10.1007@978 3 319 62539 3

Encyclopedia of Pathology
Series Editor: J. H. J. M. van Krieken
Anna Sapino
Janina Kulka Editors
Breast
Pathology
Encyclopedia of Pathology
Series Editor
J. H. J. M. van Krieken
The scope of this 15–20-volume set encompasses the entire field of pathology
ranging from general pathological terms to specific diseases to diagnostic
methods. Published as print edition and online version (eReference) in the
Springer Reference Program each topical volume sticks out by clearly and
homogenously structured entries. A team of international experts guarantee
that the essays and definitions are scientifically sound. The A-Z format of each
topical volume allows readers to quickly and easily find the information they
need. The major advantage of the encyclopedia is the way it makes relevant
information available not only to pathologists, but also to all clinicians and
researchers of the neighboring disciplines working together with pathologists
who occasionally might wish to look up terms online.
More information about this series at http://www.springer.com/series/14876

Anna Sapino • Janina Kulka
Editors
Breast Pathology
With 282 Figures and 29 Tables

Editors
Anna Sapino Janina Kulka
Unit of Pathology 2nd Department of Pathology
Candiolo Cancer Institute FPO-IRCCS Semmelweis University
Candiolo, Italy Budapest, Hungary
Department of Medical Sciences
University of Turin
Turin, Italy
ISBN 978-3-319-62538-6 ISBN 978-3-319-62539-3 (eBook)

ISBN 978-3-319-62540-9 (print and electronic bundle)
https://doi.org/10.1007/978-3-319-62539-3
© Springer Nature Switzerland AG 2020

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To our Masters and Teachers,
Dr. Gianni Bussolati
Dr. Pietro Maria Gullino
Dr. Judit Mohácsy
Dr. John Douglas Davies
ThiS is a FM Blank Page
Series Preface
When Denis Diderot started the first encyclopedia in the eighteenth century, it
was a groundbreaking and timely event. It was the time of the Enlightenment,
and knowledge was seen as something which was to be spread to many and to
build upon by creating new knowledge. His ambition was to bring all available
knowledge together in one series of books so that every person who could read
has access to all there is to know. Nowadays, in a time of easily accessible
knowledge, the question is whether there is still need of an encyclopedia. It is
obvious that the amount of knowledge is such that it is not possible to bring it
all together in one encyclopedia. One may argue that the Internet is the
encyclopedia of today, but that misses an important point of Diderot, a point
that is probably even more valid today. He created a team that valued infor-
mation and selected what was worth to be presented in the encyclopedia. He
recognized that science is not a democratic process where the majority decides
what is true and valuable, but rather a growing body of knowledge in which
radical ideas from individuals may bring about huge changes, even though
most would reject these new ideas in the beginning. Indeed, the Internet lacks
such authority and it is not easy to select valuable information from nonsense,
especially when one is not an expert in a certain field.
It is therefore that an encyclopedia is only as good as the team that creates
it. It goes without saying the team that is responsible for the Encyclopedia of
Pathology consists of recognized experts in the field. Pathology is a growing
medical discipline in which the amount of information is probably already
more than that the whole encyclopedia of Diderot contained. For experts in
subspecialties within pathology, it is already almost impossible to keep an
overview on new developments and to select relevant from less relevant new
information. There are plenty of textbooks for every disease group, and
scientific literature is available for most pathologists through PubMed or
GoogleScholar. What is lacking is a systematic overview of what we know
in an alphabetical order, easily accessible to all. The encyclopedia of pathology
fills that gap. It is written by experts with the general pathologist in mind and
also specialist from other disciplines. It will consist of a series of volumes on
subspecialties, and when it is completed there will be an online version
combining these. Yearly updates from the online version is foreseen and
readers are welcome to provide suggestions for improvement. These will be
judged by the editorial team in order to keep the encyclopedia authoritative yet
using the expertise of many.
vii
viii Series Preface
Finally, it is my hope that the encyclopedia will grow into a reliable body of
knowledge in pathology, enabling communication through a common lan-
guage, and that it will grow and adapt to new developments.
Nijmegen, The Netherlands J. H. J. M. van Krieken

