12 Angiogenesis is potentiated

by a combination of mechanisms, including inhibition of apoptosis, release
of chemokines such as interleukin-8, and activation of hypoxia-inducible
factor-1 (HIF-1).11,13–15
Histology reveals lobules of capillaries with prominent, often cuboi-
dal vascular endothelial cells, sometimes surrounding ectatic vessels among
which are dispersed neutrophil polymorphs showing leukocytoclasis and pur-
plish granules of bacilli, which can be identified best by the Warthin-Starry
reaction (Figs 18.131–18.134).4,6 Giemsa may also be used to identify the
organisms but since both the former and the latter stains are difficult to inter-
pret and often to perform, a PCR method has been developed (see below).
Sometimes solid endothelial cell proliferation is evident. Atypia and mitoses
may be present.4 Superficial lesions have a polypoid configuration and there
may be an associated epidermal collarette reminiscent of a pyogenic granu-
loma.3,16 Ulceration is seen occasionally. Associated pseudoepitheliomatous
epidermal hyperplasia has been described.17
Although collagen dissection by spindled endothelial cells is encoun-
tered at the periphery of some lesions, hemosiderin deposition and hyaline
globules as seen in Kaposi's sarcoma are not evident.16,18,19 Late, involuting
Fig. 18.129
Bacillary angiomatosis: numerous papules and nodules are present. By courtesy
of N.C. Dlova, MD, Nelson R. Mandela School of Medicine, University of KwaZulu-
Natal, South Africa.
Fig. 18.131
Bacillary angiomatosis: there is a dense nodular capillary proliferative lesion; note
the ectatic vessels.
A
Fig. 18.130
(A, B) Bacillary angiomatosis: the bright red coloration is characteristic. By courtesy Fig. 18.132
of N.C. Dlova, MD, Nelson R. Mandela School of Medicine, University of KwaZulu- Bacillary angiomatosis: the endothelial cells are swollen. Conspicuous neutrophils
Natal, South Africa. are evident.
lesions show extensive fibrosis of the vascularized dermis, and little by way
of a polymorphonuclear leukocytic infiltrate with karyorrhexis.2,16 Such
cases require a high index of suspicion, as the bacteria may be difficult to
demonstrate. Since most patients with this condition are immunocompro-
mised HIV-infected individuals, it is prudent to examine sections carefully
for additional opportunistic pathogens, such as cytomegalovirus or
mycobacteria.16,20,21
The endothelial cells can be labeled with antibodies to factor VIII-related
antigen, CD31 and CD34. Histologically, liver and splenic involvement is
seen as peliosis.5 Typical bacteria are, however, also present. The recognition
and distinction of this infection from Kaposi's sarcoma and other vasopro-
liferative lesions is of great importance, particularly as it readily responds to
antibiotic therapy.3
Ultrastructurally, the organisms appear as aggregates of bacilli within the
dermis. The bacteria have trilaminar walls.
A
Bacillary angiomatosis must be distinguished from verruga peruana, pyogenic
granuloma, epithelioid hemangioma, and Kaposi's sarcoma. Pyogenic granuloma
is not associated with Bartonella infection.22 The pyogenic granuloma-like vari-
ant of Kaposi's sarcoma in particular may be confused with bacillary angiom-
atosis.23,24 Although rare, bacillary angiomatosis and concurrent Kaposi's
sarcoma has been described.25 PCR or immunohistochemistry for detection
of HHV-8 is a useful means of differentiating Kaposi's sarcoma from bacil-
lary angiomatosis; the former is invariably associated with HHV-8 whereas
the latter has been found to be HHV-8 negative.24,26 Furthermore, PCR may
be employed to confirm the presence of Bartonella spp. in suspected cases of
bacillary angiomatosis since these organisms are difficult to culture.27
Lyme disease
Clinical features
Lyme disease is a generalized infection due to the spirochete Borrelia burgdor-
B feri (B. burgdorferi sensu lato), of which there are three main pathogenic geno-
species in humans: B. burgdorferi sensu stricto, B. garinii, and B. afzelii.1–5
Fig. 18.133 Two more recently described species in Europe are B. valaisiana and B. spiel-
(A, B) Bacillary angiomatosis: lymphocytes and histiocytes are also present. Note manii.6 The Centers for Disease Control and Prevention (CDC) reported a
the purple colony of bacteria in the center of the field (B). 40% increase in the annual incidence of this emerging zoonosis in the United
States between 2001 and 2002; more than 40 000 cases were documented dur-
ing this period.7 A more recent CDC survey revealed that more than 64 000
cases were reported in that country during the period 2003 to 2005.8 This
trend has also been observed in parts of the United Kingdom and Europe.9–11
The disease affects most organ systems of the body.1–3 Lyme disease has
been divided into three stages, I–III: 12
Stage I
The skin lesion of the primary stage (erythema chronicum migrans, erythema
migrans) consists initially of a small erythematous papule at the site of an
insect bite and expands centrifugally as a flat ring (Fig. 18.135). It devel-
ops on average 1–3 weeks after the bite.13,14 Occasionally target lesions are
described.15 Necrotic lesions are rare.16 With extension, the macules may
develop a bluish or violet hue. If untreated, the ring may spread to a diameter
of 50 cm before clearing. Although lesions are usually asymptomatic, patients
may complain of pruritus, burning or rarely pain.17 The lower extremity and
trunk are most often affected.
Approximately 50% of patients have secondary lesions, which are smaller.
The palms, soles, and mucous membranes are usually unaffected.18 Erythema
chronicum migrans may occasionally recur.17 Other cutaneous manifestations
that have been described in the early stage of Lyme disease include granuloma
annulare, papular urticaria, and Henoch-Schönlein purpura.18 Age at presen-
tation is exceedingly variable, ranging from 15 months to 80 years. The sex
Fig. 18.134 incidence is equal and lesions present most often from May to September.18
Bacillary angiomatosis: the organisms are easily identified with the Warthin-Starry Systemic symptoms (due to a spirochetemia) tend to occur early in the
stain. disease and include chills, fever, general malaise and lethargy, arthralgia,
Lyme disease 807
chronica atrophicans occurs mainly in Europe, where B. afzelii is the over-

whelmingly predominant etiologic genospecies.5 B. afzelii is not endemic in
North America, thereby accounting for the striking geographic distribution
of the condition.5
There have been rare reports suggesting a possible association between
B. burgdorferi infection and anetoderma.32,33 A case with acquired cutis
laxa has also been described.34 The conflicting role of B. burgdorferi in the
pathogenesis of morphea and lichen sclerosus et atrophicus is discussed
elsewhere.35–37
Reinfection may occur in a small but significant proportion of patients
following treatment with antibiotics. This usually manifests as a recurrent
episode of erythema migrans at a different cutaneous site from the pre-
vious lesion.38,39 A recent Swedish study showed that women were more
susceptible to reinfection than men, ascribing this phenomenon to gen-
der differences in immune reactivity, especially in the postmenopausal age
group.39

Fig. 18.135 Erythema chronicum migrans was first described in association with tick
Lyme disease: this annular, erythematous lesion developed (several weeks later)
bites; cases were subsequently reported following mosquito bites and
around the site of a tick bite. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK. thorn pricks, or without preceding trauma.29 In a proportion of cases an
encephalitis was noted and the disease was termed ‘tick-borne meningopo-
lyneuritis’. In the 1970s several cases were reported in the United States,
and because of a clustering effect near Lyme, Connecticut, the term Lyme
disease was coined (these cases had a high proportion of arthritis).40 The
myalgia, headache, and neck stiffness. Physical examination may reveal Ixodes tick has been known to be the vector for some time, but the actual
lymphadenopathy, splenomegaly, hepatitis, and orchitis.13,19 B. garinii and etiological agent, a spirochete, was only identified in the 1980s after spiro-
B. afzelii are the pathogens most often implicated in cases of Lyme disease chetes were found in Ixodes dammini ticks in an endemic disease area.12,41,42
reported from Europe, and some authors have described differences in the In Europe, Ixodes ricinus has been incriminated.19,29 It has a worldwide
clinical presentation of erythema chronicum migrans caused by these two distribution.19
organisms. Erythemas associated with B. garinii tend to evolve more rapidly, Patients recovering from the disease have been shown to have antibod-
are often larger and homogeneous, are more often located on the trunk than ies to the spirochetes in their serum.17 Spirochetes have also been identi-
the extremities, and are more frequently associated with systemic symptoms fied from biopsy sites, and cultured from or detected by PCR performed on
when compared with B. afzelii erythemas, which are usually annular.20,21 specimens of blood, cerebrospinal fluid, synovial fluid, and skin.4,19,29,43,44
Patients with B. garinii infection also tend to be older and there is a shorter Immunosuppression does not appear to alter clinical presentation, treatment
incubation period.21 response or anti-B. burgdorferi antibody production.45
Lymphocytoma cutis (borrelial lymphocytoma), a B-cell response, may pres- Borreliae have developed strategies to inactivate host immune defenses
ent in the acute stage and most often affects the lower ear lobes and nipples.13 via a variety of mechanisms, including recently described complement reg-
It is, however, more often a feature of the third stage of the illness.14,19 ulator-acquiring surface proteins (CRASPs), which confer complement resis-
tance. Borrelial CRASPs are capable of binding FHL-1/reconectin and factor
Stage II H, which are two major regulators of the alternative complement path-
Stage II disease primarily affects the cardiovascular and nervous system way.46,47 The selective up-regulation of host matrix metalloproteinase-9 by
(meningopolyradiculitis; Garin-Bujadoux-Bannwarth syndrome).1,19,22,23 B. burgdorferi in skin lesions of erythema chronicum migrans may play a role
It may involve both the peripheral and central nervous systems, and tends to in the local spread of the organism and its dissemination to other organs.48 In
present 1–2 months after the primary infection; symptoms include mening- the early stage of Lyme disease, B. burgdorferi antigens induce a strong host
ism, nerve palsies (especially Bell's palsy), and cerebral symptoms, including immune response in which the production of cytokines such as IFN-γ, TNF-α
personality changes, drowsiness or stupor.12,24 There have been isolated reports and transforming growth factor beta-1 (TGF-β1) predominates.49,50 By con-
of orbital myositis, neurosensory hearing loss, parkinsonism, and spontane- trast, chronic neuroborreliosis is associated with a lack of TNF-α and TGF-β1
ous brain hemorrhage.25–28 Cardiac involvement presents as myocarditis and responses.50 Studies performed on lesional skin have revealed high levels of
conduction defects.12,22,29 the T-cell-active chemokines CXCL9 and CXCL10 in erythema chronicum
migrans and acrodermatitis chronica atrophicans. Borrelial lymphocytoma,
Stage III on the other hand, is associated with high levels of CXCL13, a B-cell-active
Arthritis, which characterizes the third stage, presents as a recurrent, asym- chemokine.51
metrical, and oligoarticular process involving the large joints (especially The central component of the initial lesion shows the typical appearance
the knee) or as a migratory polyarthritis lasting up to a week in any one of an insect bite reaction. Histology reveals a polymorphic inflammatory cell
particular joint.19 Cutaneous lesions and peripheral nervous system involve- infiltrate including polymorphs, eosinophils, histiocytes, lymphocytes, and
ment are also frequently encountered in the third stage. The typical skin mast cells.19 Vascular proliferation and dermal necrosis may additionally be
lesions of late Lyme disease are acrodermatitis chronica atrophicans, which present. A biopsy from the periphery is non-specific, showing a perivascu-
characteristically presents as a red or violet discoloration of swollen periph- lar and interstitial infiltrate of lymphocytes, mast cells, and plasma cells in
eral skin, and lymphadenosis benigna cutis.14,17,19 Lesions are often bilateral. both the superficial and deep dermis (Figs 18.136, 18.137). Identification
Patients may also develop sclerodermatous changes. Lichen sclerosus et atro- of spirochetes by a silver stain is diagnostic.52 An immunohistochemical
phicus-like lesions have also been described.12,19 In the late atrophic stages of method for demonstrating the etiologic agent has been described.19 PCR
acrodermatitis chronica atrophicans, the skin may resemble crumpled tissue may also be used to detect the organisms in formalin-fixed, paraffin-embed-
paper.30 Nodular or bandlike juxta-articular fibrous nodules are not uncom- ded tissue specimens.53 A recent study concluded that focus floating micros-
mon, and may regress with appropriate antibiotic therapy.31 Acrodermatitis copy was more sensitive than PCR in detecting Borrelia spirochetes in the
Fig. 18.136 Fig. 18.137

Lyme disease: the epidermis is normal; a chronic inflammatory cell infiltrate Lyme disease: high-power view.
surrounds the vessel in both the superficial and deep dermis.
lesional tissue of erythema chronicum migrans, borrelial lymphocytomas,

and acrodermatitis chronica atrophicans.54 Clonal or pseudoclonal IgH gene
rearrangements have been documented in DNA extracted from erythema
migrans cutaneous lesions. Care should therefore be exercised when inter- Endemic (nonvenereal) treponematoses
preting PCR results in such cases; some authors have advocated duplicate or
triplicate testing.55 Endemic syphilis
The borrelial lymphocytoma consists of a dense (polyclonal) dermal infil-
trate composed of lymphocytes, plasma cells with macrophages, and scattered Clinical features
eosinophils. Although it has been suggested that germinal center formation, Endemic syphilis (Syrian bejel) is a form of nonvenereal treponematosis
when present, helps to exclude a cutaneous B-cell lymphoma, this is not nec- caused by Treponema pallidum subsp. endemicum, an organism nearly
essarily true; cutaneous lymphomas of marginal zone type typically display identical to Treponema pallidum subsp. pallidum, the etiological agent
germinal centers.17,19,56 The association between B. burgdorferi infection and of venereal syphilis.1–4 The condition usually occurs in children living
cutaneous B-cell lymphoma is discussed elsewhere.56,57 in conditions of poor hygiene and is transmitted by cutaneous inocula-
Acrodermatitis chronica atrophicans is characterized by vascular dilatation.1,2,4–6 Other endemic forms have been associated with shared drinking
tion in the mid and upper dermis accompanied by a dense infiltrate of lym- vessels and other contaminated domestic utensils when some members of
phocytes, plasma cells, macrophages, and mast cells.19 Scattered groups of the community have oral or labial syphilitic lesions.1,2,4,5 The disease still
‘vacuoles’ may be seen in the dermis; this phenomenon is thought to be attrib- occurs in parts of the Middle East and Africa, especially in rural desert
utable to lymphedema.30 The epidermis, which is usually hyperkeratotic, may regions.1,4,7
be acanthotic or atrophic with loss of ridge pattern.12 In some patients the Unlike venereal syphilis, a primary chancre seldom occurs in endemic
appearances are reminiscent of lichen sclerosus et atrophicus or eosinophilic syphilis; women suckling infected infants may, however, develop primary
fasciitis.17,19 Occasionally, the histological features may overlap with sclero- infections of the nipple.4 The primary lesions usually involve the orophar-
myxedema.19 The juxta-articular fibrous nodules are characterized by fibrosis ynx but are easily overlooked. Early secondary lesions manifest as soft,
of the superficial subcutaneous tissue, with hyaline collagen bundles encircling oval mucous patches with a predilection for the buccal and labial mucosae,
clusters of adipocytes. There is an accompanying perivascular and interstitial sometimes accompanied by angular stomatitis. Mucous patches may also
inflammatory infiltrate comprising lymphocytes and plasma cells.31 Smaller occur in the perianal and genital areas, where they sometimes appear
periarticular fibrous nodules on the fingers show disorganized bundles of condylomatous. Osteoperiostitis may occur, and generalized lymphadenop-
thickened dermal collagen.58 athy is common.4
The triad of meningitis, cranial neuropathy, and radiculopathy has Late (tertiary) manifestations develop following a latent period of between
been said to be unique for Lyme disease. Central nervous system lesions 5 and 15 years. The lesions may evolve in the skin, nasopharynx, bone or joints
include cortical, perivascular chronic inflammatory cell infiltrates, mild and are clinically similar to those encountered in late yaws.4 Articular and
spongiform changes and gliosis. Plasma cells, however, are said to be osseous involvement is frequently destructive. Cardiovascular involvement
absent. The similarity of the late central nervous system changes of Lyme may also occur, but the disease does not affect the central nervous system. A
disease and meningovascular syphilis has been stressed.19 Chronic lep- further point of distinction from venereal syphilis is the fact that there is no
tomeningeal inflammation may also be evident. Peripheral nervous sys- congenital form of endemic syphilis.4
tem lesions are characterized by nerve and ganglion lymphocyte and
occasional plasma cell infiltration.12,19 Adjacent vessels may show endar-
teritis obliterans.
Endocardial lesions are characterized by a lymphocytic and plasma cell Histological features
infiltrate; deep specimens show an interstitial myocarditis.12 Focal myonecrosis The histopathology of the primary lesion is poorly documented. The light
may also be evident.19 microscopic features of the secondary lesions are virtually identical to those
Histological examination of the synovium may show periadventitial cell encountered in venereal syphilis.4,8 Granulomatous dermal inflammation is
onion-skinning proliferation and chronic inflammation.12,19 encountered in the tertiary skin lesions.8
Endemic (nonvenereal) treponematoses 809
There may be a symptom-free period of 3–5 years before the lesions of

Yaws late yaws arise. The late lesions, which develop in about 10% of patients, are
destructive ulcers and gummatous nodules which affect the skin, bones (e.g.,
Clinical features saber tibia), and joints (Figs 18.140, 18.141).4,10,11,14 Cutaneous manifesta-
Yaws (framboesia tropica) is a tropical disease occurring in people living in tions of late yaws include palmar and plantar hyperkeratosis (crab yaws),
poor conditions due to infection by the spirochete Treponema pallidum subsp. loss of pigment (pintoid yaws), and gummata.4,11 Pintoid yaws includes
pertenue.1–5 Although the disease was thought to have been almost eradicated hyperkeratosis, contractures, juxta-articular nodules, and bony lesions.4,11
by the WHO treatment program, it continues to be encountered in a number Gummata characteristically involve the long bones, the bones of the hands
of warm, humid tropical regions including Africa, parts of Asia (including and feet, and typically lead to gross destruction of the face (gangosa).16 The
Southeast Asia), Oceania, and parts of South America.1,6,7 The eradication cardiovascular and nervous systems are said not to be involved, but there is
program, however, has attained success in India, where there have been no evidence to suggest that ophthalmic and myeloneuropathies may occur in
recorded cases since 2004.6,8 endemic areas.10,12,17
Yaws is not transmitted sexually, but rather by close contact, for exam-
ple by inoculation of skin previously traumatized by insects or scratch- Pathogenesis and histological features
ing.1,4,9 The disease is most common in children 6–10 years of age, who The spirochete responsible for yaws is morphologically indistinguishable from
present with lesions on the feet, legs, and buttocks.10 Clinically, it is divided T. pallidum subsp. pallidum.14 The organism is, however, differentiated from
into early and late yaws.11–13 The initial lesion, known as a ‘mother yaw’, other pathogenic treponemes by unique differences in the genetic sequences
develops 3–5 weeks after inoculation.10 It starts as a nontender papilloma, flanking the 15-kD lipoprotein gene.5
which ulcerates and is then covered with a yellow crust (Fig. 18.138).10 It Early lesions are characteristically parakeratotic, acanthotic, and papilloma-
resembles a raspberry, hence the alternative designation framboesia (Dutch tous. They show focal spongiosis and intraepidermal neutrophils with microab-
framboos, raspberry). This mother yaw may be surrounded by smaller scess formation (Fig. 18.142).14 There is a dense perivascular dermal infiltrate
papillomas, which develop 2–4 months after the initial lesion.4,9 Lesions in containing numerous plasma cells. The vascular changes in contrast to syphilis
the perineum and natal cleft may become condylomatous.9 Subsequently, are usually insignificant. Treponemes can be seen around the blood vessels, in
these warty lesions may become very widespread (‘daughter yaws’) (Fig. the tips of the dermal papillae, and within the epidermis (Fig. 18.143).15,18–20
18.139). Macules, papules, and nodules have also been described.10,14 The palmoplantar lesions are characterized by hyperkeratosis, parakerato-
They eventually resolve leaving a depressed and hyperpigmented scar.9 The sis, and acanthosis. A mild non-specific chronic inflammatory cell infiltrate is
mucous membranes, bones (osteitis and periostitis), and joints may also be present in the superficial dermis.
affected in early yaws.11 Palmar and plantar hyperkeratosis, which can The gummata show central caseation necrosis surrounded by a rim of lym-
be exceedingly painful and may result in walking difficulties (crab yaws), phocytes, plasma cells, histiocytes, epithelioid cells, and giant cells.15 There is
are characteristic.14,15 associated fibrosis.
A B
Fig. 18.138 Fig. 18.139

Early yaws: typical framboesiform ‘mother yaw’. Note (A, B) Early yaws: multiple smaller ‘daughter yaws’ may be widely distributed and usually present 2–4
the yellow crust and surrounding hypopigmentation. months after the ‘mother yaw’. By courtesy of H.J.H. Engelkens, MD, and E. Stolz, MD, University Hospital,
By courtesy of H.J.H. Engelkens, MD, and E. Stolz, Rotterdam-Dijkzigt and Erasmus University, Rotterdam, The Netherlands.
MD, University Hospital, Rotterdam-Dijkzigt and
Erasmus University, Rotterdam, The Netherlands.
Fig. 18.140 Fig. 18.141 Fig. 18.142

Late yaws: note the bowing of the lower leg with Late yaws: note the cyst with an overlying periosteal Early yaws: biopsy through an evolving papilloma.
cutaneous ulcerated and crusted lesions in this reaction. By courtesy of R.A. Marsden, MD, St There is very marked parakeratosis associated
late stage. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. with abundant neutrophil debris. The epidermis
George's Hospital, London, UK. shows intense acute inflammation. By courtesy of
H.J.H. Engelkens, MD, and E. Stolz, MD, University
Hospital, Rotterdam-Dijkzigt and Erasmus University,
Rotterdam, The Netherlands.
Fig. 18.143
(A, B) Early yaws: same specimen as that shown in
Fig. 18.142. Note the presence of numerous spirochetes.
(A) Warthin-Starry; (B) immunofluorescence. By courtesy of
H.J.H. Engelkens, MD, and E. Stolz, MD, University Hospital,
A B Rotterdam-Dijkzigt and Erasmus University, Rotterdam, The
Netherlands.
Tuberculosis 811
Pinta active reservoir of infection, and increased immunoresistance to infection.