September 2019 Series Editor
Volume Preface
This new book on breast pathology as part of the Encyclopedia of Pathology

series intends to summarize the present state of knowledge about breast
diseases. Encyclopedia of Pathology, and its individual volumes, being living
documents, will be subject to updates, inclusion of new knowledge, and new
data in the online version of the series. The printed version is, therefore, a
snapshot of breast pathology from the years 2018 to 2019. Having said that,
we, editors of this volume, hope that our readers will find this book useful and
likeable even years from now. We ambitiously hope and wish this book
becomes one of those at your right-hand side by the microscope.
We are very grateful to all coauthors of the book who did their best to write
excellent chapters summarizing up-to-date knowledge about the respective
subjects included in the table of contents of this book. Going through the
individual contributions during the review process has been both great profes-
sional and personal experience for us. We thankfully acknowledge also the
continuous support of our editorial assistants at Springer, Mrs. Sunaina
Dadhwal and Mrs. Neha Thapa.
We wish our readers pleasant working hours assisted by this volume of
Encyclopedia of Pathology!
Candiolo, Italy Anna Sapino

Budapest, Hungary Janina Kulka
September 2019 Volume Editors
ix
Editors Biography
Dr. Anna Sapino obtained her M.D. degree at the University of Turin (Italy)
in 1982 and completed her residency in anatomic pathology at the University
of Milan in 1986. She started her career as a consultant pathologist at
the University Hospital in Turin in 1984 under the supervision of Prof.
Gianni Bussolati. In 1987 she accrued experience in experimental studies on
pre-neoplastic breast lesions through a sabbatical period spent in the USA at
the Michigan Cancer Foundation and at the Columbia University. Upon her
return to Italy, she set up her own cell biology lab working on effects of
hormones on breast cancer cells and mouse mammary gland organ cultures.
Her research activity has always been paralleled and inspired by breast cancer
diagnostic pathology and her career orientation reflects this approach. In 1998
Dr. Sapino was appointed Associate Professor and in 2005 full Professor of
Anatomic Pathology and Histopathology at the School of Medicine of the
University of Turin. From 2010 to 2015 she was recruited as Director of
Surgical Pathology at the University Hospital (Città della Salute e della
Scienza) in Turin and from 2013 to 2015 as Director of the Department of
Laboratory Medicine, then she moved to Candiolo Cancer Centre FPO-IRCCS
(Italy) as Director of the Pathology Unit. This unit is recognized as training
center for breast pathology by the European Society of Pathology (ESP). In
2017 she became Scientific Director of Candiolo Cancer Institute FPO-
IRCCS, a private nonprofit institution endorsed by the Italian Ministry of
Health for oncology research. In 2018 Dr. Sapino had also been appointed
Director of the Department of Medical Sciences of the School of Medicine at
the University of Turin (Italy). She has been member of the European Working
Group for Screening of Breast Pathology and coauthor of the European
Guideline for Breast Cancer Screening. From 2014 to 2018 she had been
chairing the European Working Group of Breast Pathology of the ESP. She
is member of the teaching staff for breast pathology of the European School of
xi
xii Editors Biography
Pathology (EScoP). She serves as member of editorial boards of many scien-

tific journals and as reviewer for international grant proposals. She has been
lecturing at several national and international meetings. Her scientific works
are published in international peer-reviewed journals (more than 300 papers,
H-index: 49). Over the years her scientific activity has focused on experimen-
tal and clinicopathological studies on breast cancer, with the key mission to
translate the achievements of basic science to the patient’s bedside.
Dr. Janina Kulka studied medicine at Semmelweis University, Budapest.

After receiving her degree in 1982, she successfully applied for a trainee
position in the 2nd Department of Pathology of Semmelweis University.
Four years later, after the specialization exam, she became Assistant Professor
in the same department. From 1992 to 1994 she was Research Fellow at the
South West Regional Breast Pathology Unit of the University of Bristol, UK,
under the supervision of Dr. J.D. Davies. She received her Ph.D. in 1999,
became full Professor of pathology in 2008, and received her D.Sc. degree in
2018. She has also served as a pathologist at the MaMMa Clinic, the first
multidisciplinary breast screening center in Hungary, founded in 1992.
Dr. Kulka was a member of the Mammographic Screening Subcommittee of
the “For a Healthy Nation” program, took an active part in the establishment of
mammographic screening centers in Hungary in 2002, and subsequently
participated in the regular external quality control procedures of the centers.
She introduced specimen mammography as part of routine workup of screen-
detected breast lesions and assembled the first national breast pathology
guidelines that included a description of workup of screen-detected breast
lesions. She is coauthor of the pathology chapter of the Hungarian multi-
disciplinary breast consensus document. She has been teaching medical stu-
dents for more than three decades and breast pathology for residents in
postgraduate courses for the last 15 years. In 2002 she joined and became a
member of the European Working Group for Breast Screening Pathology. She
contributed coauthored chapters to the European Guidelines for Quality Assur-
ance in Breast Cancer Screening and Diagnosis, to the second edition of the
Oxford Textbook of Oncology, and the fourth and fifth editions of the WHO
Classification of Tumours of the Breast volume. Recently, she was invited to
participate in the development of a dataset for the reporting of invasive breast
cancer by ICCR. She is author of several breast pathology chapters in Hun-
garian pathology, oncology, and surgery textbooks. She is author of more than
Editors Biography xiii
140 peer-reviewed scientific papers and contributed lectures to more than