The late twentienth century, however, showed an apparent upward trend
Clinical features in the incidence of cutaneous tuberculosis, especially in Asian countries.3 A
This is a nonsexually transmitted treponematosis characterized by depig- particularly important aspect of cutaneous tuberculosis is that skin lesions
mented skin lesions. It is caused by Treponema carateum (Treponema pal- can readily simulate other conditions, and may be insidious in onset. The
lidum subsp. carateum), an organism that is very similar to T. pallidum subsp. source of infection is sometimes not obvious, and tissue destruction may
pallidum.1–4 It is confined to remote primitive regions in tropical Central be very marked. Cutaneous tuberculosis accounts for 1% to 1.5% of cases
and South America where the inhabitants live in poor hygiene and in close of extrapulmonary tuberculosis and around 0.14% of all cases of tuber-
proximity.1,5–7 Children and young adults are primarily affected and transmis- culosis.4,5 Although the global burden of tuberculosis is slowly declining,
sion is thought to be by direct cutaneous or mucous membrane contact, pos- data from the World Health Organization (WHO) remain disconcerting.
sibly via minute abrasions.5,6,8 According to the WHO, the worldwide prevalence of tuberculosis in gen-
The lesions present as small scaly erythematous indurated papules and eral in 2007 was around 13.7 million cases, with an estimated 9.27 million
plaques on exposed skin, usually on the hands and feet. These disappear, but incident cases.6
recur in a more disseminated form (pintids).5 Late stages of pinta are char- Mycobacterial infections (tuberculous and atypical) are of increasing
acterized by disfiguring hyperpigmentation, achromia, hyperkeratosis, and importance in the context of acquired immunosuppression, whether due to
atrophy (Fig. 18.144).9 lymphoma, AIDS or aggressive chemotherapy. Atypical modes of presenta-
Unlike syphilis and yaws, there is no evidence of systemic disease. tion with microorganisms of borderline virulence have gained significance.7
Cutaneous tuberculosis has reemerged in those parts of the world where the
incidence of HIV infection and multidrug-resistant tuberculosis is high.2,6,8,9
An estimated 1.37 million of the incident cases of tuberculosis in 2007 were
Histological features HIV positive, with around 79% and 11% of these on the African conti-
Histologically, there is hyperkeratosis with acanthosis or occasion- nent and in Southeast Asia, respectively. Approximately 23% of the esti-
ally epidermal atrophy. 4,9 Lymphocytic exocytosis, basal cell hydropic mated 2 million HIV-related deaths in 2007 were the result of concomitant
degeneration, and pigmentary incontinence are evident.4 A perivascular tuberculosis.6
lymphocytic infiltrate is usually seen without endothelial swelling. In Europe and North America cutaneous infection is still relatively infre-
quent, due to a reduction in the numbers of infected cases by therapy and
immunization programs and to an increased standard of living. Nevertheless,
there remains an apparently irreducible number of people with tubercu-
Tuberculosis losis, usually living in circumstances of poor hygiene and nutrition.10 This
is borne out by the number of unsuspected cases of tuberculosis diag-
Clinical features nosed at autopsy. Moreover, there exists an important reservoir of infected
Tuberculous (Mycobacterium tuberculosis complex) infection of the skin, immigrants, particularly of Asian origin, who often present with cervical
which was once common worldwide, had shown a declining incidence dur- lymphadenopathy.
ing the latter decades of the last century, especially in developed countries.1,2 The manifestations of the disease in the skin are influenced by previous
This was due in part to improved therapy, a reduction in the size of the infection or immunity and by the route of infection. Because of the virulence
and resistance to phagocytosis by M. tuberculosis, neutrophils are completely
ineffective in dealing with this bacterial infection, whereas macrophages and
their derivatives are characteristically seen in the cellular response. These lead
on to (giant cell) granuloma formation with or without necrosis and this
underlies the varied clinical presentations of this infection.
The majority of cases of cutaneous tuberculosis are a manifestation of
systemic disease.2,8 The usual portals of entry of M. tuberculosis include the
lungs and intestine, but the mucous membranes and skin occasionally show
primary involvement.11 Cutaneous lesions include papules, nodules, plaques,
ulcerative lesions, warty tumors or scarring reactions.12 Although preferred,
it is not always possible to package cutaneous tuberculous lesions neatly
into the categories detailed below, and on occasion tuberculous skin disease
may be reported as of non-specific type, particularly in this current era of
profound immunosuppression. In this account a modified ‘Beyt’ classifica-
tion is used.2,11,13
Appropriate classification, when possible, is important because some
variants are associated with systemic lesions and therefore clinical manage-
ment and prognostic implications are highly variable.11 Tuberculids in which
bacilli are not detectable are now rare in the West, but are still common in
developing countries and are considered separately below.
Fig. 18.144 Infections by inoculation (exogenous source)

Pinta: this is a late lesion Tuberculous chancre, which is rare, occurs by direct inoculation of infected
showing characteristic material into the skin of a previously uninfected and nonimmune patient.
complete loss of
The response is analogous to a Ghon complex in the lung.13,14 These lesions
pigmentation surrounded
by a hyperpigmented
develop 2–4 weeks after inoculation, which may be through minor trauma to
border. By courtesy of the skin of various sites, such as the face and limbs of children (Fig. 18.145).
R. Arenas, MD, and Infection may also follow minor surgery such as ear piercing, tattooing or
J. Salas, MD, Azteca, circumcision. The earliest lesion is a reddish-brown papule, which may rap-
Monterrey, Mexico. idly progress to an ulcer with ragged undermined edges. The margins of the
Fig. 18.145
Tuberculous chancre: the
cutaneous equivalent of a
Ghon complex. Note the
healing lesion on the outer Fig. 18.147
aspect of the knee and the Warty lupus: prosector's wart. This indurated lesion on the finger developed after
ulcerated inguinal nodes a pathologist had performed a tuberculous autopsy. By courtesy of R. Vellor, MD,
from this patient from St Thomas' Hospital, London, UK.
the 1950s. By courtesy of
M.M. Black, MD, Institute
UK.
Fig. 18.148
Warty lupus: in children,
Fig. 18.146 the buttock is a commonly
Warty lupus: in this example, there is a grossly hyperkeratotic lesion associated with affected site. By courtesy
destruction of the nail. By courtesy of the Institute of Dermatology, London, UK. of the Institute of
lesion become indurated and lymphadenopathy is usually noted at this stage.

Satellite papules may be seen around the original lesion and this pattern of
spread is termed ‘lupoid’. Inoculation tuberculosis from Bacille Calmette- exude. In some areas the lesion continues to extend, but elsewhere it may
Guérin (BCG) injection is a similar phenomenon.15 show focal involution to leave an atrophic pale scar. The warty component
Warty lupus (tuberculosis verrucosa cutis) occurs by inoculation of may persist for years, but usually resolves eventually.
M. tuberculosis into the skin of individuals who have some degree of immunity
or may have active infection elsewhere. It is has been the most common vari- Secondary tuberculosis (endogenous source)
ant in some series from Asia (Fig. 18.146).11,16,17 This lesion occurs classically Orificial tuberculous ulcers are rare and occur in the skin or mucosa adjacent
as ‘prosector's warts’ in pathologists or autopsy technicians, but may also be to an orifice draining an active tuberculous infection. They represent auto-
seen in butchers dealing with infected cattle (Fig. 18.147).13 Inoculation of the inoculation and are most commonly seen around the nose, mouth, genitalia
skin by infected sputum, even from the same patient, can cause a similar lesion. or anus (Fig. 18.149). Patients are usually hyperreactive to tuberculin test-
Children tend to be affected on the lower limbs or b uttocks (Fig. 18.148). ing. The lesions start as edematous red papules, which ulcerate and develop
The lesion begins as a small indurated nodule with a keratotic warty undermined edges. These ulcers are painful and neither progress or regress.
surface at the site of inoculation and then slowly extends in a serpiginous Scrofuloderma (L. scrofula, brood sow; derma, skin) is a complication
manner, producing an irregular reddish-brown warty plaque. Although much of deep tuberculous infection of lymph node, bone, joint or subcutaneous
of the lesion is firm, some softer areas may be present from which pus may tissue (Figs 18.150–18.152). The lesion is seen as a bluish-red nodule, which
Tuberculosis 813
Fig. 18.149 Fig. 18.151

Orificial tuberculosis: widespread ulcerative lesions involving the upper lip and Scrofuloderma: in this case there was underlying tuberculous osteoarticular
nostril. By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK. disease. By courtesy of the Institute of Dermatology, London, UK.
Fig. 18.150
Scrofuloderma: (A) note
the marked axillary
swelling and scarring Fig. 18.152
with multiple sinuses; Scrofuloderma: lesions
(B) in this example in the midline of the back
there was underlying commonly complicate
cervical tuberculous vertebral tuberculous
lymphadenopathy. The osteomyelitis. By courtesy
puckered scarring is of the Institute of
characteristic. By courtesy Dermatology, London, UK.
A St George's Hospital,
London, UK.
lcerates and discharges pus or necrotic material.11 Lesions are commonly
u
seen in the neck, submandibular area or axilla. There is associated scarring,
and the combination of scarring and a chronic discharging ulcer may resem-
ble hidradenitis suppurativa. Very rarely, scrofuloderma may arise from the
lacrimal system.18
Infection by hematogenous spread

Lupus vulgaris may occur following inoculation of bacteria into individuals
showing some immunity (see above); more commonly, however, it represents
hematogenous or lymphatic spread from a tuberculous focus, which is usually
occult. Lesions occur mostly on the face (particularly around the nose), neck,
and earlobes in the West, and are more common in women (Figs 18.153,
18.154).15 The extremities and buttocks are more commonly involved in
patients in the East. The arms and legs may also be affected (Fig. 18.155). It
is a very chronic disease. This form of cutaneous tuberculosis used to be par-
ticularly evident in Northern Europe and is still the most frequently encoun-
B tered variant in the West.2, 11 It is a common form of cutaneous tuberculosis
in childhood.19
Fig. 18.155
Lupus vulgaris: this is a
chronic lesion showing
Fig. 18.153 marked scaling, erythema,
Lupus vulgaris: the nose is a commonly affected site. By courtesy of N.C. Dlova, and induration. Squamous
MD, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South cell carcinoma may
Africa. occasionally supervene.
By courtesy of
R.A. Marsden, MD,
London, UK.
immunosuppressed.8,11,28 Clinically, it presents as a firm subcutaneous nodule,

usually on the arms or legs. The lesion slowly becomes fluctuant and the overlying
skin perforates to form a chronic undermined ulcer as seen in scrofuloderma.
Miliary tuberculosis of the skin (tuberculosis cutis miliaris disseminata)
occurs in association with generalized miliary tuberculosis and is very rare. It
is usually seen in infants and has a poor prognosis. The infection may be seen
in mother and child concurrently and then the cutaneous lesions may be
scanty and the prognosis less grave.29 Other cases are associated with immu-
nodeficiency and may follow a minor systemic infection such as measles. In
these patients there are numerous lesions which are usually centrally crusted
papules or pustules, but they may be ulcerative, necrotic, hemorrhagic or
vesicular.11 In recent years there have been a number of reports in patients
with AIDS, especially those with multidrug-resistant tuberculosis.8,9,30–34
The cutaneous lesions can be confused with folliculitis, resulting in delayed
diagnosis.30 The prognosis is poor.8,32
Comparison of the variants of cutaneous tuberculosis is shown in
Fig. 18.154 Table 18.2.
Lupus vulgaris: typical Other rare manifestations of cutaneous tuberculosis that have been reported
plaque with golden-yellow include tuberculous cellulitis, neutrophilic tuberculous panniculitis, and the
appearance. By courtesy presence of sporotrichoid lesions.35–40 These uncommon forms of tuberculosis
have occurred in patients who were iatrogenically immunosuppressed.
London, UK.
M. tuberculosis, an ‘obligate pathogen’, is a slender aerobic rod, characterized
Lupus vulgaris occasionally results from direct inoculation and may even by a high lipid content. This lipid is responsible for resistance to phagocyto-
occur at the site of BCG inoculation.20 sis. It also allows the bacterium to retain basic dyes, even during treatment
Lupus vulgaris is characterized by papules and raised erythematous and with strong differentiating agents, and this is the basis of the Ziehl-Neelsen/
sometimes scaly plaques of gelatinous consistency, said with diascopy to acid-fast stain (Fig. 18.156). Organisms are easily identified in tuberculous
resemble apple jelly. These lesions may gradually extend, while involuting chancre, scrofuloderma, orificial lesions, and the miliary variant. They may
with scarring in other areas. There may be adjacent cellulitis or ulceration. be difficult to find or absent in lupus vulgaris, gummata, and warty tuber-
Extensive facial lesions can result in gross disfigurement.21,22 Squamous and culosis.11 Mycobacteria are found at water–air interfaces and were so named
basal cell carcinoma, melanoma, and lymphoma may develop in chronic because of their moldlike growths on the surface of liquid media.41
lupus vulgaris.23–26 Contractures and lymphedema are late complications. The organism is highly resistant to drying and therefore can retain
Ocular involvement is an additional serious complication. Lupus vulgaris is infectivity by inoculation or contamination of minor wounds.
a rare cause of alopecia.27 The reaction to the bacterium depends on:
Tuberculous gumma represents a metastatic tuberculous subcutaneous • the size of the inoculums,
abscess derived from infection at another site by a hematogenous route.11 It • the virulence of the organism,
is most commonly seen in the malnourished, the immunodeficient or the • the immune state of the patient.
Tuberculosis 815
Table 18.2
Variants of cutaneous tuberculosis
Variant Route of infection Association with other TB Level of infection Histological features Presence of bacilli
Tuberculous chancre Inoculation None Dermis Neutrophil abscess → caseating Present
granuloma, lymphadenopathy
Warty lupus Inoculation Previous or current Dermis Scanty granulomata, Absent or very
infection papillomatous acanthosis scanty
Orificial ulcers Autoinoculation Active infection in Submucosa dermis Mixed inflammation, few Numerous
associated organs granulomata, necrosis
Lupus vulgaris Inoculation and/or Previous or current, often Superficial dermis Variable but granulomata, little May be seen in deep
hematogenous occult, infection caseation prominent aspect
Scrofuloderma Extension from Active infection Subcutaneous and Mixed inflammation, granuloma, May be seen in deep
underlying infection dermal marked fibrosis aspect
Tuberculous gumma Hematogenous Systemic infection Subcutaneous Much caseation, granulomatous Scanty
fibrosis
Miliary tuberculosis Hematogenous Systemic infection Dermis Central abscess, with Absent or scanty
surrounding histiocytic infiltrate in benign form;
present in
aggressive form
Fig. 18.156 Fig. 18.157

Ziehl-Neelsen stain: in the center of the field is a small collection of red, acid-fast Tuberculosis: characteristic Langhans giant cells with horseshoe peripheral rim of nuclei.
rods (oil immersion).
In general, the cellular response is characterized by epithelioid macrophages,

Langhans giant cells, and caseous necrosis, with perivascular lymphocytes
in the surrounding tissue (tuberculous granuloma) (Figs 18.157, 18.158).
Tuberculoid granulomata, as seen for example in sarcoidosis, by definition
do not show caseation. The presence of large numbers of bacilli in a lesion
implies a nonimmune or anergic state, such as in tuberculous chancre or ori-
ficial lesions. Caseation is an indication of hypersensitivity and is not a toxic
effect of the organisms; it is clear that it is not always beneficial to the host
because it is invariably associated with destruction of surrounding tissue.
The recruitment of large numbers of macrophages is mediated by cytok-
ines released by T lymphocytes. In M. tuberculosis infections it appears that
various cytokines operate, some of which participate in toxic or necrogenic
functions, while others mainly activate macrophages. These responses are
graded and the balance between the various components determines the even-
tual response. It is by no means clear what determines the balance between
tissue damage and protective functions.
Primary chancre Fig. 18.158

The primary chancre is characterized by a neutrophilic abscess with numer- Tuberculosis (caseation necrosis): the cell outlines are not completely lost, giving an
ous bacilli, associated with necrosis leading to ulceration. This is gradually amorphous granular appearance.
surrounded by histiocytes; after 6 weeks, giant cells (derived by fusion of

epithelioid cells) are seen. Central necrosis remains prominent, but diminishes,
along with the number of bacilli, as the granulomatous element increases.11
Warty lupus
Warty lupus is characterized by acanthotic papillomatosis with marked hyper-
keratosis (Fig. 18.159). The dermal infiltrate consists mainly of neutrophils
and lymphocytes, and abscesses may sometimes be present. Granulomata
are present in the deeper dermis and caseation is occasionally a feature (Fig.
18.160).11 Bacilli are found on careful searching.
Orificial lesions
Orificial lesions, in contrast, show extensive necrosis and numerous bacilli.
The inflammatory infiltrate is not conspicuously granulomatous and may
consist of lymphocytes and neutrophils, with few histiocytes.
Lupus vulgaris
Lupus vulgaris is more varied in its histological features. It is seen in the superfi-
cial dermis, consisting of tubercles, some of which coalesce, with scanty or absent Fig. 18.161
central caseation surrounded by epithelioid histiocytes and multinucleate giant Lupus vulgaris: there is a dense dermal infiltrate. Note the Langhans giant cell.
cells (Figs 18.161, 18.162). Peripheral lymphocytes are also usually prominent.
Fig. 18.162
Fig. 18.159 Lupus vulgaris: the granulomata are often surrounded by lymphocytes.
Warty lupus: the epidermis is hyperkeratotic and shows marked irregular acanthosis.
An inflammatory cell infiltrate is present in the dermis.
Bacteria are very infrequent. The overlying epidermis may be ulcerated (in which
case there is usually a more mixed inflammatory infiltrate), atrophic or acan-
thotic. The last may be severe (pseudoepitheliomatous hyperplasia), raising the
problem of distinction from invasive squamous carcinoma, especially as such
tumors are an important rare complication of lupus vulgaris. This may some-
times be impossible if only superficial specimens are submitted for pathological
interpretation. Transepithelial elimination of granulomata has been described.42
Lupus vulgaris typically presents around the nose: this location is deter-
mined by the presence of large venous channels with stasis of blood flow and
relative cold and hypoxia, which impair fibrinolysis and host defences. Lupus
vulgaris may affect other areas with relatively low temperature.
Miliary tuberculosis
Miliary lesions include a severe form in which numerous central bacilli within
a neutrophil abscess are surrounded by histiocytes (Fig. 18.163). Vascular
thrombi containing microorganisms may be seen.15 The less aggressive form
is similar, but lacks the large numbers of bacteria.
The skin lesions of disseminated miliary tuberculosis (especially in AIDS
patients) are often either devoid of granulomata or exhibit only poorly
formed granulomata. Extensive necrosis and abscess formation are often
Fig. 18.160 seen. Langhans giant cells are rare. Papillary dermal neutrophilic microab-
Warty lupus: in addition to neutrophils and lymphocytes, an occasional Langhans scesses reminiscent of those seen in dermatitis herpetiformis are sometimes
giant cell may be present. encountered. Special stains reveal numerous acid-fast bacilli.32,34
Tuberculosis 817
A A
B B
Fig. 18.163 Fig. 18.164

Miliary tuberculosis: (A) a neutrophil abscess is present in the mid dermis; (B) it is (A, B) Scrofuloderma: there is extensive caseation necrosis.
surrounded by histiocytes. Occasional giant cells are also evident.
Scrofuloderma
Scrofuloderma usually appears as an ulcerated dermal abscess with an
ill-defined histiocytic component. Peripheral granulomata may be present.
Marked caseation necrosis, in which bacilli may be numerous, can be seen in
the deeper tissues (Fig. 18.164).
Tuberculous gummata
Subcutaneous gummata are associated with marked caseation, but there are
few bacilli (Fig. 18.165). There is a surrounding granulomatous infiltrate,
which may be associated with dermal involvement.
Tuberculous cellulitic lesions are characterized by granulomatous inflam-
mation with giant cells and demonstrable bacilli.36,38,41 Panniculitis with
vasculitis may occasionally be seen in cutaneous tuberculous lesions.7 Rare
cases of subcutaneous mycobacterial granulomatous arteritis have been
documented.43
The typical granulomatous and caseating picture is virtually pathognomonic
for tuberculous infection, although sarcoidosis can have a similar appearance.
Sarcoid, however, can be distinguished by the lack of caseation, but often this
is not particularly helpful since necrosis is seen in only a minority of cases Fig. 18.165
of tuberculosis. Necrosis when present in sarcoidosis is rather more fibrin- Tuberculous gumma: there is massive caseation surrounded by a well-defined
oid than caseating. More helpful is the lack of a surrounding lymphocytic granulomatous infiltrate.
infiltrate and fewer giant cells in sarcoidosis and a more discrete arrangement
of the granulomata (the sarcoidal naked granuloma). Schaumann bodies are
characteristic of sarcoidosis, but may occasionally be seen in mycobacterial
infections.7
In less granulomatous forms of cutaneous tuberculosis a distinction from
leprosy must be made. The perineural distribution of the inflammation is a
pointer towards leprosy.
Deep fungal infections and leishmaniasis may also be confused with
tuberculosis and recognition of the organism is vital. Granulomatous late
secondary and tertiary syphilis is distinguished by the vascular changes and
numerous plasma cells. Caseation necrosis is typical of acne agminata and
may also be seen in foreign body reactions to beryllium and zirconium.44 It
may also be a feature of Wegener's granulomatosis, although this would be
distinctly unusual in cutaneous lesions.
Despite these points, diagnosis may still not be possible. The difficulty is Fig. 18.167
made worse by the frequent failure to demonstrate bacilli even in definite Papulonecrotic tuberculid:
cases of tuberculosis, and the results of culture take 3–4 weeks. Therefore, innumerable papules
occasionally, it may be a diagnosis of exclusion, which is confirmed by a are distributed on the
therapeutic trial of antituberculous drugs.11 The shortcomings of these tra- dorsal aspect of the legs.
ditional methods have led to increased use of PCR for confirmation of the Tuberculids imply an active
diagnosis.2,8,45 infection elsewhere in
the body. By courtesy of
N.C. Dlova, MD, Nelson
Tuberculids R. Mandela School of
Medicine, University of
Clinical features KwaZulu-Natal, South
Africa.
A tuberculid is a cutaneous immunological reaction to the presence of tuber-
culosis, which is often occult, elsewhere in the body.1–3 By definition, special
stains and cultures for tubercle bacilli from tuberculids are negative. Although
tuberculids are rare in Western countries, they are still important conditions in young people who otherwise often appear rather well. Occasional cases
in developing countries where tuberculosis is a common disease.3,4 have been reported to progress to lupus vulgaris.3,5
Tuberculids may be papular or nodular and can be separately classified on Lichen scrofulosorum characteristically presents as yellow or brown
that basis, but variations and combinations of those features may be seen and asymptomatic follicular papules, less than 3 mm across, on the trunk (Fig.
are only valid descriptively. 18.168). These lesions regress slowly and do not leave scars. This uncommon
One variety of papular tuberculid is the papulonecrotic tuberculid. This tuberculous reaction usually occurs in children and young adults.10–13 The
chronic condition presents as recurring crops of flesh-colored, erythematous eruption is said to be more frequently associated with tuberculous lymph-
or darkish red papules, most often on the ears and the limbs and in particular adenitis (cervical, hilar or mediastinal) or osseous tuberculosis than with
on extensor aspects around the elbows and knees (Figs 18.166, 18.167).4–6 pulmonary tuberculosis.11 The latter observation has not been supported by
Lesions may occur widely or present in isolated sites.6,7 The papules may others.10,11
become pustular, ulcerate or develop crusts. They are often symmetrically dis-
tributed.8 Genital involvement may occasionally occur.6 They regress slowly
over several weeks, leaving depressed, varioliform scars.8,9 Usually they occur
Fig. 18.168
Lichen scrofulosorum:
note the numerous tiny
papules on the chest
Fig. 18.166 and upper abdomen. By
Papulonecrotic tuberculid: widely distributed small purple papules are present. By courtesy of S. Lucas,
courtesy of N.C. Dlova, MD, Nelson R. Mandela School of Medicine, University of MD, St Thomas' Hospital,
KwaZulu-Natal, South Africa. London, UK.
Cutaneous complications of Bacille Calmette-Guérin vaccination 819
Until recently, the only nodular tuberculid that was generally accepted
was erythema induratum (Bazin's disease, nodular vasculitis). This condi-
tion presents as ill-defined nodules on the calves of women, characteristically
those who are obese and have erythrocyanotic skin in this area. The lesions
may be worse in cold weather, which raises the problem of distinction from
pernio. With progression, the nodules eventually form irregular ulcers, which
tend to have bluish undermined edges. Resolution is slow.
More recently, the term nodular tuberculid has been applied to a rare sub-
set of patients with nonulcerated nodules on the lower legs and in whom the
pathological changes are centered on both the dermis and the subcutaneous
fat.14,15 It has been proposed that this entity represents a hybrid between pap-
ulonecrotic tuberculid and erythema induratum of Bazin.14 Rare cases of pap-
ulonecrotic tuberculid coexistent with erythema induratum have also been
reported.16,17
The terms nodular granulomatous phlebitis of the skin and superficial
thrombophlebitic tuberculid have been proposed for an additional type of
tuberculid which presents as subcutaneous nodules along the course of a leg
vein. There is histological evidence of granulomatous inflammation centered A
on the wall of the affected vessel.18,19 This condition should be distinguished
from true tuberculous phlebitis as a consequence of miliary tuberculosis.

All tuberculids are immunological reactions thought to be due to hematog-
enously disseminated M. tuberculosis antigens or small numbers of dead bac-
teria, possibly opsonized. These embolize to produce lesions, particularly in
areas of slow circulation. As a result of changes in small dermal vessels (either
an Arthus reaction or a lymphohistiocytic vasculitis), degenerative responses
develop in the dermal collagen. In the case of papulonecrotic tuberculid, this
amounts to frank necrosis. Histologically, the lesions show variable combi-
nations of vasculitis with necrosis, a moderate to intense lymphohistiocytic
infiltrate, and granulomatous inflammation.
Papulonecrotic tuberculid, when fully developed, shows cutaneous infarc-
tion comprising a necrotic epidermis with ulceration and an underlying
V-shaped zone of dermal coagulative necrosis accompanied by a dense chronic
inflammatory cell infiltrate with scattered giant cells.4,8,9 Necrosis of hair fol-
licles may occur.20 On occasion, a histiocytic palisade has been described, B
resulting in features reminiscent of granuloma annulare. Neutrophils are gen-
erally inconspicuous. Well-formed granulomata can be present but bacilli Fig. 18.169
(A, B) Lichen scrofulosorum: note the perifollicular distribution of this well-defined
cannot be identified. Vasculitis may be present.5,8 These features can some-
granulomatous infiltrate.
times be histologically confused with pityriasis lichenoides et varioliformis
acuta.7,20
In lichen scrofulosorum, a granulomatous infiltrate in which Langhans
tuberculosis remains a serious public health problem.1 In recent years a num-
giant cells are conspicuous is centered around hair follicules and eccrine units
ber of cutaneous and other complications have been recorded, especially in
(Fig. 18.169).4
infants with primary immunodeficiency syndromes, including X-linked severe
Erythema induratum has a less histiocytic infiltrate and is indistinguish-
combined immunodeficiency.2–6 Complications have also been documented in
able from nodular vasculitis. The presence of both primary vasculitic changes
infants and children infected with HIV.7,8
and granulomatous inflammation suggests that type III and type IV hypersen-
Local infection may develop at the vaccination site, with abscess forma-
sitivity reactions are important in the latter condition.21
tion.4,6 Regional lymphadenitis is another well-recognized complication (Fig.
Although acid-fast organisms are not detectable by special stains, and
18.170), and may be accompanied by cutaneous fistula formation or scrof-
mycobacterial cultures from these lesions invariably are negative, M. tuber-
uloderma.2,5,7,9 Disseminated skin lesions may also occur, manifesting with
culosis DNA has been detected by PCR in a number of cases; this suggests
a widespread papular eruption or multiple nodules or abscesses in the skin
that mycobacterial components are indeed responsible for the pathological
and even the subcutis.1–8 Dissemination of disease can prove fatal.10 Organs
manifestations.9,22–24
that may potentially be involved include the spleen, mesenteric and medi-
The validity of the concept of the tuberculids rests on the association
astinal lymph nodes, bone marrow, liver, and lungs.2,7 Other documented
with underlying tuberculosis, a strong tuberculin reaction, and an invariable
cutaneous manifestations include lupus vulgaris, erythema induratum, and
response to antituberculous drugs.
papulonecrotic tuberculid-like lesions.11–14 A case with cutaneous involvement
secondary to intravesical BCG instillation has been reported.15
Cutaneous complications of Bacille Histological features
Calmette-Guérin vaccination In immunocompetent individuals, skin and lymph node biopsy material may
reveal multiple epithelioid cell granulomas with admixed Langhans giant cells
Clinical features and minimal caseous necrosis, with or without concomitant suppuration.10
For almost a century, the Bacille Calmette-Guérin (BCG) vaccine, which Conversely, involved tissues obtained from immunosuppressed individuals
employs a live but attenuated form of Mycobacterium bovis, has been admin- are characterized by a diffuse infiltrate of plump histiocytic cells, with poorly
istered to newborns for the prevention of tuberculosis. BCG immunization is developed or absent granuloma formation. The cytoplasm of these histiocytes
currently carried out in more than 100 countries worldwide where endemic is distended by large numbers of acid-fast M. bovis bacilli.2,8,10 The histological
diffuse inflammation, and frequent abscess formation.6–8 Systemic spread is

obviously of particular importance in this latter group. As the features may be
atypical, diagnosis is facilitated by a healthy index of suspicion.
Clinical features
Mycobacterium marinum
M. marinum (balnei) is a slow-growing photochromogen, which is associated
with injuries in aquatic environments or by fish or equipment, usually under
water.9 The upper limb is the site of infection in more than 90% of cases.10
Infections have been contracted most often in swimming pools (swimming
pool granuloma, fish tank granuloma), usually on the elbows and knees of
children, or from aquaria, usually on the hands (Fig. 18.171).11 In some stud-
ies inoculation related to fish tank exposure has accounted for more than
80% of cases.10 The lesions usually present 1 week to 2 months (average 2–3
weeks) after superficial injury and are typically painless inflammatory nod-
ules or plaques.12 They may ulcerate and discharge yellow fluid and older
lesions can be warty (Fig. 18.172). Occasionally abscesses are seen. Quite
often there is extension along lymphatics, with the development of second-
Fig. 18.170 ary nodules in a pattern comparable to sporotrichosis (Fig. 18.173).11,13,14
BCG reaction: there is marked swelling with overlying erythema and sinus
formation. Histologically, massive caseation with innumerable acid-fast bacilli was
present. Courtesy of W. Hendson, MD., Rahima Moosa Mother and Child Hospital
and the University of the Witwatersrand, Johannesburg, South Africa
findings in this latter group are similar at all sites of involvement, including
cutaneous, subcutaneous, lymph node or visceral tissues. The diagnosis may
be confirmed by PCR.16,17
Mycobacterial culture and PCR studies facilitate distinction between
cutaneous, subcutaneous or disseminated BCG infection in immunocom-
promised hosts from infection with Mycobacterium avium-intracellulare
complex and other nontuberculous mycobacterial infections. The degrad-
ing intracytoplasmic organisms contained within macrophages in the
subcutaneous nodules of Whipple's disease are PAS-positive but fail to stain
with Ziehl-Neelsen method.
Nontuberculous environmental
mycobacterial infections Fig. 18.171
Mycobacterium marinum (balnei): inflammatory nodule on the finger of an aquarium
Nontuberculous mycobacteria (atypical mycobacteria; mycobacteria other enthusiast. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
than tubercle bacilli), which are usually nonpathogenic, are widespread in
varied sites throughout the world.1–3 They inhabit vegetation and water (stag-
nant, fresh or salty), and are saprophytic in soil, on animals, and within ani-
mal feces. They are traditionally subdivided according to their growth rate on
culture media and by their ability to produce a yellow pigment in culture with
and without exposure to light. There are therefore four categories:3,4
• Group I organisms are photochromogens, which produce pigment after
exposure to light (e.g., Mycobacterium marinum and Mycobacterium
kansasii).
• Group II organisms are the scotochromogens, which produce
pigmented colonies whether light is present or not (e.g., Mycobacterium
scrofulaceum and Mycobacterium szulgai).
• Group III organisms are consistently nonpigmented and include
Mycobacterium avium and Mycobacterium intracellulare.
• Group IV organisms are the fast growers and include Mycobacterium
chelonei, Mycobacterium fortuitum and Mycobacterium abscessus.
Exact species identification may also be facilitated by PCR performed on
mycobacteria that are grown in liquid media.5 The environmental mycobac-
terial infections are becoming of increasing importance in immunocompro-
mised patients, particularly in those with HIV/AIDS. Cutaneous infection
with these organisms in the immunocompent patient usually follows an epi-
sode of trauma and gives rise to a localized lesion often clinically resembling Fig. 18.172
panniculitis. In the immunosuppressed, a history of trauma is usually lack- Mycobacterium marinum (balnei): close-up view of an erythematous plaque with
ing and patients tend to present with multiple subcutaneous nodules, more scaling. By courtesy of the Institute of Dermatology, London, UK.
Nontuberculous environmental mycobacterial infections 821
Fig. 18.174
Mycobacterium fortuitum
Fig. 18.173 chelonae: numerous
Mycobacterium marinum (balnei): this example demonstrates sporotrichoid spread. abscesses are distributed
By courtesy of the Institute of Dermatology, London, UK. along this patient's
leg. This infection is
more often seen in the
Sporotrichoid spread has also been reported in the context of HIV infection immunosuppressed. By
and following infliximab therapy.15,16 Penetrating injuries sometimes result in courtesy of the Institute of
tenosynovitis.17,18 Infection in immunodeficient individuals produces a deeply Dermatology, London, UK.
undermined ulcer; otherwise, lesions usually resolve within a few months. In
one large retrospective study the mean duration of disease was 19 months.19
Mycobacterium fortuitum chelonae (M. fortuitum complex)