150 national and international conferences. Dr. Kulka had been Secretary
and later President of the Hungarian Society of Pathologists, and a member
of the Executive Committee of the European Society of Pathology (ESP). She
has been a member of the Pathology Council of the Medical College, President
of the Hungarian Division of IAP, and a member of the Advisory Board and the
Educational Committee of ESP. Dr. Kulka has three grown-up children.
Series Editor Biography
J. H. J. M. van Krieken is a pathologist with special expertise in the fields of

hematopathology and the pathology of the gastrointestinal tract. He was
Professor for tumor pathology since 1999 and kept from 2005 to 2015 the
Chair of pathology at the Radboud University Nijmegen Medical Centre in
Nijmegen. He furthermore served as Chairman of the Board of the Oncology
Institute of the Radboud University, Nijmegen, from 2008 to 2016. Since
2016, he is the Rector Magnificus (Vice Chancellor) of the Radboud
University.
He was the Treasurer/Secretary of the European Association for
Hematopathology from 2000 to 2008, from 2003 to 2011 the Treasurer, from
2013 to 2015 the President of the European Society for Pathology (ESP), and
from 2015 to 2017 the past-President of the ESP. Furthermore, he coordinated
the ESP quality assessment program from 2008–2018 and was the chair of
IQN path from 2005–2008. He is (co) author of more than 600 papers in peer-
reviewed journals (H-index 86), has written chapters in books on pathology
and oncology, is editor of a Dutch textbook on oncology, and serves on the
editorial board of the American Journal of Surgical Pathology, was managing
editor of Virchows Archive from 2009–2015, and was the chief editor of the
Journal of Hematopathology from 2008–2018. Since 2011, he is member of
the German Academy of Sciences Leopoldina, and since 2014 of Academia
Europea and Honorary Fellow of the Royal Society of Pathology of Great
Britain and Ireland.
xv
Contributors
Francesca Ambrosi Department of Biomedical and Neuromotor Sciences

(DIBINEM)-Surgical Pathology Section, Alma Mater Studiorum – University
of Bologna, Bologna, Italy
Isabel Amendoeira Centro Hospitalar de São João (CHSJ), Porto, Portugal

IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade
do Porto, Porto, Portugal
Laura Annaratone Department of Medical Sciences, University of Turin,

Turin, Italy
Sofia Asioli Department of Biomedical and Neuromotor Sciences
Chiara Baldovini Pathology Unit, Giannina Gaslini Institute, Genoa, Italy
Davide Balmativola Unit of Pathology, Candiolo Cancer Institute FPO-

IRCCS, Candiolo, Italy
Guillaume Bataillon Institut Curie, Paris, France
Jean-Pierre Bellocq Department of Pathology, Strasbourg University Hos-

pital, Strasbourg, France
Simonetta Bianchi Division of Pathological Anatomy, Department of Sur-

gery and Translational Medicine, University of Florence, School of Human
Health Sciences, Florence, Italy
Werner Boecker Gerhard Domagk-Institute of Pathology, University of

Münster, Münster, North-Rhine Westphalia, Germany
Horst Bürger Institute of Pathology Paderborn/Höxter, Paderborn, Germany
Grace Callagy Discipline of Pathology, NUI Galway, Galway, Ireland

NUI Galway Clinical Science Institute, Galway, Ireland
Eliano Cascardi Department of Emergency and Organ Transplantation,

Unit of Pathology, University of Bari, Bari, Italy
Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
xvii
xviii Contributors
Isabella Castellano Department of Medical Sciences, University of Turin,

Turin, Italy
Suzanne Chartier Institut Curie, Paris, France
Catherine N. Chinyama Department of Pathology, Princess Elizabeth Hos-

pital, St Martins, Guernsey, Channel Islands, UK
Brighton and Sussex Medical School, Brighton, UK
Ewa Chmielik Tumor Pathology Department, Maria Sklodowska-Curie

Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
Chiara Corti Division of Pathology, Fondazione IRCCS Ca’ Granda –

Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
Gábor Cserni Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary

Department of Pathology, University of Szeged, Szeged, Hungary
Margaret C. Cummings Centre for Clinical Research, Faculty of Medicine,

The University of Queensland, Brisbane, QLD, Australia
Pathology Queensland: The Royal Brisbane and Women’s Hospital, Brisbane,
QLD, Australia
Clare D’Arcy Department of Histopathology, Irish National Breast Screen-

ing Programme and St. Vincent’s University Hospital, Dublin, Ireland
Dario de Biase Department of Pharmacy and Biotechnology, University of

Bologna, Bologna, Italy
Laurence de Leval Institute of Pathology, University Hospital Lausanne,

Lausanne, Switzerland
James S. DeGaetano Pathology Department, Mater Dei Hospital, Msida,

Malta
Luca Di Tommaso Pathology Unit, Humanitas Clinical and Research Cen-

ter, Department of Biomedical Sciences, Humanitas University, Milan,
Rozzano, Italy
Maria Giulia Disanto Unit of Pathology, Candiolo Cancer Institute

FPO-IRCCS, Candiolo, Italy
Ian Ellis Department of Histopathology, City Hospital Campus, Nottingham

University Hospitals, Nottingham City Hospital, Nottingham, UK
Vincenzo Eusebi Department of Pathology, University of Bologna, Bologna,

Italy
Margarida Sá Fernandes Centro Hospitalar de São João (CHSJ), Porto,

Portugal
Paulo Figueiredo Instituto Português de Oncologia de Coimbra, Coimbra,

Portugal
Contributors xix
Maria P. Foschini Department of Biomedical and Neuromotor Sciences

(DIBINEM), Unit of Anatomic Pathology at Bellaria Hospital, University of
Nicola Fusco Division of Pathology, Fondazione IRCCS Ca’ Granda –
Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
Zoran Gatalica Caris Life Sciences, Phoenix, AZ, USA
Emma Josephine Groen Department of Pathology, The Netherlands Cancer
Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Malcolm Hayes Pathology Department, BC Cancer Agency, University of
British Columbia, Vancouver, BC, Canada
Matthew P. Humphries Leeds Institute of Cancer and Pathology, University
of Leeds, Leeds, UK
Sergejs Isajevs Riga East University Hospital, Centre of Pathology/Faculty
of Medicine, University of Latvia, Riga, Latvia
Ivan Ivanov Department of Pathology, Medical University, Pleven, Bulgaria
Handan Kaya Pathology Department, Marmara University, Istanbul,
Turkey
Reena Khiroya University College London Hospital, London, UK
Anikó Kovács Department of Clinical Pathology, Sahlgrenska University
Hospital, Gothenburg, Sweden
Ute Krüger Department of Pathology, County Hospital, Kalmar, Sweden
Thomas Krausz Department of Pathology, University of Chicago, Chicago,
IL, USA
Janina Kulka 2nd Department of Pathology, Semmelweis University, Buda-
pest, Hungary
Manuela Lacerda Instituto de Patologia e Imunologia Molecular da
Universidadedo Porto (IPATIMUP), Porto, Portugal
Sunil R. Lakhani Centre for Clinical Research, Faculty of Medicine, The
University of Queensland, Brisbane, QLD, Australia
Pathology Queensland: The Royal Brisbane and Women’s Hospital, Brisbane,
QLD, Australia
Inta Liepniece-Karele Riga East University Hospital, Centre of Pathology/
Faculty of Medicine, University of Latvia, Riga, Latvia
Enrica Macorano Department of Emergency and Organ Transplantation,
Università degli Studi di Bari Aldo Moro – Policlinico, Bari, Italy
Lilla Madaras 2nd Department of Pathology, Semmelweis University,
Budapest, Hungary
xx Contributors
Gaetano Magro Department of Medical and Surgical Sciences and