M. fortuitum chelonae (M. fortuitum complex) comprises a group of rapid-
growing organisms found in soil and water and occasionally nonpatho-
genically in sputum. The organisms are M. fortuitum, M. chelonae, and M.
chelonae subsp. abscessus (M. abscessus). Lesions, which are uncommon, usu-
ally develop 3–4 weeks after contamination of skin wounds, including surgi-
cal incisions, injections, liposuction, liposculpture, and even acupuncture.9,20–22
Outbreaks of mycobacterial furunculosis due to M. fortuitum have occurred
due to communal use of footbaths at nail salons during pedicures.23–25 Reports
emerged of M. fortuitum and M. abscessus infection among survivors of the
2004 tsunami disaster off Thailand; these patients had sustained contaminated
crush trauma injuries to their lower extremities.26 A large subcutanous abscess
due to M. abscessus has been described in a patient with systemic lupus ery-
thematosus.27 Disease may present in a disseminated form, often associated
with immunosuppression, including HIV/AIDS (Figs 18.174, 18.175).7,28
Pulmonary infection with subsequent cutaneous dissemination has also been
reported in an apparently immunocompetent patient.29 The lesions comprise
indolent abscesses with fistula formation, purulent discharge, and scarring. A
sporotrichoid distribution has also been recorded (Fig. 18.176).6,30 Healing
Fig. 18.175
is usually delayed for many months, but may be helped by adequate debride-
Mycobacterium fortuitum chelonae: close-up view. By courtesy of the Institute of
ment. The M. chelonae variant is the more refractory to treatment. Dermatology, London, UK.
Mycobacterium kansasii
M. kansasii is a slow-growing photochromogen found worldwide in various a slow-growing nonchromogen, which is present sporadically on lush vegeta-
habitats. This is a disease mainly of the lungs and lymph nodes; it only rarely tion in swampy areas in the tropics.43–45 It is particularly seen in the tropical
causes skin lesions and these are most common in the immunosuppressed, wetlands of West and Central Africa (Buruli ulcer), but was characterized
when they are usually associated with disseminated disease.31–33 Iatrogenically in Australia (Bairnsdale ulcer). It has subsequently been recorded in the
immunosuppressed patients and patients with HIV/AIDS may, however, koala bear in the same region.46 The condition also occurs in tropical regions
also present with primary cutaneous infection.34,35 Cases of infection by of Asia and South America.45 Comparative genomic studies indicate that
M. kansasii are varied in their presentation: they may appear as nodules M. ulcerans recently evolved from M. marinum to become a niche-adapted
(which can be verrucous), crusted ulcers, papulopustules, cellulitis or as a specialist.47–49 Two distinct lineages exist: the ‘classic’ lineage comprising more
spreading infection resembling sporotrichosis.36,37 virulent strains from Africa, Australia, and Southeast Asia, and an ‘ancestral’
lineage, which includes genotypes encountered in China, Japan, and South
Mycobacterium ulcerans America.48 Although it has been stated that M. ulcerans infection is not linked
M. ulcerans infection is a rapidly reemerging disease, and is currently to HIV infection, a recent study from Benin suggests that there might indeed
recognized as the third most common mycobacterial disease in immunocom- be an association.45,50 Genetic polymorphism in the SLC11A1 gene may play
petent people (after tuberculosis and leprosy).38–42 The causative organism is a role in susceptibility to the disease.51
Fig. 18.176
Mycobacterium fortuitum chelonae: note the indurated, nodular, ulcerated lesion
on the hand with sporotrichoid spread. By courtesy of S. Lucas, MD, St Thomas'
The lesion develops about 8 weeks after minor trauma or skin abra-
sions which came into contact with contaminated water, soil or vegeta-
tion.38,52 Consequently, the infection usually appears on the legs and tends
to occur more often in children.52,53 A second peak occurs in late adult
life.53 Serological evidence, however, suggests that only a relatively small
proportion of infected patients develop clinical disease.54 The initial ery-
thematous nodule progresses to an indolent ulcer, which may be very
large, up to 50 cm across (Fig. 18.177). The ulcer is without exudate or
surrounding reaction, but extends to involve underlying fascia or fat and
typically has an undermined border.41,52 There is little or no malaise or
fever. After 6–9 months, a granulomatous response develops, which pre- B
cedes healing. This is usually associated with scarring, which may lead
to severe deformity and contractures.38 Surgery remains the treatment of Fig. 18.177
choice.40 Mycobacterium ulcerans: (A) note the extensive ulceration with undermining of the
The extensive tissue necrosis and ulceration that are hallmarks of the edge; (B) gross specimen showing opaque necrosis of the central subcutaneous
infection are attributable to production of mycolactone, a potent soluble fat. (A) By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK; (B) by
courtesy of the late M. Hutt, MD, St Thomas' Hospital, London, UK.
toxic macrolide possessing both cytotoxic and immunosuppressive proper-
ties.41,44,55–59 Mycolactone leads to cell death via both apoptosis and necro-
sis. This polyketide toxin has antiphagocytic properties and not only limits
the initiation of a primary immune response, but also impedes the recruit- Mycobacterium avium-intracellulare (M. avium complex)
ment of inflammatory cells to the site of infection.41,56,58,59 A nonulcerative M. avium-intracellulare (MAI) complex is a group of slow-growing nonchro-
form of the disease is recognized with increasing frequency in highly endemic mogens, which are present widely in dust, soil, and water.68,69 Exposure to soil
areas.55 Associated osteomyelitic bone lesions are not uncommon, espe- appears to represent an important environmental risk factor for infection.70
cially when multiple cutaneous lesions are present on the lower extremities.53 They are seen most commonly causing a cervical lymphadenitis or dissemi-
Occasionally, severe systemic disease and death may result from secondary nated infection in immunocompromised hosts. MAI is one of the commonest
infection or tetanus.38 Rarely, squamous cell carcinoma can arise in a chronic causes of bacteremia in AIDS patients and is also frequently isolated from the
Buruli ulcer.60,61 liver, bone marrow, lung or gastrointestinal tract. Although the skin may be
M. ulcerans infection tends to occur in parts of Africa where there is a involved as part of disseminated MAI disease, primary cutaneous infection
high prevalence of Schistosoma haematobium infection. This observation is uncommon.71 A disseminated varioliform pustular eruption due to MAI
led some authors to suggest that schistosomiasis may be a risk factor for has been described in a patient with AIDS.72 Primary infections may develop
the development of Buruli ulcer by driving the host immunological reac- in immunocompetent individuals who present with subcutaneous nodules,
tion away from a Th1 response and toward a Th2 response.45 This appar- which subsequently undergo ulceration.73–75 Isolated lesions such as perineal
ent association with schistosomiasis, however, is purely fortuitous, with no ulcers or subcutaneous masses may also occur in AIDS patients.71 Skin and
clear evidence to support the hypothesis that coinfection with Schistosoma soft tissue involvement can occur as part of the immune reconstitution inflam-
spp. confers susceptibility to infection with M. ulcerans.62 Instead, trans- matory syndrome in HIV-infected patients receiving highly active antiretro-
mission of the disease appears to be related to the close spatial proximity viral therapy.76,77 Dermal and subcutaneous infection has been reported in an
of human activities to high-risk aquatic environments.63 Current epidemio- iatrogenically immunosuppressed individual receiving treatment for systemic
logical and experimental evidence suggests that predatory aquatic insects act lupus erythematosus.78
as a potential vector of M. ulcerans, and that the aquatic snails on which Generally, the skin lesions present as a panniculitis, often in relation to
these insects feed serve as passive intermediate hosts.64,65 In the Australian affected lymph nodes, or as nodules progressing to abscesses and ulcers (Fig.
context, however, mosquitoes have been implicated in the transmission of 18.178). Healing is slow, even with appropriate drug therapy, and excision
M. ulcerans.66,67 may be necessary.
Nontuberculous environmental mycobacterial infections 823
Fig. 18.178
Mycobacterium avium Fig. 18.180
intracellulare: these Mycobacterium marinum (balnei): conspicuous Langhans giant cells are present.
multiple nodules on
the thighs resemble encountered more frequently than with other nontuberculous mycobacte-
panniculitis. By courtesy rial infections.80 Caseation is absent, but there may be fibrinoid necrosis.
of S. Lucas, MD,
Langhans cells may be conspicuous or scanty (Fig. 18.180). A lymphohistio-
St Thomas' Hospital,
London, UK.
cytic infiltrate is present in the surrounding dermis. The overlying epidermis
is parakeratotic, acanthotic or ulcerated. Pseudoepitheliomatous hyperplasia
may occur (Fig. 18.181).7 The sporotrichoid nodules, which are frequently
Other mycobacteria present, are tuberculoid granulomata without the preceding abscess phase.
There is often a poor yield of positive isolates from culture specimens, and
An expanding number of other mycobacteria, including M. scrofulaceum,
PCR (including PCR restriction analysis) may thus be a more useful means of
M. gordonae, M. simiae, M. xenopi, M. malmoense, and M. haemophilum
confirming the diagnosis.19,81
may rarely cause cutaneous lesions, mostly following inoculation, to produce
nodules and abscesses, usually with ulceration and sinus formation.2,18
Mycobacterium fortuitum chelonae (M. fortuitum complex)
Histological features M. fortuitum chelonae (M. fortuitum complex) infection shows early acute
inflammation, which progresses to ill-defined granulomata with occasional
Most of these,atypical, mycobacteria show early cutaneous necrosis with
necrotic foci. Panniculitis and acute suppurative folliculitis may also be
neutrophil abscess formation. This phase is usually associated with readily
observed (Fig. 18.182).7 Bacilli are easily seen and are present in clusters
demonstrable bacilli. The abscess phase is gradually replaced by granuloma-
(Figs 18.183, 18.184).30,82
tous inflammation and fibrosis, often with sinus formation.
M. marinum follows the common histological progression from abscess to
granuloma, but few of the broad, long bacilli are seen, except in immuno-
compromised patients (Fig. 18.179).7,79 Granulomatous inflammation is
Fig. 18.181
(balnei): abscess formation
and granulomatous
inflammation have eroded
the overlying epidermis.
The features of this
Fig. 18.179 condition closely mimic
Mycobacterium marinum (balnei): there is hyperkeratosis and very marked acanthosis. the deep fungal infections.
Mycobacterium kansasii
M. kansasii infection shows a pattern similar to other nontuberculous
mycobacterial infections. The early mixed inflammation is usually intense
before becoming tuberculoid. Abscesses may be present. Bacilli are frequent.
M. kansasii organisms are larger, broader, and more coarsely beaded.83 Some
cases show overlying acanthosis with hyperkeratosis and parakeratosis. The
acute lesions seen in immunosuppressed patients typically show an intense
neutrophil infiltrate with abscess formation.32,36
Mycobacterium ulcerans
M. ulcerans infection is characterized by extensive coagulative necrosis
and ulceration with very little inflammatory reaction for a few months
(Fig. 18.185).43,52,84 Tissue destruction is mediated by the production of
mycolactone, which induces both necrosis and apoptosis.57,83 In this aner-
gic stage, bacilli are very numerous and are seen clustering in the collagen
of fascia or in fat at the base of the ulcer (Fig. 18.186). Leukocytoclastic
vasculitis has been described in both the dermis and septa of the sub-
cutaneous fat.52,85 Focal calcification may be seen. Healing of the ulcer
Fig. 18.182 corresponds with progressive positivity of the ‘burulin’ test and a granu-
Mycobacterium fortuitum chelonae: this is a predominantly neutrophil-mediated lomatous reaction. Mycobacteria are then sparse or absent.52 Caseation is
infection.
Fig. 18.183
Fig. 18.185
Mycobacterium fortuitum chelonae: aggregates of bacilli are typically visible in the
(A, B) Mycobacterium
hematoxylin and eosin stained sections.
ulcerans: there is
widespread coagulative
necrosis. Note
A the absence of an
inflammatory reaction.
Fig. 18.184 B
Mycobacterium fortuitum chelonae: the bacilli are strongly acid fast.
Leprosy 825
Other mycobacteria
M. haemophilum may produce a mixed suppurative and granulomatous
reaction in addition to a paucigranulomatous reaction, lichenoid interface
dermatitis, and lymphocytic vasculitis.92
Leprosy
Clinical features
Mycobacterium leprae is the bacillus recognized as causing leprosy, and until
recently could only be cultured in experimental animals, particularly the nine-
banded armadillo. It is an obligate intracellular, Gram-positive, weakly acid-
fast organism. The disease is found worldwide, due to extensive traveling
and migration, but is endemic in the tropics.1–4 The past two decades have
seen a dramatic decrease in the global disease burden from over five million
people in the mid-1980s to around 800 000 by the mid-1990s. More than
250 000 new cases were detected in 2006, a decrease of more than 13% when
compared with 2005. The gobal registered prevalence of leprosy was around
Fig. 18.186 224 000 at the beginning of 2007.5–8
Mycobacterium ulcerans: the lesions contain numerous acid-fast bacilli (Ziehl- Although the disease has been recognized for many centuries and its
Neelsen). causative organism has been known for over 100 years, many aspects of
the pathogenesis remain unclear, and leprosy is still a problem to diagnos-
ticians, epidemiologists, and pharmacologists. The complexity of the pre-
sentation is related intimately to the varied immunological responses. The
not a feature. Variable septolobular panniculitis can be present. Resolving incubation period may be as short as 1–2 years, but is usually 3–5 years,
lesions may exhibit pseudoepitheliomatous hyperplasia of the epidermis.86 and may be 10 years or more. The recent ability to culture infected
In the nonulcerated form there is massive contiguous necrosis of the der- macrophages isolated from patients with multibacillary leprosy holds
mis and subcutaneous tissue.55 The ulcerated lesions may demonstrate promise for the ex vivo study of M. leprae and its interaction with its
immunoreactivity for phenolic glycolipid-I (PGL-I).85 Local recurrence host.9
has been linked to the presence of persistent infection in macroscopi- There are two extreme modes of presentation:
cally healthy tissue beyond the surgical excision margins.87 A sensitive • the tuberculoid form, tuberculoid leprosy (TT),
dry reagent-based PCR method for confirmation of the diagnosis has been • the lepromatous form, lepromatous leprosy (LL).
described.88,89 Between these are:
• borderline tuberculoid leprosy (BT),
Mycobacterium avium-intracellulare (M. avium • borderline lepromatous leprosy (BL),
complex) • borderline leprosy (BB) occupying an intermediate position.1–4
M. avium-intracellulare (M. avium complex) infection sometimes appears to
have an early abscess phase before the granulomatous phase, but in other Tuberculoid leprosy
cases the inflammatory infiltrate is more lymphohistiocytic, so that it resem- Tuberculoid leprosy (TT) is associated with high resistance to the lepra bacil-
bles lepromatous leprosy (Fig. 18.187).68,69 Bacilli are present, but are usually lus, but in the lepromatous form resistance to the lepra bacillus is low.3,4,10
intracellular. Rarely, infected histiocytes become large and voluminous and TT occurs in individuals with good cell-mediated immunity, but low
have been referred to as pseudogaucher cells.90 The histological picture may antibody titers to M. leprae. It appears as localized, sometimes single, asym-
also mimic histoid leprosy.91 A case of cutaneous mycobacterial spindle cell metrical truncal or limb lesions. The lesion is typically an erythematous
tumor due to M. intracellulare has also been reported.78 plaque with raised margins and a flat hypopigmented center (Fig. 18.188).
A B
Fig. 18.187
(A, B) Mycobacterium avium intracellulare: in this variant, the infiltrate typically consists of histiocytes, lymphocytes, and neutrophils. Bacteria are often numerous.
Fig. 18.190
Lepromatous leprosy:
Fig. 18.188 note the symmetry and
Tuberculoid leprosy: note the hypopigmentation and erythema. By courtesy of B characteristic loss of the
Al-Mahmoud, MD, Doha, Quatar. eyebrows. By courtesy of
N.C. Dlova, MD, Nelson
Sensory impairment is invariable because of associated involvement of R. Mandela School of
nerves by the bacilli; these nerves may be palpably thickened. Alternatively, Medicine, University of
KwaZulu-Natal, South
the skin lesion may be an erythematous macule, hypopigmented in dark
Africa.
skins. Sometimes the skin is not involved primarily, cutaneous manifes-
tations being seen as a result of minor trauma associated with anesthesia
from the neural lesion.
groins, and perineum. These lesions become anesthetic due to widespread
Lepromatous leprosy neural involvement with resultant claw hand and foot drop (Fig. 18.191).
Lepromatous leprosy (LL) is a systemic disease that occurs in patients with A rare phenomenon occurring in patients with LL is the development of numer-
poor cell-mediated immunity to M. leprae, but with higher levels of anti- ous histiocytoma-like lesions: the histoid variant (Fig. 18.192).11–13 Large
bodies. The cutaneous lesions are multiple, symmetrical, and may affect cutaneous and subcutaneous nodules and plaques, sometimes measuring in
the whole skin, giving a sclerodermatous appearance (diffuse or Lucio-type excess of 3 cm in diameter have been described.14–16
leprosy). The lesions are typically firm and nodular and are concentrated on
the face and backs of hands, facial lesions being associated with hair loss Borderline leprosy
round the eyes (Figs 18.189, 18.190). The distribution of the lesions is said Lesions in BT, BL and BB manifest in a form intermediate between the polar
to be favored by lower skin temperature. The mucosa of the nose is character- forms TT and LL (Figs 18.193–18.195). The lesions are fewer in number
istically involved and becomes hyperemic with frequent epistaxes. The nasal and less symmetrically distributed than in LL and there is less localization and
cartilages and bone may be affected, and collapse can result in a picture simi- nerve involvement than in TT. There is, however, a continuous spectrum and
lar to the saddle nose of congenital syphilis. A variety of macules, papules, individual patients may downgrade to more closely resemble LL or upgrade
and plaques may be present at one time, characteristically sparing the axillae, towards the tuberculoid pole.
Fig. 18.191
Fig. 18.189 Lepromatous leprosy: these hands show loss of the digits and trauma-related
Lepromatous leprosy: numerous nodules are present on the face. By courtesy of ulcers due to gross nerve damage. By courtesy of S. Lucas, MD, St Thomas'
S. Lucas, MD, St Thomas' Hospital, London, UK. Hospital, London, UK.
Leprosy 827
Fig. 18.195
(A, B) Borderline
lepromatous leprosy:
there are gross infiltrated
erythematous plaques
with well-defined borders.
(A) By courtesy of
Fig. 18.192 S. Lucas, MD, Institute
Histoid leprosy: these numerous brown papules and nodules may be histologically of Dermatology, London,
mistaken for a ‘fibrohistiocytic’ tumor if the clinical information is not available. By UK; (B) by courtesy of
courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK. N.C. Dlova, MD, Nelson
R. Mandela School of
Medicine, University of
A KwaZulu-Natal, South
Africa.
Fig. 18.193
Borderline tuberculoid leprosy: an early hypopigmented macule. By courtesy of
B
S. Lucas, MD, St Thomas' Hospital, London, UK.
Lepra reactions
Type I Lepra (reversal) reactions, which usually develop in BL patients, are
associated with an upgrading to a more resistant tuberculoid pole of the
spectrum and the development of a positive Mitsuda (lepromin) reaction.3,17
Patients therefore have developed an improved immunological reaction. Less
often, type I reactions may be associated with downgrading. They may be
associated with treatment, and consequently are characterized by an accel-
erated destruction of bacilli. Type I Lepra reactions are also associated with
pregnancy, stress, and intercurrent infections. The upgrading causes marked
inflammatory changes within the skin: nerve lesions manifest as nerve swell-
ing and pain; cutaneous lesions may become tender and edematous with an
increased cellular infiltrate (Fig. 18.196).3
Type II reaction, also known as erythema nodosum leprosum (ENL),
occurs in LL and BL, usually during treatment. It may also be provoked
by physical or mental stress, injury, other infections, vaccinations or preg-
nancy.3,18,19 There appears to be a direct relationship between an increasing
bacterial index and the risk of developing ENL. Increasing age, on the other
Fig. 18.194 hand, has been found to have an inverse relationship with ENL. The reac-
Borderline tuberculoid leprosy: note the ulceration and muscle wasting due to median and tion may occur prior to, during or after the introduction of multidrug ther-
ulnar nerve involvement. By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK. apy.20 The changes of ENL are believed to be due, at least in part, to immune
Fig. 18.196
Type I Lepra reaction: note the unilateral edema and intense erythema. By courtesy
of S. Lucas, MD, St Thomas' Hospital, London, UK. Fig. 18.198
Lucio's phenomenon: note the multiple infarcted cutaneous nodules, which have
developed against a background of diffuse lepromatous leprosy. By courtesy of
R. Arenas, MD, and J.C. Salas, MD, Monterrey, Mexico.
acular, then soon break down to become irregular jagged ulcerations, which
m
heal to leave irregular atrophic scars. The extremities are most commonly
affected. Although Lucio's phenomenon, like ENL, was considered to be
mediated by immune complexes, this concept has since been challenged. It
has recently been suggested that the triggering event is thrombotic vascular
occlusion secondary to massive invasion of vascular endothelial cells by the
bacilli, r esulting in necrosis.30
Indeterminate leprosy
Indeterminate leprosy is an early form of leprosy, which often resolves spon-
taneously.31 However, in 25% of patients, evolution to one of the determinant
types occurs. It appears as poorly defined areas of slight hypopigmentation
or erythema, without systemic or neural changes. The condition is only likely
to be recognized readily in endemic areas where there is a high awareness of
leprosy. It must be carefully distinguished from other dermatoses.
The Mitsuda reaction (intradermal injection of armadillo-derived Lepra
bacilli) has proved useful for classification purposes.4 Tuberculoid patients
Fig. 18.197 develop a granulomatous response; lepromatous patients do not (Fig.
Erythema nodosum leprosum: note the erythematous nodules on the dorsal aspect 18.199).3
of the forearms and shins. By courtesy of S. Lucas, MD, St Thomas' Hospital,
Although leprosy has been reported in patients infected with HIV, cur-
London, UK.
rent evidence suggests that M. leprae is not an opportunistic pathogen in
these individuals.32–34 In recent years there have been a number of reports of
complex deposition in vessels following the release of bacterial antigens in leprosy occurring as a manifestation of the immune reconstitution inflamma-
patients who have high levels of antibodies. Both immunoglobulins and com- tory syndrome (IRIS) following the initiation of highly active antiretroviral
plement have been identified in blood vessel walls. Delayed hypersensitivity therapy in HIV-infected individuals.35–38 Leprosy is only rarely encountered in
mechanisms, however, are also thought to have a pathogenetic role. In ENL immunosuppressed organ transplant recipients.39
there are, therefore, increased numbers of T-helper cells and an increased Leprosy patients with chronic cutaneous ulcers (especially plantar lesions)
lesional helper:suppressor T-cell ratio is characteristic.18 Studies performed on are at increased risk for the development of squamous cell carcinoma.40,41
lesional tissue have confirmed a preponderance of CD4+ T cells and a Th1
type immune response.21 The symptoms are nocturnal pains, mainly of the Pathogenesis and histological features
face, thighs, and arms. Lesions include tender erythematous or deep purple The varied clinical manifestations of leprosy are the result of a number of fac-
nodules with fever and painful nerve swelling, swollen joints, myositis, pain- tors, including the host's immune response, the mode of infection, and cer-
ful fingers, iritis, lymphadenitis, glomerulonephritis, and epididymo-orchitis tain genetic factors.42 It was long assumed that transmission of leprosy was
(Fig. 18.197).18 Cases with bullous skin lesions have been reported.22–25 by long-term close direct skin contact, but this can be seriously questioned
as there is no evidence that infection can occur through intact skin. LL is far
Lucio's phenomenon more infective than other forms and the nasal mucosa and nasal secretions
Lucio's phenomenon (erythema necroticans) is seen in Mexican and Central of patients with LL are heavily infected with bacilli. This is a most important
American patients who present with untreated, diffuse, non-nodular lep- source of infection, but it is not clear that the route of transmission is via
romatous leprosy (pure and primitive diffuse lepromatous leprosy (PPDLL); the lungs or gastrointestinal tract, even though inhalation of droplets and
diffuse leprosy of Lucio and Letapí) associated with hemorrhagic infarc- ingestion of bacilli do occur. Lactating mothers with LL produce high counts
tion and epidermal necrosis (Fig. 18.198).18,26–30 Lesions, which are initially of bacilli in milk and yet do not appear to spread leprosy to their babies.
Leprosy 829
Fig. 18.199 Fig. 18.200

Mitsuda reaction: this is Tuberculoid leprosy:
positive in a patient with there is extensive
tuberculoid leprosy. infiltration of the dermis
By courtesy of R. Arenas, and subcutaneous
MD, and J.C. Salas, MD, fat by noncaseating
Monterrey, Mexico. granulomata.
It seems most likely that infection in leprosy occurs by a combination of nasal Histologically, TT is characterized by an epithelioid histiocyte response
discharge and digital impregnation of the skin, as bacilli can be carried under around small cutaneous nerves (Figs 18.200–18.202). It may be entirely
the nails and inoculated into the skin by scratching. A recent study revealed confined to the immediate vicinity of nerves in highly immune patients, but
that untreated patients with multibacillary leprosy may shed organisms into it often extends into the adjacent dermis. When there are clinical cutaneous
the environment via their skin and nasal epithelia.43 Inoculation leprosy is a lesions the infiltrate involves the papillary dermis up to the epidermis. In con-
rare phenomenon acquired through skin tattooing.44 trast, BT and more lepromatous forms have a preserved Grenz zone in the
The responses of those that are infected may be determined by a genetic papillary dermis. Tuberculoid lesions usually contain a number of Langhans
predisposition, as suggested by associations with human leukocyte antigen giant cells, but necrosis is not a feature. Bacilli are so scarce in tuberculoid
(HLA) types (e.g., DR2 and DR3). In tuberculoid lesions there is an efficient lesions that they are usually not identified; they are present in increasing num-
granulomatous macrophage response, associated with a preponderance of bers in variations closer to the lepromatous type of response. Distinguishing
T-helper (CD4+) cells over T-suppressor cells (CD8+) and no antibody pro- TL from other forms of granulomatous infiltrate of the skin is dependent on
duction. There is associated elimination of the bacteria, which are therefore noting the association with nerves, which often gives the granuloma a ser-
difficult to find in tuberculoid lesions. The tuberculoid response is therefore pentine shape. In addition, there are numerous lymphocytes, largely T-helper
characterized by a persistent or chronic delayed hypersensitivity reaction, type, which may infiltrate the nerves in highly immune cases; the lymphoid
with a Th1 immune response.3,9 A Th2 response characterizes multibacillary infiltrate may be intense and extensive.
leprosy.3,9 In lepromatous lesions T-suppressor cells are more numerous and
IL-2 producing cells are scarce, whereas they are 10 times more common in
TT. One explanation for the different response suggests that T-helper cells are
defective or absent in individuals who develop LL. An alternative theory sug-
gests that T-suppressor cells are activated by the leprosy bacilli in patients of
certain HLA-DR types. It is proposed that this represents a response to PGL-I,
which is peculiar to the cell envelope of the leprosy bacillus. The T-suppressor
cells effect a reduction of T-helper cells reactive to M. leprae. In this way
the T-suppressor and T-helper theories are not incompatible. The variable
immune response to the Lepra bacillus is manifest in the wide variety of clini-
cal manifestations in leprosy.45 Other genetic factors including Lewis factor
and natural resistance-associated macrophage protein 1 (NRAMP1) may also
play a role.42 A recent study from India found that BCG vaccination played a
beneficial role in the prevention of leprosy.46
In LL there is an inability to develop a significant T-cell-mediated delayed
hypersensitivity reaction to the leprosy bacillus.3 The high level of antibodies
in LL appear to have no beneficial effect, but are relevant to the development
of the immune complex-mediated ENL lesions (see above). Lucio's phenom-
enon, in which purpura and leg ulcers develop, was thought to involve a simi-
lar immune complex-mediated mechanism to produce episodes of necrotizing
vasculitis in this diffuse type of leprosy. Others, however, have since suggested
that direct invasion of vascular endothelium by large numbers of bacilli, with Fig. 18.201
subsequent thrombosis of vessels, is the major factor in the evolution of this Tuberculoid leprosy: lymphocytes are present in addition to giant cells and
reaction.30 Antiphospholipid antibodies may also play a role.47 granulomata.
A B
Fig. 18.202
Tuberculoid leprosy: (A) this small nerve is almost completely replaced by the granulomatous infiltrate; the residual nerve tissue is arrowed; (B) S-100 protein immunohistochemistry
is invaluable in identifying damaged nerves.
Fig. 18.203 Fig. 18.204

Lepromatous leprosy: Lepromatous leprosy: a
there is infiltration of the Grenz zone of sparing of
dermis by large numbers the papillary dermis is
of histiocytes. characteristic.
In LL, as in TL, the macrophage is the most important cell, but it Plasma cells are rarely seen in leprosy. They may, however, be found
is not arranged in discrete granulomata nor clearly related to nerves. in subpolar LL, which clinically lies between BL and polar LL (Figs
Rather, macrophages are found in poorly circumscribed masses in the 18.207–18.209).
dermis with few, if any, lymphocytes (Figs 18.203, 18.204). Those lym- In borderline leprosy perineural fibrosis with a lamellar or ‘onion skin’
phocytes that are present are T-suppressor cells. The macrophages are pattern may be seen. Borderline leprosy shows increased circumscription of
inert and often vacuolated or foamy (Fig. 18.205). They may be dis- the granulomatous response, more lymphocyte, and more relation to nerves
tended with large groups (or globi) of leprosy bacilli. These give the cyto- as it approaches the polar tuberculoid form.
plasm a grayish tinge on staining with hematoxylin and eosin; the bacilli Indeterminate leprosy shows only a scanty superficial and deep lympho-
are revealed more clearly with a modified Ziehl-Neelsen stain (Wade- histiocytic infiltrate in the dermis, with some tendency to localization around
Fite) (Fig. 18.206). The bacteria are present in large numbers of cutane- appendages (Fig. 18.210). Bacilli are infrequent, but scantily present in
ous nerves and are also seen in that site in the borderline forms of leprosy. nerves (Fig. 18.211). Mast cells are increased.50 S-100 protein immunohis-
Bacilli may also be present in the endothelium and media of small and tochemistry is a useful means of identifying dermal nerves and foci of nerve
large vessels, in arrector pili muscles, and in the eccrine secretory and damage in skin biopsy specimens.51,52
ductal cells.48 Exceptionally, clumps of bacilli may even be encountered Histologically, in most instances Lucio's phenomenon is characterized by
in epidermal keratinocytes.49 the features of a leukocytoclastic vasculitis and epidermal infarction.18,30,53
Rhinoscleroma 831
Fig. 18.205
Lepromatous leprosy: the cytoplasm of the histiocytes is bubbly and has a
grayish hue.
Fig. 18.207
Subpolar lepromatous
leprosy: there is a dense
dermal infiltrate. A Grenz
zone is present.
Fig. 18.206
Lepromatous leprosy: large numbers of bacilli are present; note the globi (Wade-
Fite).
Severe passive venous congestion of the superficial veins is common.18

Occasionally, however, some vessels are thrombosed and there is endothe- Fig. 18.208
Subpolar lepromatous leprosy: in addition to histiocytes and lymphocytes, there are
lial cell proliferation and swelling.26,53,54 Marked intraendothelial cell bacil-
conspicuous plasma cells.
lary proliferation is characteristic.18,53 It has been suggested that this feature
is indicative of a very poor immune response facilitating antigen–antibody
interaction with consequent acute necrotizing vasculitis. This seems to be
rather unlikely (on its own) as similar numbers of leprosy bacilli have been Molecular techniques (PCR) may prove useful in confirming the diagno-
described in the endothelium of 100% of small vessels in untreated polar and sis of leprosy, especially in paucibacillary forms or when organisms are not
subpolar LL.30,48 readily apparent in sections stained with the Wade-Fite method.56–58
Histoid leprosy shows a spindle cell proliferative pattern suggestive of
fibrous histiocytoma (Figs 18.212, 18.213). A storiform pattern may be
conspicuous. Careful examination, however, will reveal foci of Lepra cells. Rhinoscleroma
A Wade-Fite reaction reveals large numbers of bacilli, often arranged in
sheaves.13 Clinical features
ENL is characterized by an inflammatory cell infiltrate in the der- Rhinoscleroma is usually seen in adults and is now confined to the trop-
mis and adjacent subcutaneous fat (Figs 18.214–18.216). In addition to ics, although it was previously common in Eastern Europe.1–3 The disease
Lepra cells, large numbers of neutrophils are typically present, and there has been linked to poor socioeconomic conditions and is still encountered
is often an acute vasculitis (Fig. 18.217).21,55 Bullous lesions are charac- in parts of Africa, Southeast Asia, Mexico, Central and South America, and
terized by dermal edema.25 Organisms are demonstrable within capillary Central and Eastern Europe.3,4 Rhinoscleroma has also been described in the
endothelium.25,30 Arabian Gulf.5 It is a severe chronic infection of the upper respiratory tract,
Fig. 18.209
Subpolar lepromatous leprosy: leprosy bacilli are numerous (Wade-Fite).
Fig. 18.211
Indeterminate leprosy: (A) the inflammation involves the small nerve trunks; (B) a
Wade-Fite reaction may reveal one or two bacilli (arrowed). By courtesy of S. Lucas,
MD, St Thomas' Hospital, London, UK.
Fig. 18.210
(A, B) Indeterminate
leprosy: a perivascular
chronic inflammatory cell
infiltrate is present in the
deep dermis. Diagnosis
A depends on a high index
of suspicion.
Fig. 18.212
B Histoid leprosy: in this field appearances are highly suggestive of a fibrohistiocytic
tumor. By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK.
Rhinoscleroma 833
Fig. 18.213
Histoid leprosy: there is a well-developed storiform pattern. By courtesy of
S. Lucas, MD, St Thomas' Hospital, London, UK.
Fig. 18.215
Erythema nodosum
leprosum: note the
perivascular lymphocyte
and histiocyte infiltrate.
Fig. 18.214
Erythema nodosum
leprosum: an intense
inflammatory cell infiltrate
outlines the dermal Fig. 18.216
vasculature and extends Erythema nodosum leprosum: numerous polymorphs are intermingling with the
into the subcutaneous fat. Lepra cells.
e specially the nose. The disease is contracted by direct droplet infection or, usual, but has been reported.6 Nasal obstruction, loss of smell, loss of
more indirectly, by contamination of material that is subsequently inhaled. It voice, laryngeal stenosis, and increasing difficulty with breathing may
has a very long incubation period. follow.4,7 Respiratory obstruction may cause death; alternatively, the
There are three phases to the clinical features of the disease: process can persist with some temporary remissions for years. Squamous
• It begins with a catarrhal phase, with symptoms suggesting a non-specific carcinoma is an occasional late complication.
rhinitis or coryza with frontal headaches.2 These symptoms persist for weeks Contiguous involvement of the soft and hard palate, the upper lip, and the
or months, becoming gradually more severe with superimposed epistaxes and maxillary sinuses may occur; the term respiratory scleroma has been proposed
difficulty in nasal breathing associated with swollen mucous membranes. for these cases with extranasal extension of the disease.8 Rosai-Dorfman
• An infiltrative phase follows during which the nasal septum and base disease has been documented in the regional lymph nodes of a patient with
of the nasal fossa become swollen by a reddish waxy induration.2 This rhinoscleroma.9
change is painless and the soft palate is anesthetic. Similar involvement of
the larynx causes changes in the voice. Pathogenesis and histological features
• The infiltrative phase merges into a nodular phase during which there is The causative bacterium Klebsiella rhinoscleromatis is a Gram-negative
increasing deformity as the nose, upper lips, and gums become grossly aerobic diplobacillus.8,10 It is spread during the rhinitis (catarrhal) phase
enlarged and distorted.2 Involvement of regional lymph nodes is not of the disease and appears to be confined to close-living groups, and has
Fig. 18.217 Fig. 18.219

Erythema nodosum leprosum: several small vessels show fibrinoid necrosis. Rhinoscleroma: numerous organisms are revealed by the Warthin-Starry reaction.
This type II reaction develops on the basis of an immune complex-mediated By courtesy of S. Lucas, MD, Institute of Dermatology, London, UK.
vasculitis.
even been documented in siblings.11 There is no animal reservoir. An HLA- Differential diagnosis
DQA1*03011-DQB1*0301 haplotype has been identified as a poten- This includes midfacial granulomata, lymphoma, tertiary syphilis,
tial risk factor for development of the disease, while other investigators lepromatous leprosy, leishmaniasis, and rhinosporidiosis. The histology, as
have suggested that altered lymphocyte subsets may play an important described above, should exclude these clinical alternatives.
pathogenetic role.12,13
The incubation period is very long, so that presentation is most often
in adults. The organism is phagocytosed, but not killed by neutrophils.
When the neutrophils rupture the still viable bacteria are phagocytosed Nocardiosis
by histiocytes, which become greatly distended. These eventually appear
vacuolated with an eccentric nucleus (Fig. 18.218). Warthin-Starry or Clinical features
Giemsa staining reveals that this vacuole contains bacteria (Fig. 18.219). Nocardia is found in soil and rotting vegetation worldwide and man
This cell, 10–100 μm in diameter, is termed a Mikulicz cell and, together is only rarely infected.1–4 Initially, three main pathogenic species were
with Russell bodies (plasma cells grossly distended with proteinaceous recognized:
product), is characteristic of the disease. As well as these characteristic • Nocardia asteroides, which is most common in North America,
cells, there is a dense infiltrate of plasma cells and lymphocytes, which • Nocardia brasiliensis in South America,
becomes very extensive and eventually causes such gross thickening of the • Nocardia caviae in Southeast Asia.1,3,5
mucosae that the respiratory tract tends to be occluded at several points. Other species of Nocardia have since been associated with infection in
The mucosa can be ulcerated or atrophic. Amyloid deposition has been humans, including N. transvalensis, N. otididiscaviarum, N. nova, N. farcinica,
described.14 N. paucivorans, N. abscessus, N. cyriacigeorgici, and N. asiatica.1,4,6–17 Infection
A B
Fig. 18.218
(A, B) Rhinoscleroma: in addition to lymphocytes and numerous plasma cells, foamy macrophages (Mikulicz cells) are present.
Botryomycosis 835
complicates inhalation or direct inoculation into a wound.1,3 Nocardiosis

therefore represents a respiratory illness, with or without dissemination (the
majority), or a primary cutaneous disease.1,2
N. asteroides, N. caviae, and N. farcinica most often affect immunocom-
promised hosts, causing pulmonary lesions from which systemic dissemina-
tion may involve the skin.3 Predisposing factors include steroid therapy, HIV
infection, and solid organ transplantation.1,4,11–13,18–21 Central nervous system
involvement is an important cause of morbidity and high mortality.11,19 Primary
cutaneous infection has been reported in an immunocompetent adult follow-
ing a cat scratch.22 Dissemination is a frequent complication of N. paucivorans
infection in both immunocompromised and immunocompetent hosts.14
N. brasiliensis causes primary skin lesions in immunocompetent individu-
als and can also cause primary pulmonary lesions.4,23 The cutaneous lesions
are varied and usually follow trauma. They include a mycetoma, usually on
the limbs, and a sporotrichosis-like pattern (including a cervicofacial variant
that occurs in children), i.e., with multiple lesions following the line of lym-
phatics.3,24,25 In addition, superficial nodules, ulcers, and abscesses, with or
without fistulae and pustules, may occur (Fig. 18.220).26,27 Some more trivial
infections resemble staphylococcal infections and are usually self-limiting; the
deeper infections are progressive and can be destructive without treatment. Fig. 18.221
Nocardia: the organisms appear mainly as irregularly staining filaments in this
Dissemination of primary cutaneous nocardiasis is exceptionally uncom-
specimen, but a variety of forms, including rods and cocci, is often seen. By courtesy
mon.28 Infection has been reported after an insect bite.29 Lymphocutaneous of A.E. Prevost, MD, and H.P. Lambert, MD, St George's Hospital, London, UK.
nocardiosis may also be caused by N. transvalensis.6 Mycetomas due to
N. nova and N. otididiscaviarum have been reported.7,10 N. otididiscaviarum
is a rare cause of cellulitis.9 histologically by its weak acid-fastness, distinguishing it from Actinomyces.
Differential culture may be necessary to distinguish the two, although the
Pathogenesis and histological features presence of sulfur grains is a pointer towards actinomycosis.31
Nocardia is a Gram-positive, partially acid-fast aerobic beaded rod, which
grows with branching filaments in a way similar to Actinomyces (Fig.
18.221).30 Infection by N. asteroides, a relatively avirulent organism, is usu- Botryomycosis
ally by inhalation. N. brasiliensis is more virulent and can infect the immu-
nocompetent through inoculation of soil into skin. It is the most commonly Clinical features
identified organism in the sporotrichoid form of nocardiosis.4,24 Botryomycosis (Gr. botrys, bunch of grapes) is also known as bacterial
Grains, analogous to the sulfur granules of actinomycosis, can develop pseudomycosis and is due to a chronic bacterial infection, usually of skin.1,2 It
in the mycetoma lesions of the immunocompetent. Filamentous growth is has also been described in lung, bone, kidney, and liver.1–6 A case of gingival
a feature of greater virulence or less immunity; methenamine silver is most botryomycosis resembling a pyogenic granuloma has been reported.7
satisfactory for demonstrating the filaments in tissue sections. In the skin, the lesions are chronic suppurative nodules which may resem-
The histological features in the skin are of ulcers, abscesses with pus, necro- ble infected epidermoid cysts, plaques, and ulcers. The interconnecting fis-
sis, hemorrhage, and fibrosis associated with sinus tracks. The organism is not tulae which develop give it a similarity to acne conglobata and hidradenitis
readily seen with hematoxylin and eosin staining, but can be demonstrated suppurativa, but the sites commonly involved are the hands, feet, and head.1
Fig. 18.220
Nocardiosis: (A) this cutaneous nodule developed in an
immunocompromised young male; (B) a different lesion
A B is shown in close-up. By courtesy of R.A. Marsden,
There may be a history of preceding trauma or the presence of a foreign

body. Deeper tissues, including muscle and bone, may become involved.
Botryomycosis of the cervicofacial region has also been described in a patient
with mandibular chronic osteomyelitis.3
The pulmonary involvement has the radiological features of lobar consoli-
dation, sometimes with adjacent osteomyelitis. Involvement of liver, tongue,
orbit, bowel, and brain has also been described. Cystic fibrosis appears to
predispose to some pulmonary cases. Although immunodeficiency has been
noted in some cases and the condition has been reported in association with
HIV/AIDS, most patients who develop botryomycosis have no detectable
abnormality of the immune system.8–13 The cutaneous lesions of botryomyco-
sis in patients with HIV/AIDS may, however, present with atypical features;
lesions resembling prurigo nodularis, lichen simplex chronicus, and pruritic
papules have been described.11,13

The lesions of botryomycosis include a characteristic granule surrounded by
suppuration and the features of a chronic abscess. The granule consists of
nonfilamentous bacteria in a hyaline matrix, containing IgG and complement
Fig. 18.223
C3 (the Splendore-Hoeppli phenomenon), and is a lobulated or ‘bunch of Botryomycosis: note the blue-staining bacteria surrounded by an intensely eosinophilic
grapes-like’ structure (Figs 18.222, 18.223).10 The granule is basophilic in fibrillary coat (the Splendore-Hoeppli phenomenon). The inflammatory response is characteri
the center and eosinophilic at the periphery.1 It is PAS positive. The bacteria stically neutrophil mediated.
present are not specific to the condition; S. aureus is most common, but
Pseudomonas, E. coli, Proteus, Micrococcus, and streptococci may also
be found.1,3,11,14 Fungi, actinomycetes, and Nocardia are not causes. There
have, however, been isolated case reports of botryomycosis due to combined
S. aureus and Actinobacillus actimomycetemcomitans infection, and S. aureus
in association with Pneumocystis jiroveci.12,15
The abscess persists with numerous sinuses and extensive fibrosis, and may
extend to involve deep adjacent structures. Rarely, the granules are eliminated
transepithelially.16 The reasons for the persistence and for granule formation are
not fully understood. Although some patients show immunodeficiency, sometimes
analogous to the anergy of lepromatous leprosy, this is not so for most cases. The
size of the original inoculum appears to be critical – excessive numbers of bacte-
ria produce an overwhelming abscess and cellulitis, too few bacteria are rapidly
eliminated by normal inflammatory responses – but an intermediate size of inoc-
ulum can produce what may be interpreted as a balance between the bacteria and
the inflammatory response, with granule and chronic abscess formation.1,2,17 This
balance may be attained more easily with less virulent strains.
A foreign body may contribute to the initiation of the lesion, but is not
invariable. A local factor may be important, such as some as yet undemon-
strated defect in the cutaneous immune mechanisms, diabetes mellitus or an
underlying dermatosis such as follicular mucinosis.18 In pulmonary cases,
Fig. 18.222 cystic fibrosis represents that local underlying defect. Botryomycosis with
(A, B) Botryomycosis: concurrent cutaneous small vessel vasculitis has been documented.19
there are multiple dermal
A abscesses surrounding
discrete bacterial colonies. Malakoplakia
Clinical features
Malakoplakia (soft plaque) most often affects the urinary tract, but it can
involve many other organs including the gastrointestinal tract, lymph nodes,
genitalia, brain, bone, lungs, retroperitoneum, adrenals, and skin.1–4 The
median age at presentation is approximately 53 years, and the disease appears
to be twice as common in males as in females.3 Cutaneous lesions are most
common around the genitalia or perineum, but are occasionally seen in other
sites.2–4 Their appearance is variable and includes plaques, ulceration, polyps,
and sinuses, with surrounding induration, as well as nodules and papules.4,5
They may be associated with malakoplakia elsewhere.
Underlying or associated conditions (which are usually linked with immu-
nosuppression) can include carcinoma, rheumatoid arthritis, systemic lupus
erythematosus, diabetes mellitus, leukemia, lymphoma, and immunosuppres-
sion following transplantation.2,3,6 However, the condition remains distinctly
uncommon in patients with HIV/AIDS; this has been ascribed to selective or
B relative preservation of antimicrobial monocytic function.5,7 The skin lesions
are nonprogressive but are persistent.
Actinomycosis 837
Pathogenesis and histological features then calcify; the reason for these changes is not clear, although some cases
occur in systemic disease associated with a probable impairment of mac-
Lesions of malakoplakia are characterized by confluent sheets of histiocytes
rophage function.1,4 Other organisms that have been cultured from lesions
(von Hansemann cells) with eosinophilic granular cytoplasm and small,
of malakoplakia include Gram-negative bacilli (Klebsiella spp., Enterobacter
usually eccentric nuclei. These cells also contain characteristic cytoplas-
spp., Proteus spp., Pseudomonas spp.) and Gram-positive cocci, including
mic basophilic bodies shown to be calcified with von Kossa staining (Figs
Staphylococcus aureus, Streptococcus spp., and enterococci.3,4,9
18.224, 18.225). These round, sometimes laminated structures are known as
Michaelis-Gutmann bodies. Their targetoid pattern is accentuated by staining
with periodic acid-Schiff. They may also be positive on staining with Perls'
reaction for iron. The Michaelis-Gutmann body is sufficiently distinctive Malakoplakia should be distinguished from infectious granulomata, histio-
to allow cytological distinction of malakoplakia in a preparation from skin cytosis, and granular cell tumor, and from pseudomalakoplakia,3,9,10 which
scrapings.8 Immunohistochemistry with an antibody to BCG may highlight refers to an abnormal histiocytic proliferation in a previous surgical site.
the intracytoplasmic bacteria.9 Although pseudomalakoplakia also comprises sheets of large histiocytes with
The histiocytic infiltrate may be mixed with neutrophils, lymphocytes, intracytoplasmic calcific material, this condition is distinguished from true
and plasma cells, with associated granulation tissue. Electron microscopy malakoplakia by the lack of concentric lamination of the granules.9,10
of malakoplakia shows that the histiocytes contain numerous phagolyso-
somes that occasionally contain intact and partly digested bacteria. It has
been suggested that phagolysosomes in macrophages accumulate in response
Actinomycosis
to chronic bacterial infection. The infection is not by one specific organism,
but the agent is usually E. coli.3 The phagolysosomes tend to fuse and
Clinical features
Actinomyces israelii is a commensal in the human mouth, along with other
organisms including Aggregatibacter (formerly Actinobacillus) actinomycet-
emcomitans.1 A. israelii is the usual pathogen but occasionally other species
including A. viscosus, A. naeslundii, A. odontolyticus, A. meyeri, A. turicensis,
and A. radingae are implicated.2–5 The most common manifestation is cervi-
cofacial actinomycosis, but more grave pulmonary and intestinal infections
can occur and, rarely, purely cutaneous lesions.1,6–9 The cervicofacial form is
common in farm workers and is associated with poor oral hygiene, usually
starting from carious teeth and following dental extractions or oral trauma.
The condition is infrequent in children and most common in young men.
Respiratory involvement as lung abscess and fistulae may ‘point’ through
the thoracic wall (Fig. 18.226).10 Abdominal lesions include appendiceal and
colonic actinomycosis and hepatic involvement and it may complicate the
use of intrauterine contraceptive devices, with lesions affecting the internal
female genitalia. Cutaneous fistulae may subsequently develop.11,12
The cervicofacial lesion presents as a hard swelling on the lower jaw or
occasionally as a plaquelike infiltration of the cheek from the upper jaw
(cf. bovine lumpy jaw). These firm thickened areas tend to discharge through
sinuses and are associated with scarring and the formation of new nodules
(Fig. 18.227). Yellow granules measuring up to 2 mm in diameter – the
so-called ‘sulfur granules’ – are occasionally found in the discharging pus.
Fig. 18.224 Extensions of some maxillary lesions may reach the orbit and base of the
Malakoplakia: the infiltrate consists of histiocytes with eosinophilic granular skull. Uncommonly, a large facial mass may develop.5,13
cytoplasm. Note the pale blue, laminated Michaelis-Gutmann bodies.
Fig. 18.225 Fig. 18.226