Advanced Technologies, G.F. Ingrassia, Azienda Ospedaliero-Universitaria
“Policlinico-Vittorio Emanuele,” Anatomic Pathology Section, School of
Medicine, University of Catania, Catania, Italy
Eugenio Maiorano Department of Emergency and Organ Transplantation,
Unit of Pathology, University of Bari, Bari, Italy
Elena Maldi Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, Italy
Caterina Marchiò Unit of Pathology, Candiolo Cancer Institute FPO-
IRCCS, Candiolo, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
Institut Curie, Paris, France
Mauro Giuseppe Mastropasqua Department of Emergency and Organ
Transplantation, Università degli Studi di Bari Aldo Moro – Policlinico,
Bari, Italy
Jasna Metovic Department of Oncology, University of Turin, Turin, Italy
Dina Milowich Institute of Pathology, University Hospital Lausanne,
Lausanne, Switzerland
Luca Morandi Department of Biomedical and Neuromotor Sciences
(DIBINEM), Unit of Anatomic Pathology at Bellaria Hospital, University of
Linda Moskovszky Institute of Pathology and Molecular Pathology, Univer-
sity Hospital Zurich, Zurich, Switzerland
Mark O’Loughlin Discipline of Pathology, NUI Galway, Galway, Ireland
Gyula Pekar Division for Laboratory medicine, Department of Pathology,
Lund University, Lund, Sweden
Alberto Pisacane Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, TO, Italy
Savelina Popovska University of Pleven, Pleven, Bulgaria
Department of Pathology, Medical University, Pleven, Bulgaria
Cecily Quinn Department of Histopathology , Irish National Breast Screen-
ing Programme and St. Vincent’s University Hospital, Dublin, Ireland
School of Medicine, University College Dublin, Dublin, Ireland
Moira Ragazzi Department of Oncology and Advanced Technologies, Oper-
ative Unit of Pathology, Azienda USL-IRCCS, Reggio Emilia, Italy
Emad Rakha Department of Histopathology, Division of Cancer and Stem
Cells, University of Nottingham, Nottingham City Hospital, Nottingham, UK
Peter Regitnig Diagnostic- and Research Institute of Pathology, Medical
University of Graz, Graz, Austria
Contributors xxi
Costantino Ricci Department of Biomedical and Neuromotor Sciences

Lauren E. Rosen Department of Pathology, University of Chicago, Chicago,
IL, USA
Ales Ryska The Fingerland Department of Pathology, Charles University
Medical Faculty and University Hospital, Hradec Kralove, Czech Republic
Ian Said Huntingford Pathology Department, Mater Dei Hospital, Msida,
Malta
Lucia Salvatorelli Department of Medical and Surgical Sciences and
Advanced Technologies, G.F. Ingrassia, Azienda Ospedaliero-Universitaria
“Policlinico-Vittorio Emanuele,” Anatomic Pathology Section, School of
Medicine, University of Catania, Catania, Italy
Anna Sapino Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
Ivana Sarotto Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, Italy
Abeer M. Shaaban Department of Cellular Pathology, Queen Elizabeth
Hospital Birmingham and University of Birmingham, Birmingham, UK
Angelo Sidoni Department of Experimental Medicine, Section of Pathologic
Anatomy and Histology, Medical School, University of Perugia, Perugia, Italy
Peter T. Simpson Centre for Clinical Research, Faculty of Medicine, The
University of Queensland, Brisbane, QLD, Australia
Alena Skalova Department of Pathology, Faculty of Medicine in Plzen,
Charles University, Plzen, Czech Republic
Biopticka laborator s.r.o, Pilsen, Czech Republic
Valerie Speirs Leeds Institute of Cancer and Pathology, University of Leeds,
Leeds, UK
Folakemi A. Torgersen The Fingerland Department of Pathology, Charles
University Medical Faculty and University Hospital, Hradec Kralove, Czech
Republic
Paul J. van Diest Department of Pathology, University Medical Center
Utrecht, Utrecht, The Netherlands
Zsuzsanna Varga Institute of Pathology and Molecular Pathology, Univer-
sity Hospital Zurich, Zurich, Switzerland
Vania Vezzosi Division of Pathological Anatomy, Department of Surgery
and Translational Medicine, University of Florence, School of Human Health
Sciences, Florence, Italy
xxii Contributors
Anne Vincent-Salomon Institut Curie, Paris, France