Malakoplakia: use of the von Kossa reaction renders the Michaelis-Gutmann bodies Actinomycosis: extensive intrathoracic disease has resulted in involvement of the
more conspicuous and reveals that they are much more numerous than was anterior chest wall. Numerous sinuses are evident. By courtesy of P. Duhra, MD,
apparent in the hematoxylin and eosin stain. Coventry and Warwickshire Hospital, Coventry, UK.
Fig. 18.227 Fig. 18.229

Actinomycosis: infection of the cervicofacial region; note the scarring and dimple at Actinomycosis: a bacterial colony lies in the center of an abscess.
the site of the draining sinus. By courtesy of T.F. Sellers, MD, and H.P. Lambert, MD,
Fig. 18.230
Actinomycosis: high-power view.
Fig. 18.228
Actinomycosis: multiple sinuses are present about the lateral malleolus. By courtesy
of R. Hay, Institute of Dermatology, London, UK.
is a Gram-negative coccobacillus which inhibits growth of fibroblasts and
keratinocytes. It is speculated that this, together with its different susceptibil-
ity to antibiotics, helps to maintain the actinomycotic lesion.
Histologically, the lesions have the features of chronic abscesses and
Rarely, direct inoculation of skin may produce a similar chronically dis- sinuses, containing pus and surrounded by fibrosis and a mixed inflammatory
charging abscess with adjacent scarring (Fig. 18.228). Alternatively, a myce- infiltrate (Fig. 18.229). Locules separated by granulation tissue are present.
toma or chronic discharging abscess mass with multiple sinuses may develop. Sulfur granules of intertwined bacteria are seen, radiating mycelial filaments,
This primary form of cutaneous actinomycosis is rare. Sites have included the often with opaque clubs at their tips (Figs 18.230, 18.231).21 These granules
thigh, the arm, and the nose.14–17 Most cases are the result of external trauma may be associated with the Splendore-Hoeppli phenomenon.
and local ischemia, but this is not always the case.14,15,17,18 Some infections
have been acquired through injection wounds, including one report where
an A. odontolyticus-associated subcutaneous abscess evolved in an intrave- Whipple's disease
nous cocaine user who admitted to licking his hypodermic needle prior to
injection.14,19 Clinical features
An uncommon form of the disease is the presence of disseminated cutane- Whipple's disease is a rare, chronic multisystem infective disorder caused by
ous lesions in the absence of demonstrable extracutaneous infection; this has Trophyrema whippelii, a Gram-positive bacillus and member of the actino-
been reported in a patient with acute leukemia.20 mycetes.1–3 The condition has a propensity to occur in middle-aged Caucasian
males.1 The gastrointestinal tract is the main target of infection, resulting
Pathogenesis and histological features in low-grade fever, weight loss, abdominal pain, diarrhea, and malabsorp-
The mixture of organisms involved in actinomycosis is not purely accidental tion syndrome. Other potential manifestations include lymphadenopathy,
but is synergistic. A. israelii is a Gram-positive, nonacid-fast, microaerophilic seronegative arthritis, neurological signs, uveitis, endocarditis, and pleuritis,
bacterium with filamentous branching organisms. A. actinomycetemcomitans sometimes in the absence of concomitant gastrointestinal symptoms.1,4
Erythrasma 839
Fig. 18.232
Fig. 18.231 Erythrasma: (A) note the
Actinomycosis: Gram-positive bacteria with club-shaped ends are present at the well-demarcated axillary
periphery of the granule. scaly red patch; (B)
there is a scaly inguinal
patch with associated
Skin involvement in the form of cutaneous hyperpigmentation is rela- hyperpigmentation.
By courtesy of the
tively common, occurring in 17% to 40% of patients.4,5 Rarely, erythema
A Institute of Dermatology,
nodosum-like subcutaneous nodules may develop as a result of infective pan- London, UK.
niculitis. The latter comprise painful red-brown nodules. Lesions may occur
on the thighs, arms, buttocks, lower legs and, rarely, the chin and neck.6–9
Erythema nodosum is another potential cutaneous manifestation.6

Although T. whippelii is a ubiquitous organism in the environment, Whipple's
disease remains a very rare condition.10 It would seem that susceptible indi-
viduals have defects in T-cell immunity and impaired ability of macrophages
to degrade the intracellular organisms.11 The subcutaneous nodules have
the appearance of a predominantly septal panniculitis, with a conspicuous
infiltrate of foamy macrophages. Careful examination reveals cytoplasmic
distension of these histiocytes by PAS-positive, diastase-resistant intracyto-
plasmic material representing degenerate bacteria.2,8,9 These macrophages
closely resemble those encountered in duodenal biopsy material. The viable
bacilli have a characteristic double-walled (trilaminar) appearance on ultra-
structural examination.1,6 The organism may be cultured in specialized lab-
oratories. PCR and immunohistochemical methods for confirmation of the
diagnosis exist.10–12 B
Whipple's disease should be distinguished from histoplasmosis, histoid lep-
romatous leprosy, and infection with Mycobacterium avium-intracellulare not seen.4 Erythrasma rarely presents as a disciform eruption with an atro-
(MAI) complex, as all of the aforementioned conditions are characterized by phic appearance involving nonintertriginous areas.5,6 Involvement of the feet
intracytoplasmic organisms contained within macrophages. PAS-positive fun- (particularly the toe webs) and toenails has also been documented.7–9 Rarely,
gal yeasts, however, are observed in histoplasmosis, whereas Ziehl-Neelsen lesions on the feet have a vesiculobullous appearance.10 Nail involvement is
and Wade-Fite stains will confirm the presence of acid-fast mycobacterial characterized by hyperkeratosis and onycholysis. Erythrasma may coexist
bacilli in MAI infection and lepromatous leprosy, respectively. with a dermatophyte infection or, rarely, pityriasis versicolor.11,12 An associa-
tion with trichomycosis axillaris and pitted keratolysis may also occur.13,14
A biopsy is only exceptionally performed as the diagnosis is confirmed by
Erythrasma the use of Wood's light or scrapings stained by Gram, PAS, Grocott, Giemsa
or methylene blue.
Clinical features Corynebacterium minutissimum has rarely been associated with bacter-
Erythrasma is a bacterial infection caused by Corynebacterium minutissi- emia, abscess formation, cellulitis or visceral involvement in immunocompe-
mum, a Gram-positive bacillus.1,2 It characteristically presents as asymptom- tent or immunocompromised patients.15–18
atic, well-defined, scaly red patches on the inguinal and intergluteal skin
(Fig. 18.232). It has a predilection for obese and diabetic patients and it Histological features
is more common in areas with a humid and hot climate. The clinical diag- A skin biopsy usually appears unremarkable when stained with hematoxylin
nosis is easy because of the demonstration of a typical coral-red fluores- and eosin except for mild hypergranulosis and occasional superficial perivas-
cence under Wood's light.3 This fluorescence is the result of production of cular lymphocytes. The special stains mentioned before, particularly Gram,
coproporphyrin III by the organism. In exceptional cases, fluorescence is show the presence of bacilli in the stratum corneum (Fig. 18.233).
the nodules are usually black and the disease mainly involves the scalp.
Distinction from white piedra may be more difficult as the disease has a wide
anatomical distribution and it has been suggested that the latter disease is the
result of a synergistic interaction between corynebacteria and Trichosporon
beigelii, the organism previously implicated in white piedra.10 Trichomycosis
has been reported in association with erythrasma and pitted keratolysis.11,12
Pitted keratolysis
Clinical features
Pitted keratolysis (keratolysis plantare sulcatum) is an unusual bacterial infec-
tion of plantar skin occurring predominantly but not exclusively in humid
tropical regions of the world.1,2 The condition has been recorded in soldiers
and paddy field workers.3,4 The cause of the disease remained elusive for many
years although it was initially ascribed to infection with Corynebacterium
spp. Two Gram-positive organisms have since been implicated in the patho-
genesis of pitted keratolysis: Dermatophilus congolensis (accounting for the
majority of infections) and Kytococcus (Micrococcus) sedentarius.1,2,5,6 The
Fig. 18.233 disease occurs predominantly in young men. Children are rarely affected.7
Erythrasma: bacilli are evident in the stratum corneum. Frequent presenting symptoms include hyperhidrosis, malodor or even slimi-
ness of the feet.2 Soreness and pruritus may also occur. D. congolensis causes
a variety of dermatidites in domesticated herbivores, and it has been sug-
gested that human infections result from contact with infected animals or
Trichomycosis contaminated soil.8
As indicated by the name, pitted keratolysis is associated with superficial
Clinical features pitlike erosions of the stratum corneum of the plantar skin. These coalesce
Despite the name, trichomycosis is a bacterial infection caused by different to form characteristic crateriform defects which are concentrated on the
species of corynebacteria, including Corynebacterium tenuis.1,2 The Gram- pressure-bearing areas of the foot (Figs 18.235, 18.236). The circular cra-
positive bacteria invade the cuticle of the hair and it has been suggested that teriform pits measure 0.7– mm or more in diameter and appear to be distrib-
they adhere to the hair shaft by producing a cement-like substance.3 However, uted along the plantar furrows.1,2 Rarely, the palms may be involved.9 In one
this view has been challenged and it is proposed that the material that pro- recent report, treatment of hyperhidrosis with botulinum toxin injection lead
vides support for the organisms is the apocrine sweat.4 The disease typically to resolution of pitted keratolysis, suggesting that hyperhidrosis itself could
involves the axillary hair (trichomycosis axillaris) and exceptionally may be play a pathogenetic role in the condition.10 An increased prevalence among
seen in the pubic hair and scrotum (trichomycosis pubis) (Fig. 18.234).5–9 hepatitis B virus surface antigen carriers was suggested in a recent study.11
The disease is characterized by yellow, red or (more uncommonly) black nod-
ules along the hair shaft. These nodules may be confused with nits. However, Pathogenesis and histological features
the nodules in trichomycosis fluoresce under Wood's light. In black piedra, In vitro studies have shown that both D. congolensis and K. sedentarius pro-
duce keratinolytic enzymes, thus accounting for the superficial defects in the
stratum corneum.5,12 The early lesions demonstrate stratum corneum pallor.
Biopsies of the plantar pits show small defects in the upper stratum cor-
neum, the walls being almost vertical in configuration.1,2 Special stains (Gram,
Fig. 18.234
Trichomycosis: this matted
appearance of the hair
results from the presence
of multiple tiny nodules.
By courtesy of the Fig. 18.235
Institute of Dermatology, Pitted keratolysis: note the typical scaliness and pitlike areas. By courtesy of the
London, UK. Institute of Dermatology, London, UK.
Sago palm disease 841
Cutaneous infection by C. ulcerans may mimic true cutaneous diphtheria
both clinically and histologically.9 The distinction is made by microbiological
investigations. A case of cutaneous ulceration due to C. pseudodiphtheriticum
infection was reported recently.10
Sago palm disease

Clinical features
Sago palm disease is an exceedingly uncommon chronic bacterial infection
of the skin which appears to be restricted to a swampy region of Papua
New Guinea where there are groves of sago palms.1–3 The disease was first
described in 1973 and is caused by a hitherto unclassifiable Gram-positive
bacillus.2,3 Infection is acquired by traumatic inoculation while handling the
palms.1
The primary cutaneous lesions manifest only months later and tend
to spread contiguously over a prolonged period, ranging from months to
years. The limbs, trunk, and face are the major sites of predilection.1–3 The
Fig. 18.236 clinical appearances are those of verrucous, hyperkeratotic nodules which
Pitted keratolysis: note
are not associated with ulceration or hemorrhage (Fig. 18.237).2 Systemic
the tiny pits on the
spread has not been documented thus far.2 The infection is resistant to
weight-bearing aspect of
the foot. By courtesy of treatment.
S. Glassman, MD, Division
of Dermatology, University
of Witwatersrand,
Johannesburg, South
Africa.
methenamine silver, PAS or Giemsa) are required to visualize the organisms,

which comprise both coccoid and filamentous forms.1,2,6 The coccoid forms
tend to be concentrated near the surface of the pit whereas the filamentous
forms are present in relation to the deeper portions of the defect.2,6 The fila-
mentous forms show both branching and septation. The filamentous form
of D. congolensis is characteristically composed of chains of small coccoid
bodies.1
Cutaneous diphtheria
Clinical features
Cutaneous diphtheria is an uncommon condition caused by the Gram-positive
bacillus Corynebacterium diphtheriae.1,2 Toxicogenic and nontoxicogenic A
strains exist. Although cutaneous diphtheria is essentially a tropical condi-
tion, increasing tourism to tropical regions and a decline in adult booster vac-
cination against diphtheria have resulted in numerous cases being reported
from developed countries.2–6 The disease usually results from inoculation of
C. diphtheriae organisms into pre-existing lesions such as burns, ulcers, and
eczematous rashes; cutaneous diphtheria may also manifest in apparently
normal skin.1–3 The condition has been reported in intravenous drug users.7
The lower legs and feet are sites of predilection but sites such as the face,
trunk, and even the genitalia may be involved.1,8 Initially there is a vesicle
or pustule. This later evolves into an ulcer which is often reddish-purple in
color, with rolled and undermined borders, and a yellow-gray membrane or
dark crust covering its base.1,3 The ulcers are painful initially but are later
hypoanesthetic.3 Regional lymphadenopathy may occur, and toxicogenic
strains may result in systemic complications involving the nervous system or
heart.1
Histological examination of the ulcer reveals a necrotic epidermis and der- B
mis. The dermal base of the ulcer contains necrotic debris, fibrin, and an
admixture of acute and chronic inflammatory cells.2 Since the club-shaped Fig. 18.237
and beaded Gram-positive rods are often difficult to visualize in histological (A, B) Sago palm disease: widely distributed keratotic nodules and plaques
material, microbiological examination of swabs from the center of the lesion are present. By courtesy of E. Wilson Jones, MD, Institute of Dermatology,
is required for confirmation of the diagnosis.1 London, UK.
Histological features The diagnosis of tularemia is usually confirmed by serology or culture

of the organism.2 F. tularensis is not demonstrable in routinely stained
The pathological changes in sago palm disease are centered on the dermis,
sections. It may, however, be detected in histological material by direct
which is expanded by a relatively circumscribed nodular mass composed of
immunofluorescence or PCR.2,3,14
sheets of foamy histiocytes, lymphocytes, plasma cells, and fibroblasts.1,2 The
overlying epidermis is hyperkeratotic. The causative bacteria are difficult to
identify in routinely stained sections. The Gomori methanamine silver stain
reveals large numbers of bacteria which appear to be embedded in amorphous
ground substance.1,2 The bacilli measure approximately 1.8 μm in length and
Infections caused by Rickettsiae
0.5 μm in width; beading and branching of the organisms may be observed.1,2 Clinical features
The ultrastructural features are characteristic.2
Rickettsiae are small, obligate, intracellular pathogens. Rickettsial infections
Since the etiological agent has not been cultured successfully, the diagno-
can be divided into three groups:
sis of sago palm disease is based upon the clinicopathological features, sup-
ported by electron microscopy.2 • The typhus group includes epidemic typhus fever (a louse-borne infection
caused by Rickettsia prowazekii), the recrudescent form of the latter
(Brill-Zinsser disease), murine (endemic) typhus fever (a tick-borne
infection caused by R. typhi), and R. felis infection (which is clinically
Tularemia indistinguishable from classic murine typhus).
• The spotted fever group includes Rocky Mountain spotted fever
Clinical features (a tick-borne infection caused by R. rickettsii), other spotted fevers/
Tularemia is a zoonotic infection caused by Francisella tularensis, a nonmotile forms of tick typhus (e.g., Boutonneuse fever and Mediterranean
Gram-negative bacillus.1–3 Five subspecies exist, but only F. tularensis subsp. spotted fever caused by R. conorii conorii, geographically specific
tularensis and F. tularensis subsp. holarctica are known to be associated with strains of R. conorii resulting in conditions such as South African
disease in humans.4 The infection is usually acquired via the bite of an arthro- tick-bite fever, Israeli spotted fever, Astrakhan spotted fever or Indian
pod (such as a tick or deerfly) or by handling the carcasses of infected animals, tick typhus, Queensland tick typhus caused by R. australis, African
especially rabbits, hares, and rodents.1–3 Tularemia is a disease of the northern tick-bite fever caused by R. africae, etc.), and rickettsial pox (caused
hemisphere, with the majority of infections reported from North America, by R. akari, and the only infection in this group to be transmitted by
Scandinavia, and other parts of Europe.2,3,5–10 The incubation period is approx- a mite).
imately 3–6 days.5 The potential threat of the organism being used as a bioter- • Scrub typhus is caused by Orientia tsutsugamushi (formerly R. tsutsugamushi)
rorism agent has led to renewed interest in the disease in recent years.4 and transmitted by infected chiggers or larval mites of Leptothrombium
The most common form of tularemia is the ulceroglandular type, which spp.1–11
accounts for 80% or more of infections.3,9 Other clinical forms include Coxiella burnetii (the cause of Q fever), Ehrlichia spp. (the cause of ehrli-
typhoidal, oculoglandular, oropharyngeal, and primary pulmonary tulare- chiosis), and Bartonella (formerly Rochalimaea) spp. represent a separate
mia.3 The ulceroglandular form is characterized by a small, painful erythema- group of rickettsia-like organisms and are not discussed here.
tous papule at the site of inoculation, usually on an exposed limb. After a Advances in molecular taxonomic methods have led to not only the
few days the papule breaks down to form a punched-out ulcer which may reclassification of rickettsial diseases but also recognition of an ever increas-
discharge seropurulent material.2 This is almost invariably associated with ing spectrum of rickettsial pathogens.11 In addition, there has been renewed
lymphangitis and severe, acute painful lymphadenitis of the regional lymph interest in pathogenic rickettsiae as potential agents of bioterrorism.2,12
nodes.2,7 Other potential cutaneous manifestations, which may develop in all Although all of the true rickettsial infections listed above are associated
of the clinicopathologic forms of tularemia, include macular, papular, vesicu- with variable cutaneous manifestations, there is great diversity in the extent
lar or pustular eruptions, erythema nodosum lesions, and erythema multi- of involvement and degree of clinical severity. A detailed discussion of the
forme.2,6 Vesicular lesions may be mistaken clinically for herpes simplex or epidemiological, clinical, and pathological characteristics of each entity is
varicella-zoster virus infection.11 Skin lesions (other than a primary lesion) beyond the scope of this text; for more information the reader is referred to
were documented in 43% of patients in a recent analysis of 234 Scandinavian reference numbers 1, 2, and 3, which provide outstanding overviews of the
cases.9 Associated constitutional symptoms and signs may be pronounced subject.
and include fever, chills, headache, weakness, myalgia, and coughing.2,7,9 Endemic typhus and rickettsial pox are mild infections, whereas Rocky
Ulceroglandular tularemia generally carries a good prognosis, although death Mountain spotted fever is a severe multisystem disease which may involve
due to septicemia may occur in untreated patients.3,5 Acute tularemic pneu- the central nervous system, kidneys, lungs, heart, and liver. Gangrene of the
monia, which is acquired by inhalation of aerosolized organisms, carries a extremities and a coagulopathy may also occur.3,13 Scrub typhus is extremely
high mortality.3 variable, ranging from an asymptomatic illness to a severe infection with
significant mortality if untreated. The earliest symptoms of rickettsial infec-
Pathogenesis and histological features tion are non-specific and include fever, headache, chills, and myalgias. Rocky
F. tularensis is a highly virulent pathogen; as few as 10 organisms inocu- Mountain spotted fever often has additional symptoms of nausea, vomiting,
lated into the subcutis may initiate infection.5 The organism is also extremely and abdominal pain. Lymphadenopathy is encountered in rickettsial pox, tick
hazardous to laboratory personnel. It is an elusive facultative intracel- typhus, and scrub typhus.
lular pathogen that possesses novel mechanisms to ensure its survival in An eschar characteristically develops at the site of the arthropod bite in
macrophages.12,13 the spotted fever group (with the exception of Rocky Mountain spotted
The early papular lesions show non-specific features, including intercel- fever) and in scrub typhus; eschar formation is not a feature of the typhus
lular and intracellular edema of the epidermis, sometimes accompanied by fever group (Fig. 18.238).13 Eschars may be multiple.14 Initially, there may
vesiculation.2 There is also dermal edema, telangiectasia, and a mild perivas- be a papule or papulovesicle. After a variable interval a skin rash evolves. In
cular infiltrate. Early cutaneous ulcers are characterized by fibrinopurulent most cases this is macular, eventually becoming maculopapular. Generally,
exudation and an accompanying infiltrate of lymphocytes and macrophages.2 the rash commences on the trunk and spreads to the extremities, frequently
Later, there is a well-developed zonal pattern of suppurative granulomatous involving the palms and soles; the converse is true for Rocky Mountain spot-
inflammation, a phenomenon that is recapitulated in the affected regional ted fever. Vesiculation and scab formation are features of rickettsial pox,
lymph nodes.3 The central zone contains necrotic material and karyorrhectic and the palms and soles are usually not involved in the latter condition.
debris. An intermediate zone comprising epithelioid histiocytes and giant cells A petechial or hemorrhagic rash may occur in epidemic typhus fever, Rocky
envelops this. An outer mantle containing lymphocytes, histiocytes, plasma Mountain spotted fever, and the other spotted fevers but is not observed in
cells, and extravasated erythrocytes in turn surrounds the latter zone.2,5 scrub typhus.3
Infections caused by Rickettsiae 843
by hematogenous dissemination. R. rickettsii has the unique capacity to