Elena Vissio Department of Medical Sciences, University of Turin, Turin,
Italy
Semir Vranic Department of Pathology, Clinical Centre and School of Med-
icine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
College of Medicine, Qatar University, Doha, Qatar
Celien Vreuls Department of Pathology, University Medical Center Utrecht,
Utrecht, The Netherlands
Noëlle Weingertner Department of Pathology, Strasbourg University Hos-
pital, Strasbourg, France
Clive Wells University College London Hospital, London, UK
Jelle Wesseling Department of Pathology, The Netherlands Cancer Institute-
Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
A
Abscess Puerperal Abscess
Noëlle Weingertner and Jean-Pierre Bellocq Puerperal abscess is the natural course of acute
Department of Pathology, Strasbourg University puerperal mastitis. It occurs at the end of preg-
Hospital, Strasbourg, France nancy but especially during lactation. Clinically,
it presents with the same symptoms as mastitis
but with a palpable mass (Mahoney and Ingram
Synonyms 2014). This mass is painful and inflammatory, with
a purulent flow at incision and possible general
Pyogenic mastitis signs (fever and malaise). Spontaneous evolution
may be fistulization. There is usually a context of
cracked nipple or skin abrasion, leading to retro-
Definition grade infection. Staphylococcus aureus is the most
common organism responsible (50% of cases), but
A breast abscess is defined as a collection of Staphylococcus epidermidis and streptococci are
infected fluid or pus within the breast. occasionally isolated. Breast abscesses associated
Breast abscesses are mainly classified as with methicillin-resistant Staphylococcus aureus
“puerperal” (or “lactational”) – related to (MRSA) has been reported and is likely to be an
childbirth – and “non-puerperal.” In a non- increasing problem. Typhoid is a well-recognized
puerperal context, the subareolar abscess is cause of breast abscess in countries where this
the most frequently observed. Other rarer disease is common (Kataria et al. 2013).
situations include peripheral non-puerperal
abscesses, neonatal infections, skin-associated Clinical Features
infections, infections associated with breast • Incidence
surgery, with medical or non-medical proce- Puerperal abscesses affect 1–9% of breast-
dures, and unusual infections. Abscesses repre- feeding mothers (Mahoney and Ingram 2014).
sent 3–4% of all benign breast masses (Kasales Infection is more frequent following a first
et al. 2014). child and occurs most commonly within the
In this chapter, we will detail the most frequent first 6 weeks of breastfeeding. Risk factors
presentations of breast abscesses, namely, puer- include the first child at maternal age over
peral abscesses and non-puerperal periareolar or 30, gestation of more than 41 weeks, and mas-
subareolar abscesses. titis (Kataria et al. 2013). Breast abscesses may

A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
2 Abscess
also occur at weaning, when the breasts

are more likely to be engorged (D’Alfonso
et al. 2015). An additional factor after about
6 months is that the baby’s teeth increase the
likelihood of nipple trauma.
• Site
Puerperal abscesses tend to be peripheral in
location.
• Treatment
Puerperal abscesses are readily managed with
appropriate antibiotics and aspiration or drainage
(Kataria et al. 2013). Ultrasound examination
must be performed to determinate whether an
abscess with visible pus is present. Aspiration
of pus may be guided with ultrasonography. Bac-
teriological examination of the aspirated material
must be performed, to help direct antibiotic ther-
apy. Incision and drainage may be performed if
aspiration is insufficient. Breast cancer should be
excluded in patients with an inflammatory lesion
that is solid on ultrasonography or on aspiration
or that does not settle entirely despite apparently
adequate antibiotic treatment.
• Outcome
Puerperal abscesses are readily recognized and
treated by clinicians. Recurrence is rare,
because they respond well to antibiotic therapy
and when indicated, percutaneous drainage Abscess, Fig. 1 Lactational abscess – clinical (A) and
(Kasales et al. 2014). ultrasound (B) features. (A) The breast is edematous and
indurated and there is a painful lump in the internal part of
the breast (star). (B) Ultrasound demonstrates a cystic
Macroscopy lesion (star) with a thick content, irregular contours and
Lactational abscesses are edematous pink-red perilesional edema (courtesy of Sébastien Molière, Depart-
masses with a central cavity filled with yellow ment of Radiology, Strasbourg University Hospital)
viscous fluid (pus) (Fig. 1). Enlarged axillary
lymph nodes may be encountered. Breast abscess presents as an acute inflam-
matory infiltrate with numerous neutrophils
Imaging associated with fibrin. In abscess resolution, neu-
Mammographic features of abscesses are non- trophilic inflammation is progressively replaced
specific and may include a mass, an architectural by granulation tissue with fibrosis and chronic
distortion or skin thickening. Ultrasound is useful inflammation. Epithelial changes linked to lacta-
to confirm the presence of an abscess, with a hypo- tion are observed around puerperal abscesses
echoic mass or a multiloculated fluid collection (Fig. 2).
with a thick, echogenic rim (D’Alfonso et al. 2015).
Differential Diagnosis
Microscopy Inflammatory carcinoma may be difficult to dif-
Core biopsy is sometimes indicated to rule out ferentiate from mastitis clinically and by imaging.
malignancy, or a specimen may be analyzed When a solid area is present on imaging studies
when surgery is indicated. or when treatment is not efficient, breast cancer
Abscess 3
1–2% of all symptomatic breast processes