also invade and induce necrosis of vascular smooth muscle cells, thereby
accounting for the greater severity of the illness and multiorgan involve-
ment.3 In vitro studies performed on the spotted fever group of rickettsiae
have shown that infection of endothelial cells leads to induction of cycloox-
ygenase 2 (COX-2) and the release of vasoactive prostaglandins.15 Vascular
leakage appears to be the consequence of gaps forming in interendothelial
adherens junctions.16
Histological examination of the eschar reveals wedge-shaped coagulative
necrosis of the epidermis and superficial dermis, sometimes accompanied by
necrotizing vasculitic changes in small venules and arterioles, and an infil-
trate of macrophages at the base. A dense backgroud perivascular lympho-
cytic infiltrate often accompanies these changes (Fig. 18.239).14,17 A small
vessel lymphocytic vasculitis of variable severity is encountered in biopsies
from the maculopapular lesions. This is usually mild in cases of endemic
typhus and scrub typhus, whereas the dermal vessels in established cases
of Rocky Mountain spotted fever show severe involvement, with endothe-
lial hyperplasia and nonocclusive intravascular fibrin-platelet thrombi, focal
lymphocytic vasculitis, and leukocytoclastic vasculitis.3,18–20 Dermal eryth-
Fig. 18.238 rocytic extravasation is a feature of the petechial and hemorrhagic lesions.
South African tick bite fever: an eschar marks the site of the arthropod bite on
There is epidermal basal layer vacuolar degeneration. Biopsies from the
the inner thigh. The patient also had lymphadenopathy. By courtesy of M. Hale,
MD, National Health Laboratory Service and University of the Witwatersrand, vesicular lesions of rickettsial pox will show an intraepidermal vesicle, some-
Johannesburg, South Africa. times accompanied by a neutrophilic infiltrate at the base or subepidermal
edema.21,22
In the past, the diagnosis was confirmed by the Weil-Felix test. Although
this has been superseded by tests employing complement fixation, latex agglu-
Pathogenesis and histological features tination, and immunofluorescence methods, these are generally not capable of
A hallmark of the rickettsial infections is the presence of vascular endothe- yielding a more rapid result. Immunofluorescence studies on frozen skin biopsy
lial invasion by the organisms. Following the bite of the vector, the material, however, may be a useful and relatively rapid means of confirming
Rickettsia organisms adhere to vascular endothelium and later become the diagnosis of a suspected rickettsial infection. Immunohistochemistry and
internalized into the cytoplasm of these cells. Replication occurs, followed PCR have also been used with success.3,13
Fig. 18.239
South African tick bite fever: (A) there is upper dermal
A B edema, vascular ectasia, and a dense perivascular chronic
inflammatory cell infiltrate; (B) note the thrombosed vessel.
Protozoal infections
Leishmaniasis
Clinical features
Leishmania is an organism related to the trypanosomes. The life cycle con-
tains a flagellate phase (promastigote) which occurs in the intestine of its vec-
tor, a female Phlebotomus or Lutzomyia sandfly, and a phase in which the
flagellum is retracted (amastigote). The latter is the form seen in the human
host. Various mammals, including gerbils, rodents, dogs, jackals, and foxes,
may act as reservoirs of infection.1–5
An estimated 12 million people are affected worldwide, with as many as
2 million new cases occurring annually, including 1.5 million with cutaneous
leishmaniasis and some 500 000 with visceral leishmaniasis.6,7 Visceral leish-
maniasis and to a lesser extent cutaneous leishmaniasis are increasingly rec-
ognized as opportunistic diseases in immunocompromised patients, especially
those infected with HIV.6,8,9
The various species of Leishmania are distinguished on the grounds of bio-
A
chemical and antigenic differences. Although leishmaniasis tends to be seen in
Asia, Africa, the Americas, and the Mediterranean countries, it is being seen
more often in nonendemic countries, particularly among refugees and return-
ing holidaymakers.10,11 There are eight main types of cutaneous presentation,
with many local geographic and species variations.
In endemic regions a significant number of people appear to have asymp-
tomatic (subclinical) infection, so-called cryptic leishmaniasis.10
Confirmation of the diagnosis has traditionally been achieved by visual-
ization of the organisms in smears or tissue sections, or with the aid of the
Montenegro (leishmanin) skin test, especially in the developing world. Over
the years these investigations have been complemented or superseded by
serology, culture or PCR-based methods.5,7
Cutaneous leishmaniasis
Cutaneous leishmaniasis has many local names, including oriental sore,
Baghdad boil, Chiclero's ulcer, and Aleppo boil. It is caused by Leishmania
tropica, Leishmania major, and Leishmania aethiopica and affects men,
women, and children. Mediterranean cutaneous leishmaniasis is caused pre-
dominantly by Leishmania infantum.10 B
Lesions occur on any site accessible to biting by the sandfly vector, most
commonly the hands, arms, and face (Fig. 18.240). They present as an ery- Fig. 18.240
thematous papule that enlarges over the course of a few weeks into an ulcer- Cutaneous leishmaniasis: (A) this healing lesion shows crusting and scarring; (B)
ated and crusted nodule. Occasionally, multiple lesions are seen. Lesions there is an extensive ulcerated erythematous plaque with scaling. (A) By courtesy
of J.C. Pascual, MD, Alicante-Spain; (B) From the collection of the late NP Smith
show a tendency to orientation along the skin creases, and grossly the ulcers
MD., the Institute of Dermatology, London, UK.
have been compared to a volcano in surface appearance and configuration.12
Variants may be hypoesthetic, psoriasiform, eczematous, varicelliform,
paronychial, chancriform, zosteriform, annular, whitlow-like, erysipeloid, emisphere, but some subvariants can cause destructive ulceration of the ear. Most
h
verrucous or keloidal or present as macrocheilia.10,13,14 Regional lymphade- infections with L. (V.) braziliensis are local and heal without much damage.
nopathy can be a feature.15 Chronic cutaneous leishmaniasis represents persistence (or spread) of an
In the Eastern hemisphere, where the disease has traditionally been referred acute lesion for more than 1 year. Lesions are particularly seen on the face as
to as, “Old World”, leishmaniasis, these lesions may be ‘wet’ or ‘dry’: raised erythematous plaques which may resemble erysipelas (Fig. 18.241).10
• The wet type has a short incubation period (2 weeks) and occurs in rural The erysipeloid lesions are erythematous and infiltrative and are said to occur
areas. It is caused by L. major and develops like a suppurative folliculitis more frequently in women above the age of 50 years.19
which ulcerates, the surrounding edematous, indurated erythema The acute lesions may be followed by a relapsing chronic or lupoid stage
extending gradually to reach a maximum of 6 cm. Small secondary (leishmaniasis recidivans or leishmaniasis recidiva cutis) in which brownish
nodules may be seen around this. Slow resolution with cribriform papules develop close to the scar of the earlier stages. This occurs in 3–10%
scarring occurs over 3–12 months. of patients.20 These papules extend to resemble lupus vulgaris; they may
• The dry form is caused by L. tropica, has a longer incubation period develop hypertrophic scars or become verrucous. They are extremely slow to
(2 months), and is mostly seen in urban areas.16 The initial lesion is a brown resolve, even under treatment, and may persist for many years. It is thought
nodule and this becomes a plaque up to 2 cm across. It may ulcerate centrally that a change in local immunity results in reactivation of intracytoplasmic
with a firm crust. Resolution occurs with scarring over 12 months or longer. organisms.20 The leishmanin or Montenegro skin test for cellular immunity to
The American forms, traditionally referred to as ‘New World’ leishma- Leishmania is strongly positive in nearly all cases. It has been suggested that
niasis, are caused predominantly by L. mexicana and L. (subgenus Viannia) leishmaniasis recidivans represents a hypergic form of the disease, but this has
braziliensis. Other species implicated recently include L. amazonensis, been disputed by others.21 Although this presentation is typically encountered
L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana.17,18 The lesions in Eastern hemisphere leishmaniasis, a small number of cases of leishmaniasis
of L. mexicana are usually like those of cutaneous leishmaniasis in the Eastern recidiva cutis complicating American leishmaniasis have been reported.21–23
Leishmaniasis 845
A
Fig. 18.241
Cutaneous leishmaniasis:
chronic cutaneous
leishmaniasis showing
intense edema, erythema,
and scaling. By courtesy
of S. Lucas, MD,
St Thomas' Hospital,
London, UK.
Skin infections with L. (V.) braziliensis are liable to recur as mucosal

lesions, known as espundia (in which there is much tissue destruction), some-
times years later. The mucosal lesions occur most often in the nasal septum
and mouth and rarely around the eyes, genitalia, and anus (Fig. 18.242).
Patients may also develop ‘tapir nose’ in which there is considerable damage
to the nasal cartilage resulting in a free-hanging nose.10 The mucosal lesions
start as superficial erosions, but become deeply ulcerative and destructive.
The Montenegro skin test is almost always positive.
Diffuse cutaneous leishmaniasis, also known as pseudolepromatous leish-
maniasis, is caused by variants of L. mexicana and L. aethiopica. The former Fig. 18.242
occurs in Bolivia, Venezuela, Mexico, and Brazil, while the latter is seen pre- (A, B) Mucocutaneous
dominantly in Ethiopia. It develops as a consequence of an impaired cellu- leishmaniasis: the lesions
lar immune response.20 A study from Egypt showed a significant association are destructive and very
between histocompatibility antigens HLA-A11, B5, and B7 and the occur- disfiguring. By courtesy of
rence of this disease.24 It begins as a nodule, which grows and becomes sur- B S. Lucas, MD, St Thomas'
rounded by other similar lesions. This process is repeated until eventually, Hospital, London, UK.
over many years, most of the skin becomes nodular (Fig. 18.243). The nod-
ules do not ulcerate and can closely resemble lepromatous leprosy. Although
lesions may develop in the nasal mucosa, these are not destructive like those with lymphadenopathy, pancytopenia, irregular and intermittent fever, and
of the mucocutaneous form of American leishmaniasis. Response to therapy marked weight loss. In India, some patients develop earthy-gray pigmenta-
is slow and relapse is common. The Montenegro test is invariably negative. tion, particularly on the temples, around the mouth, and on the hands and
L. major and L. (V.) panamensis may be associated with a sporotrichoid feet.10
spreading reaction.6 A small number of patients who recover subsequently develop post-kala-
There have been rare reports of neoplasms such as basal cell carcinoma, azar dermal leishmaniasis.33 This has been reported from India and East Africa.
squamous cell carcinoma or even dermatofibrosarcoma protuberans arising The lesions start as erythematous or hypopigmented macules (particularly
in scars associated with cutaneous leishmaniasis.25–28 on the face) and become nodular and coalesce so that they closely resemble
lepromatous leprosy, but they lack sensation abnormalities. The lesions are
Visceral leishmaniasis persistent, but resolve slowly on treatment.34,35
Visceral leishmaniasis (kala-azar, black fever) is due to infection by L. donovani
complex and occurs widely in South America (L. chagasi), Africa (L. infantum), Pathogenesis and histological features
the Mediterranean (L. infantum), and Asia (L. donovani and L. infantum).7,29,30 In all variants of the disease the amastigote form of the parasite multiplies
It may be a manifestation of HIV infection.6,8,31 In patients with HIV/AIDS, within the histiocytes of the mammalian host. The host response is related to
leishmaniasis may occur in herpes zoster lesions and dermatofibroma cells the number of amastigotes and the degree of cellular immunity. Large num-
may be parasitized by the organisms. Nodular cutaneous lesions arising in bers of amastigotes are associated with an anergic response and many histio-
AIDS-related visceral leishmaniasis may mimic Kaposi's sarcoma clinically.32 cytes without other inflammatory cells. Moderate numbers of amastigotes
Following inoculation, the organisms multiply in histiocytes; the onset of are usually associated with necrosis, which is an important mechanism for
disease is insidious, taking 2–4 months. The macrophages of the liver and eliminating infection. Smaller numbers are associated with a good epithe-
spleen take up the organisms, resulting in hepatosplenomegaly associated lioid granulomatous response after the necrosis phase. Some infections are
degeneration of the basal keratinocytes has been described.20 The epidermis

may show pseudoepitheliomatous hyperplasia, and intraepidermal neutro-
phil microabscesses are not infrequent. The dermis typically contains an
intense infiltrate of histiocytes, lymphocytes, and plasma cells. Rarely, a
Grenz zone is evident. Neutrophils and eosinophils are usually sparse.39 Large
numbers of amastigotes are evident and these may be seen within the overly-
ing keratinocytes (Fig. 18.245).20,39 Foci of dermal necrosis may be evident.
Vascular changes are usually not seen.39 Perineural and intraneural chronic
inflammatory changes associated with perineural Leishmania organisms
have been described.40 The patient was found to be hyperesthetic clinically.
In chronic lesions the dermis contains large numbers of small noncaseating
granulomata (Fig. 18.246). Giant cells tend to be sparse. Leishman bodies
are sparse or absent.20 Necrosis is very rare at this stage.39
Histologically, mucocutaneous leishmaniasis is extensively necrotic, with
many plasma cells, lymphocytes, neutrophils, and macrophages, but few
organisms. Occasional tuberculoid or suppurative granulomata may be
present.1,3
As with lepromatous leprosy, diffuse cutaneous leishmaniasis is character-
Fig. 18.243 ized histologically by numerous macrophages distended with amastigotes and
Diffuse cutaneous a lack of granuloma formation. There are few lymphocytes and plasma cells.
leishmaniasis: note the These features indicate anergy, but not primary immunodeficiency.
widespread lesions,
many of which appear
keloidal. By courtesy
of the late M.S.R. Hutt,
London, UK.
eliminated by an effective granulomatous response without necrosis, while

others are associated with focal necrosis and ulceration when organisms are
released. In others there is more extensive necrosis. The events following
necrosis depend on the rate at which an effective epithelioid granulomatous
reaction develops.36,37 An unusual case of late-stage cutaneous leishmaniasis
harboring foci of caseous necrosis with no demonstrable organisms has been
reported.38
Healing is often relatively rapid once necrosis has occurred. In parallel with
developing immunity, the overlying epidermis shows pseudoepitheliomatous
hyperplasia. Lymphocytes and plasma cells also become more numerous at
the periphery of the granuloma. Scarring eventually replaces the granuloma.
Histologically, the acute lesion (oriental sore) is characterized by hyperker-
atosis and acanthosis although occasionally epidermal atrophy and parakera-
tosis are features.20 Ulceration is frequently seen (Fig. 18.244). Liquefactive
Fig. 18.245
Oriental sore: the infiltrate consists of parasite-laden histiocytes with small numbers
of lymphocytes.
Fig. 18.244 Fig. 18.246

Oriental sore: there is extensive ulceration and the adjacent epithelium is acanthotic; Oriental sore: epithelioid cell granulomata as seen in this field are a feature of
intense inflammation is seen deep to the ulcer bed. chronic lesions.
Leishmaniasis 847
The features of post-kala-azar dermal leishmaniasis are similar to those

of the diffuse cutaneous variety; the overlying epidermis is atrophic, but is
not usually ulcerated (Figs 18.247–18.249). Nodular lesions show a dense
dermal lymphohistiocytic infiltrate. There are a variable number of organ-
isms. Vascular hyalinization is evident, and marked follicular plugging may
be observed.41 Degeneration of basal epidermal keratinocytes was observed in
one recent study. The dermal infiltrate was noted to comprise T-lymphocytes
and macropahges, with a preponderance of CD4+ T-cells over CD8+ lympho-
cytes. Plasma cells, however, were inconspicuous or absent.42
The lupoid form of chronic cutaneous leishmaniasis may be difficult to
diagnose because it represents an exaggerated tuberculoid response to very
few organisms (and as such closely resembles lupus vulgaris) or perhaps only
leishmanial antigen; it is best distinguished from other tuberculoid diseases
on the basis of its positive Montenegro skin test.20 There is no necrosis, and
plasma cells are sparse.
Fig. 18.249
Post-kala-azar dermal leishmaniasis: in this example, organisms are no longer visible.
Fig. 18.247
Post-kala-azar dermal
leishmaniasis: there is
a dense dermal nodular
infiltrate. The Grenz zone Fig. 18.250
is spared. Visceral leishmaniasis: promastigote forms of Leishmania donovani; note the
anterior kinetoplast and flagellum (the latter is not seen in human infection) (Giemsa
stain). By courtesy of H.P. Lambert, MD, and the London School of Hygiene and
Tropical Medicine, London, UK.
In all other forms of cutaneous leishmaniasis the diagnosis is confirmed

by the demonstration of amastigotes in a smear or skin section.43 The organ-
isms are best revealed by Giemsa stain as reddish cytoplasmic round to
oval structures measuring from 1.5 × 2.5 μm to 4.5 × 6.8 μm.6 They appear
blue-gray on hematoxylin and eosin staining. A small rodlike similarly
stained kinetoplast may be visible (Fig. 18.250). Many of the organisms
are within macrophages, but some occur extracellularly. They are termed
Leishman-Donovan bodies. These features must be distinguished from the
similar bodies of histoplasmosis and, to a lesser extent, those of granuloma
inguinale and rhinoscleroma. The clinical features will usually be distinctive;
skin testing, serology, and culture of the organisms will confirm the diagno-
sis. PCR may be useful in providing a rapid diagnosis with precise species
identification.44,45
A diagnosis of cutaneous leishmaniasis may easily be overlooked by histo-
Fig. 18.248 pathologists who are seldom exposed to biopsy material from such cases, espe-
Post-kala-azar dermal leishmaniasis: there is a heavy mixed infiltrate of histiocytes, cially when not alerted to a significant travel history. This is particularly the
lymphocytes, and plasma cells. case when organisms are sparse or if unusual histological features are present,
such as sarcoidal granulomas, palisaded granulomas with central fibrinoid Differential diagnosis
change, elastophagocytosis, and conspicuous numbers of multinucleated
E. histolytica infection is distinguished from infection with free-living
histiocytic giant cells. Lesions may thus be misdiagnosed as sarcoidosis,
amebae (Acanthamoeba spp. and Balamuthia mandrillaris) by the presence
foreign body granuloma, granuloma annulare or lupoid rosacea.46
of e rythrophagocytosis in the former condition.
Amebiasis cutis Infections caused by free-living amebae