(Kasales et al. 2014) and 5% the incidence
of breast cancer (Pereira et al. 2012). A
• Age
Non-puerperal subareolar abscesses affect
a wider age range (mid-teens through eighth
decade) with a peak incidence in the mid to late
fourth decade (Kasales et al. 2014).
• Sex
Non-puerperal subareolar abscesses may rarely
affect males (Kasales et al. 2014).
• Site
Most cases are unilateral but bilateral abscesses
Abscess, Fig. 2 Lactational abscess – microscopic fea- are reported (Habif et al. 1970).
tures (H&E x10). Acute inflammatory infiltrate (star);
mammary glands show lactational changes (arrow)
• Treatment
Treatment with antibiotics and aspiration or
drainage often fails in the management of non-
should be considered and tissue biopsy with his- puerperal subareolar abscesses, with a high rate of
tologic analysis should be undertaken. recurrence. These should be treated with a course
of appropriate antibiotics that include anaerobic
cover and most cases require surgical intervention
Non-puerperal Periareolar or Subareolar for definitive resolution, with excision of the
Abscess abscess, sinus track, and the involved terminal
portion of the subareolar duct (D’Alfonso et al.
Non-puerperal periareolar or subareolar 2015). Cessation of smoking can be associated
abscesses are often subacute or chronic. Zuska’s with reversal of the process (Pereira et al. 2012).
disease is sometimes used to describe patients • Outcome
with subareolar abscess who present with nipple Subareolar nonpuerperal abscesses are difficult
retraction and a draining sinus (Mahoney and to treat. They recur frequently (>50% of cases)
Ingram 2014). Subareolar abscesses result from and often require multiple drainage or surgical
obstruction of the lactiferous ducts by squamous procedures. Fistulas form in one third of
metaplasia of their epithelium, with production of patients, most often after aspiration, incision,
keratin and plugging. Subsequent inflammation or drainage (Kasales et al. 2014).
and infection then occur. Initial cases are usually
associated with staphylococcus but recurrent epi- Macroscopy
sodes often have mixed flora, including anaerobic Periareolar non-puerperal abscesses result in an
organisms (D’Alfonso et al. 2015). edematous pink-red and indurated nipple (Fig. 3),
which may have a cavitated central mass-like
Clinical Features lesion filled with pus. Lesions range in size from
• Incidence 1 to 5 cm (Kasales et al. 2014). Retraction of
Subareolar non-puerperal abscesses are the nipple may develop, as well as duct fistula.
strongly associated with cigarette smoking, An enlarged axillary lymph node may be
70–90% of patients reporting a history of encountered.
smoking. An association with vitamin defi-
ciency has also been suggested, as well as Microscopy
increased prolactin level, phenothiazine Core biopsy is sometimes indicated to rule out
intake, and decreased estrogen level (Pereira malignancy, or a specimen may be analyzed when
et al. 2012). Their incidence is approximately surgery is indicated.
4 Abscess
Subareolar abscesses present with acute, keratin plugs (Fig. 4). A foreign-body-like reaction
subacute, or chronic inflammatory infiltrate with to keratin may also be seen (Kasales et al. 2014).
fibrosis. Some subareolar abscesses may show
ducts with squamous metaplasia that contain Differential Diagnosis
Subareolar abscesses have to be differentiated
from breast cancer, especially inflammatory
carcinoma.
Subareolar abscess are distinct from duct
ectasia (▶ Duct Ectasia and Periductal Mastitis).
Duct ectasia affects an older age group and is not
associated with smoking. The subareolar ducts are
dilated and the inflammation is less extensive and
less active.
Granulomatous lobular mastitis (▶ Granulo-
matous Mastitis) (GLM) may be associated with
abscess formation. This condition should be differ-
entiated from non-puerperal subareolar abscesses,
in which granulomatous inflammation may
develop in the late stages. In contrast to subareolar
abscess, GLM is generally peripheral and lobulo-
centric, is not associated with epithelial duct squa-
mous metaplasia and with smoking, but is associ-
ated with pregnancy (Pereira et al. 2012).
Others
Peripheral non-puerperal abscesses are rare and