Entamoeba histolytica can cause cutaneous lesions, although this is rare.1,2 Four free-living amebae are responsible for human disease, namely, Naegleria
These are most commonly seen after surgical treatment of intestinal or hepatic fowleri (the cause of primary amebic meningoencephalitis), Acathamoeba
amebiasis, but may also occur by direct extension perianally from the bowel spp. (which cause granulomatous amebic encephalitis), Balamuthia man-
or from hepatic involvement, and by direct inoculation of the skin from other dillaris (another cause of granulomatous amebic encephalitis), and, more
infected lesions. In recent years, a number of cases have been recorded in recently, Sappinia diploidea, an exceptionally rare cause of encephalitis.1–3 Of
HIV-infected patients, who may have an increased mortality due to other these, only Acathamoeba spp. and B. mandillaris are potentially associated
coinfections.1,3 Penile amebiasis can follow anal intercourse.4 Cutaneous with cutaneous lesions. These latter two free-living amebae are seldom impli-
lesions have been recorded on the trunk, abdominal wall, buttocks, genita- cated in human disease with the possible exception of Acanthamoeba contact
lia, and perineum and on the legs.1,3–7 In addition to ulcers, cutaneous ame- lens-associated keratitis.2,3 However, in recent years acanthamebiasis and bal-
biasis may present with fistulae, fissures, abscesses, and polypoid or warty amuthiasis have received increasing recognition as opportunistic pathogens
lesions.1 Subcutaneous swellings called amebomas have also been described.8 in immunocompromised patients, especially debilitated, malnourished hosts
Primary disease is uncommon; the majority of patients develop contiguous and those with HIV/AIDS.1–13 Acanthamoeba spp. appear to be more impor-
skin lesions in the presence of underlying visceral infection.1,9 Although the tant in immunosuppressed organ transplant recipients.14,15 Infection with
condition is encountered mainly in adults, amebiasis cutis may sometimes B. mandrillaris (formerly referred to as leptomyxid ameba) may nevertheless
occur in children.2,6,10 occur in immunocompetent individuals, including children.1,2,16,17
The lesions have a central necrotic zone with a purulent exudate, gray Infection with Acathamoeba spp. B. mandrillaris results in an often fatal
slough, an undermined margin, and an erythematous halo. The ulcers are progressive encephalitis, and associated cutaneous lesions are a frequent
irregular but sharply defined. They spread and do not heal spontaneously. occurrence.1–4,6,11 Acanthamebiasis is a condition reported almost exclu-
They are extremely painful and may be destructive. Occasionally, the lesions sively from the United States, although cases have occurred in Korea.1,2,18
resemble ulcerating tumors and are associated with surrounding verrucous Similarly, the majority of cases of balamuthiasis have been reported from the
lesions. United States.1–3,11 The latter condition has nevertheless occurred in patients
from a number of South American countries and rarely, Thailand, India, and
Australia.13,16,17,19–25 B. mandrillaris infection of the CNS carries a mortality
Histological features in excess of 98%.10
The trophozoites of E. histolytica are found among the purulent exudate of Spread of Acanthamoeba spp. to the central nervous system (CNS) and
the ulcer and are seen more clearly with PAS staining (Fig. 18.251). They skin is usually from a primary source of infection in the lungs or paranasal
are 12–20 μm in diameter and are distinguished by their tendency to phago- sinuses.1,5,18 Involvement of the skin may be the presenting manifestation of
cytose red cells. Lesions may be superficial or deep, with the latter involv- disseminated infection.4 Isolated cutaneous disease with chronic, nonhealing
ing the subcutis. Necrosis is common and may be liquefactive, coagulative skin lesions may be the sole manifestation in patients with AIDS-associated
or suppurative.1,2 Trophozoites and cysts are usually found in the patient's acanthamebiasis (Fig. 18.252).7
feces. The organisms are surrounded by neutrophils, with some lymphocytes Acanthamebiasis of the skin presents as multiple deep dermal and subcu-
and plasma cells. The adjacent epidermis appears acanthotic and this may taneous nodules, usually on the extremities and face.4,6,9,12,14,15 Necrotizing
be marked or pseudoepitheliomatous in verrucous forms. Spongiosis may be panniculitis may occur.8 Pustular, ulcerating, purpuric, and sporotrichoid
conspicuous in superficial lesions.1 lesions have also been described.5,6,26
A B
Fig. 18.251
Amebiasis cutis: (A) this biopsy is from a woman with vulval ulceration due to direct spread from the anus; the epithelium is hyperplastic and the lamina propria is chronically
inflamed. (B) There are numerous trophozoites present; note the ingested red cells.
Toxoplasmosis 849
Fig. 18.252
Acanthamebiasis: there are widespread ulcers in this HIV-positive patient.
There was underlying vasculitis. Courtesy of N.-N. Moti-Joosub, MD. Division of
Dermatology, University of the Witwatersrand, Johannesburg, South Africa.
B. mandrillaris is present worldwide and is encountered in fresh

water, soil, and dust. It is thought that the organism gains access to the
CNS via hematogenous spread from a focus of primary infection in the
upper or lower respiratory tract or the skin.2,21 Transmission is probably
through the inhalation of airborne cysts or contamination of a skin
lesion.19,21,22 Cutaneous involvement is usually in the form of multiple
nodular or ulcerative lesions, similar to those encountered in cutaneous
acanthamebiasis. One reported case developed an ulcerative mass 10 cm
in diameter on the thigh.20 A number of patients, however, have presented
with a centrofacial or sometimes destructive nasal lesion, which preceded
symptoms and signs of CNS involvement by several months.17,21,23 In fact, B
the cutaneous signs may antedate the neurological signs by months.27
Some cases have evolved following penetrating injury or a prior Fig. 18.253
fracture.16,23,28 Acanthamebiasis (A, B): trophozoites and cysts are present. The wall of the latter is
characteristically double layered (B).
Cutaneous infection with Acanthamoeba spp. results in severe suppurative
inflammation in the dermis with extension into the subcutis, where necro- Toxoplasmosis
tizing neutrophilic lobular panniculitis, tuberculoid granulomatous inflam-
mation, and vasculitis may occur.4,6,8,9,16 The epidermis is usually intact. Clinical features
Purpuric lesions are associated with leukocytoclastic vasculitis.5 B. mandril-
Toxoplasmosis is the result of infection with Toxoplasma gondii, an obli-
laris is associated with granulomatous and suppurative inflammation. This
gate intracellular parasite.1 Infection in humans, who serve as the interme-
inflammation is frequently angiocentric and direct invasion of vessel walls
diate host, usually occurs following ingestion of T. gondii oocysts that are
by trophozoites results in vasculitis and necrosis.21 The trophozoites of both
present in the feces of infected cats, or via consumption of undercooked,
genera, which tend to concentrate near blood vessels, generally measure
contaminated meat containing tissue cysts. The oocysts and tissue cysts then
20–30 μm in diameter, but may range from 15–50 μm.1,3,8,18,21 Recognition
transform into tachyzoites, which in turn develop into bradyzoites after local-
of the trophozoites may be difficult in view of their macrophage-like appear-
ization in brain or muscle tissue. These slowly replicating forms are contained
ance.6,11 The trophozoites have abundant vacuolated cytoplasm and a nucleus
within pseudocysts in the involved tissues.1
containing a discrete nucleolus. PAS and Gomori methenamine silver stains
The zoonosis exists in a number of clinical forms: as an acute infection in
highlight the amebic cyst walls. The cysts possess an outer wrinkled cyst wall
immunocompetent individuals, the vast majority of whom are asymptomatic;
(ectocyst) and a thin inner wall (endocyst) (Fig. 18.253).1,3,11,21 The tropho-
congenital toxoplasmosis due to transplacental spread of a maternal infection,
zoites and cysts of Acanthamoeba spp. are virtuallly indistinguishable from
forming part of the TORCH group of infections; and acute disease in immu-
those of B. mandrillaris by routine light microscopy. Diagnosis is therefore
nocompromised hosts, which is either acquired or the result of reactivation of
confirmed by culture, immunofluorescence studies, immunohistochemistry or
latent infection.1,2 Although fever, lymphadenopathy, chorioretinitis, and cerebral
PCR.4.11,12,22,29
involvement are well-recognized manifestations of symptomatic toxoplasmosis in
general, presentation with skin lesions is uncommon. Cutaneous involvement is
Differential diagnosis encountered more frequently in immunocompromised patients with disseminated
Acanthamebiasis and balamuthiasis are distinguished from cutaneous infec- infection, such as those with HIV/AIDS or in immunosuppressed recipients of bone
tion with Entamoeba histolytica by the presence of erythrophagocytosis in marrow, hematopoietic or solid organ transplants.1,3–10 Toxoplasmosis-associated
the latter condition. N. fowleri does not form cysts, and infection is not hemophagocytic syndrome has been reported in a renal allograft recipient.11 The
associated with skin involvement. disease has also occurred following chemotherapy for lymphoma.10
Skin manifestations of the disease are very rare but may be encountered for the intracellular yeast forms and amastigotes usually contained within
in cases of acquired or congenital toxoplasmosis.12 Potential dermatologi- macrophages in the aforementioned conditions, respectively. Leishmania
cal manifestations include a maculopapular skin rash, widespread purpuric organisms have a discernible kinetoplast. Rare cases of cutaneous toxoplas-
papules and nodules, thrombocytopenic purpura, lichenoid and erythema mosis following hematopoietic stem cell transplantation may mimic interface
multiforme-like eruptions, ulcerative and vegetating lesions, panniculitis, and dermatitis, resulting in confusion with an adverse drug reaction or graft-
erythroderma.7,8,10,13–17 versus-host disease if the encysted bradyzoites are overlooked.9
A majority of reported cases have shown a superficial and deep perivascular
inflammatory cell infiltrate composed of lymphocytes and histiocytes.3,13,15
Small ‘cysts’ containing tiny bradyzoites may be encountered in the der-
mis, including vascular endothelial cells, follicular epithelium, and the sweat
glands and their ducts (Fig. 18.254).7 Rarely, similar structures are observed
within in the epidermis.8 The organisms may be highlighted by staining tis-
sue sections with the May-Grünwald-Giemsa method.13 Free parasites are
sometimes haphazardly distributed in the dermis, and there may be dermal
edema, erythrocytic extravasation, necrobiotic collagen bundle, and karyor-
rhectic debris.7 Biopsies from severely immunocompromised patients may
reveal little by way of a host response.7 Interface dermatitis and panniculi-
tis have been described.9,10 One reported case presenting with erythroderma
showed features of exfoliative dermatitis, with no discernible organisms.16
Vegetating lesions are characterized by pseudoepitheliomatous hyperplasia,
sometimes accompanied by necrosis.13 The diagnosis may be confirmed by
ultrastructural examination, immunohistochemistry or polymerase chain
reaction.7,8,10
Differential diagnosis Fig. 18.254

Toxoplasmosis: a cyst containing numerous bradyzoites is present within a
Cutaneous toxoplasmosis should be distinguished from histoplasmosis superficial blood vessel. By courtesy of H. Diwan, MD, Baylor College of Medicine,
and leishmaniasis. Toxoplasma bradyzoites may potentially be mistaken Houston, Texas, USA.
Algal infections
Protothecosis
Clinical features
Protothecosis is a rare condition, representing infection by the achloric
(achlorophyllic) alga Prototheca, usually P. wickerhamii.1–3 Approximately
100 cases have been reported.4–6 P. zopfii is also responsible for occasional
human cases.1,7 The alga is assumed to be inoculated into the skin by minor
trauma, presumably from contaminated water or soil. Prototheca are ubiq-
uitous in nature, being found in the mucus flux of trees, water stabilization
ponds, acid rivers and lakes, and a variety of animals including cows, dogs,
cats, and deer.8,9 The disease has been reported worldwide.10 One recorded
case occurred after an arthropod bite.9
Diseases caused by Prototheca include isolated cutanous lesions, olecranon
bursitis, and disseminated infection.1 Protothecosis occurs in both iatrogeni-
cally immunosuppressed patients and those with AIDS.1,4,6,7,9–14 The condition
manifests as a papular or eczematoid dermatitis, usually over an extremity.4,10
The dermatitis form is often extensive and scaly, hypertrophic, and resistant to
therapy. Vesicular, herpetiform, pustular, plaquiform, ulcerative, granuloma-
tous, and verrucous variants have been described (Fig. 18.255).1,4,15,16 Lesions
may also resemble pyoderma gangrenosum.4 Disseminated lesions have been Fig. 18.255
rarely reported.9,10,17 In immunocompetent patients the infection is most Protothecosis: numerous
crusted and ulcerative
often localized to the olecranon bursa following trauma.1,10 Localized teno-
lesions are present.
synovial involvement of the finger has been reported, one in an HIV-positive By courtesy of the
patient.5,11 Institute of Dermatology,
London, UK.
The localized lesions consist of necrotic centers surrounded by granulation occasional multinucleate giant cells (Fig. 18.256). Organisms (3–15 μm in
and fibrous tissue with a few multinucleate giant cells. The algae are found diameter) can be found at all levels of the epidermis and in the superficial
in the necrotic centers. dermis (Figs 18.257, 18.258).3,10 Infection can also involve the regional
In the dermatitis lesions the epidermis is parakeratotic, acanthotic, and lymph nodes. Only basophilic spherical bodies are seen with hematoxylin
papillomatous, and there is a mixed infiltrate in the upper dermis, including and eosin staining, while a silver stain or a PAS reaction reveals sporelike
Protothecosis 851
Fig. 18.256
Protothecosis: note the crusting, marked acanthosis, and heavy dermal infiltrate.
By courtesy of I. Van den Berghe, AZ, Sint-Jan AV Hospital, Bruges, Belgium.
Fig. 18.258
Protothecosis (A, B): (A) the internal septation is characteristic; (B) the organisms
have thick cell walls and are PAS positive. (A) By courtesy of I. Van den Berghe, AZ,
Sint-Jan AV Hospital, Bruges, Belgium; (B) By courtesy of C. Thatcher, MD, Eritzman &
Thatcher Inc. Anatomical Pathologists, Johannesburg, South Africa.
Fig. 18.257
Protothecosis: numerous organisms are present in the dermis. By courtesy of I. Van
den Berghe, AZ, Sint-Jan AV Hospital, Bruges, Belgium. Bursal lesions show stellate caseating necrosis surrounded by a palisade of
epithelioid cells, Langhans giant cells, plasma cells, and lymphocytes.10,11 The
organisms are present within the necrotic centers. Sinus tracts may be evident.
bodies in the epidermis and among the inflammatory infiltrate. Sporangia There is associated fibrosis.
with symmetrically arranged endospores is characteristic; these have been
described as morula-like or daisy-like.4,11,18 Identification of the organism Differential diagnosis
depends on culture characteristics. Diagnosis may also be confirmed by direct Prototheca are distinguished from green algae (Chlorella) by the absence of
immunofluorescence.11 chloroplasts and from Coccidiodes immitis by its smaller size.2,19
Fungal infections
Fungal infections include: Dermatophytes can infect the keratin of the stratum corneum, hair or nail,
• superficial variants involving skin, hair, nails, and mucous membranes, without extending into deeper parts of the skin. They may also be associated
for example ringworm (dermatophytosis), and the dermatomycoses (tinea with intradermal spread (Majocci granuloma). Causative organisms may be
versicolor and candidiasis), anthropophilic, zoophilic or geophilic. With few exceptions, identification
• subcutaneous lesions, of pathogenic fungi is better served by culture rather than by histological
• disseminated infection.1,2 scrutiny.5–7 Dermatophytes use the soluble nonkeratin parts for nutrition and
Ringworm fungi include three species: Microsporum, Trichophyton, rely on the keratin for protection from serum and the host response.8,9 The
and Epidermophyton.3,4 Epidermophyton invades epidermal keratin while keratin is penetrated by means of putative keratinases. Other virulence fac-
Microsporum and Trichophyton also affect the hair. Cutaneous ringworm tors include elastase and proteinases.9,10 T. rubrum produces mannan, which
on nonhairy skin presents as slowly enlarging, scaly, erythematous, annular suppresses or diminishes the host immune response, presumably by inhibit-
lesions with central clearing (Fig. 18.259). ing critical steps in antigen presentation or processing.9,11 The epidemiology
Fig. 18.260
Fig. 18.259 Tinea capitis: there is
Tinea corporis: note the annular configuration and erythematous margin. From the marked hair loss. In this
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. example scaling and
crusting are pronounced.
and pathogenesis of dermatophytosis is complex and beyond the remit of From the collection of the
this text. For suitable review articles the reader is referred to references 1,
3, 4, and 10. London, UK.
Tinea capitis
Dermatophyte infections of the scalp are characterized by involvement
of the hair shaft by pathogenic fungi. The pattern of hair invasion, related to
the type of dermatophyte, determines the degree and site of hair damage and
the clinical picture. Patients therefore present with variable features includ-
ing hair loss with scaling, follicular inflammation, pustulation, and kerion
formation, often in association with drainage lymphadenopathy. A carrier
state is recognized. Infection depends upon contact with spores and follicular
trauma. Tinea capitis (scalp ringworm) frequently presents as small epidem-
ics (e.g., in schools). Disease may develop as a consequence of sharing combs
or hairbrushes. Tinea capitis is the most common dermatophytosis of child-
hood. The disease may also occur in adults, the elderly, and even infants. The
past two decades have seen a rise in its prevalence and a change in the pattern
of etologic agents, both in Europe and the USA.
Infections caused by Microsporum canis

and Microsporum audouinii
Tinea capitis: note the characteristic fluorescence under Wood's light. By courtesy
M. canis and M. audouinii grow on the outside of the hair shaft, an ectothrix of M.M. Black, MD, Institute of Dermatology, London, UK.
type of hair involvement.1–3 The lesions present as areas of alopecia, with
numerous broken-off, dull hairs (Fig. 18.260). Some scaling is present, but
overt inflammation is not marked. The infected areas are recognized by fluo-
rescence under Wood's lamp (Fig. 18.261). The process commonly affects Kerion
children, boys much more often than girls. Microsporum ferrugineum may
also cause this picture. Clinical features
M. canis and M. audouinii were once the most common causes of tinea capi- Kerion (kerion celsi) is a severe, boggy inflammatory form of tinea, most
tis in North America and Western Europe.3,4 M. canis, a zoophilic dermato- often caused by Trichophyton mentagrophytes.1,2 Kerion is seen as an area
phyte, is the organism most frequently implicated in cases of tinea capitis in of inflamed alopecia in which the broken-off hairs are loose in their folli-
Europe. Urban areas of Europe (and France in particular) have shown a shift cles and are associated with suppuration (Figs 18.262, 18.263). This may
towards infection with M. audouinii, an anthropophilic dermatophyte.5,6 be severe enough to discharge via sinuses, with the formation of fibrin-
opurulent crusts around adjacent hairs. Secondary bacterial infection
Histological features may play a part. Fluorescence is not a feature. Involvement of the beard
The fungal arthrospores coat the outside of the hair shaft and the hyphae area (tinea barbae, tinea sycosis), which occurs most often in farm work-
extend into the hair shaft down to the level of the mid follicle. The epidermis ers, invariably affects adult males.3 The lesions appear as erythematous
shows some acanthosis and patchy parakeratosis and there is usually a mixed areas of pustular folliculitis in the beard area and may present as a kerion
inflammatory infiltrate in the superficial dermis, more marked with M. canis. (Fig. 18.264).
Infections caused by Microsporum canis and Microsporum audouinii 853
Fig. 18.264
Kerion: in males, dermatophyte infection of the beard area may also present as a
Fig. 18.262 kerion. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Kerion: in addition to alopecia there is marked erythema and matting of hairs due
to purulent exudate. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
Fig. 18.265
Kerion: there is hyperkeratosis, acanthosis, epidermal edema with acute
inflammation, and abscess formation.
Fig. 18.263
Kerion: there is marked
alopecia and crusting.
From the collection of the tinea capitis in a recent study from Nigeria.5 T. violaceum is the most com-
late N.P. Smith, MD. the mon cause of tinea capitis in South Africa.6 The hair break is at the ostium
Institute of Dermatology, of the follicle so that broken hairs are seen as dots rather than stumps. The
London, UK. intervening skin usually shows only slight scaling, but occasionally pus-
tules and kerion can develop.7 Drainage lymphadenopathy may be evident.
The hairs do not fluoresce with a Wood's lamp.
Trichophyton is a large-spored fungus with an ectothrix pattern of hair Histological features
involvement. There is much associated pus with abscess formation. The epi- The hyphae of T. tonsurans and T. violaceum exten

McKees Pathology of The Skin

Uploaded by

Copyright:

Available Formats

McKees Pathology of The Skin

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

McKees Pathology of The Skin

Uploaded by

Copyright:

Available Formats

Aung Kyaw Oo

Eduardo Calonje MD, DipRCPath Alexander Lazar MD, PhD

For additional online references and video content visit expertconsult.com

© 2012, Elsevier Limited All rights reserved.

First edition 1989

British Library Cataloguing in Publication Data

McKee's Pathology of the Skin. – 4th ed.

List of Contributors vii

2 Specialized techniques in dermatopathology 32 12 Diseases of the anogenital skin 437

3 Disorders of keratinization 46 13 Degenerative and metabolic diseases 520

19 Human immunodeficiency virus (HIV) 22 Diseases of the hair 967

20 Disorders of pigmentation 912 24 Tumors of the surface epithelium 1076

26 Melanoma 1221 30 Cutaneous metastases and Paget's disease

Josette André, MD Alistair J. Cochran, MD

Boris C. Bastian, MD Antonio C. Cubilla, MD

Wayne Grayson, MBChB, PhD, FCPath(SA) Sallie Neill, MB ChB, FRCP

Anne Theunis, MD Sook-Bin Woo, DMD, MMSc

To my wife Claudia who always gives without expecting anything in return.

To Anne, Yaelle, Sanja and Walter.

I am assured that my two beautiful children, Elliott and Abigail, have no

Skin is a double-layered membrane covering the exterior of the body and

Regional variations in skin anatomy

Fig. 1.9 Fig. 1.11 Fig. 1.12

Fig. 1.15 Fig. 1.16

Fig. 1.17 Fig. 1.18

Inner root sheath

Markers of interfollicular stem cells

Markers of hair follicle bulge stem cells

Epidermal barrier: Keratohyalin granules composed of profilaggrin Micro-organisms

Occur in up to 10% Loss-of function Are a major risk factor for

large number of resident T cells. Indeed, there are approximately 2 × 1010

Melanin is transferred from melanocytes in melanosomes to neighboring

Mature melanosomes of eumelanin are ellipsoidal in shape, while pheomela-

Autosomal dominant Autosomal recessive

Arrhythmogenic right Arrhythmogenic right

Woolly hair, keratoderma, Woolly hair, keratoderma,

Striate palmoplantar Lethal acantholytic

Desmocollin Plakophilin Keratin Striate palmoplantar

Fig. 1.52 Fig. 1.54

cells can be identified by antibodies to S-100 protein, desmin and smooth

­cuboidal to columnar eosinophilic cells (Figs 1.67, 1.68). Although a histo-

aspect of the duct is strongly outlined. Cytoplasmic granules express epider-

Hemidesmosomal inner plaque

Hemidesmosomal outer plaque

Dermal–epidermal junction Fig. 1.73

­molecules ­consist of three subunit polypeptides which can either be iden-

On the basis of their fiber architecture in tissues, collagens can be divided

Fig. 1.85 Fig. 1.87

Fig. 1.86 Fig. 1.88

Fibroblasts from different anatomical sites all have similar morphology

Nervous system of the skin

Fig. 1.96 Fig. 1.99

appear to be derived from nonmyelinated fibers, occur in the superficial der-

Specimen fixation, grossing/put-through, Immunofluorescence 35 Polymerase chain reaction (PCR) 43

Routine and ‘special’ stains

manual IHC, to achieve optimal, reproducible results.

Fig. 2.7 Fig. 2.9

Fig. 2.8 Fig. 2.10

Electron microscopy EB simplex

cuboidal to columnar eosinophilic cells (Figs 1.67, 1.68). Although a histo-

molecules consist of three subunit polypeptides which can either be iden-

translocations seen in different neoplasms can be associated with the same

eripheral leukocytes and cultured skin fibroblasts. Diagnosis may also be