Abscess, Fig. 3 Non-puerperal subareolar abscess –
are associated with chronic conditions such as
clinical aspect. Indurated, pink-red nodule on the nipple
(courtesy of Marie-Noëlle Roedlich, Department of Radi- diabetes, rheumatoid arthritis, steroid treatment,
ology, Strasbourg University Hospital) and trauma (Kasales et al. 2014).
Abscess, Fig 4 Non-puerperal subareolar abscess – epidermis of the nipple (arrow) and malpighian metaplasia
microscopic features (A: H&E x4 and B: H&E x20). of the distal part of a galactophorous duct (star)
Dense, subacute, inflammatory infiltrate beyond the
Acinic Cell Carcinoma 5
Neonatal breast infection and abscess Habif, D. V., Perzin, K. H., Lipton, R., & Lattes, R. (1970).
are uncommon but can occur in the first few Subareolar abscess associated with squamous metapla-
sia of the lactiferous ducts. American Journal of
weeks of life when the breast bud is enlarged. Surgery, 119, 523–526. A
Staphylococcus aureus is the usual organism, but Kasales, C. J., Han, B., Stanley Smith, J., Jr.,
occasionally it may be due to Escherichia coli Chetlen, A. L., Kaneda, H. J., & Shereef, S. (2014).
(Weidner 2012). Nonpuerperal mastitis and subareolar abscess of
the breast. American Journal of Roentgenology, 202,
Primary infection of the skin of the breast, W133–W139.
which can present as cellulitis or an abscess, most Kataria, K., Srivastava, A., & Dhar, A. (2013). Manage-
commonly affects the skin of the lower half of the ment of lactational mastitis and breast abscesses:
breast. These infections are often recurrent in review of current knowledge and practice. Indian
Journal of Surgery, 75(6), 430–435.
women who are overweight, have large breasts Mahoney, M. C., & Ingram, A. D. (2014). Breast
or have poor personal hygiene, and in people emergencies: types, imaging features, and manage-
with skin conditions such as eczema. Epidermal ment. American Journal of Roentgenology, 202(4),
cysts are common in the skin of the breast and W390–W399.
Pereira, F. A., Mudgil, A. V., Macias, E. S., &
may become infected. Hidradenitis suppurativa Karsif, K. (2012). Idiopathic granulomatous lobular
may affect the breast. Pilonidal abscesses affect- mastitis. International Journal of Dermatology, 51(2),
ing the nipple have been reported in hairdressers 142–151.
or sheep shearers (Weidner 2012). Staphylococ- Weidner, N. (2012). Infections of the breast. In D. J. Dabbs
(Ed.), Breast pathology (pp. 34–43). Philadelphia:
cus aureus is the usual causative organisms in Elsevier Saunders.
skin-associated infections (Weidner 2012).
Breast infection and abscesses may occur
following needle biopsy, or surgery for breast
cancer, breast implants or mammoplasty. Acinic Cell Carcinoma
Nipple rings can cause recurrent infection,
particularly in smokers. Maria P. Foschini and Luca Morandi
Factitial diseases are created by the patient. Such Department of Biomedical and Neuromotor
patients may undergo many investigations before Sciences (DIBINEM), Unit of Anatomic
the nature of the disease is recognized. The diagnosis Pathology at Bellaria Hospital, University of
is difficult to establish but should be considered Bologna, Bologna, Italy
when the clinical situation appears suspicious.
Unusual Breast Infections Definition

Breast abscesses are usually caused by staphylo-
coccus aureus, streptococcus, or anaerobic bacte- Acinic cell carcinoma (ACC) is a special type
ria. Tuberculosis may rarely be encountered of breast carcinoma showing serous differenti-
(▶ Granulomatous Mastitis). It may present with ation, with zymogen-type cytoplasmic granules,
an abscess resulting from infection of a tubercu- similar to acinic cell carcinoma arising in the
lous cavity by an acute pyogenic organism such as parotid gland (Eusebi et al. 2012; Foschini
Staphylococcus aureus. Syphilis, actinomycosis, et al. 2017).
mycotic, parasitic, and viral infections occasion-
ally affect the breast but are rare (Weidner 2012).
Clinical Features
References and Further Reading • Incidence

ACC is a rare tumor, but its real incidence is
D’Alfonso, T. M., Ginter, P. S., & Shin, S. J. (2015).
A review of inflammatory processes of the breast with
difficult to assess, as most of our knowledge is
a focus on diagnosis in core biopsy samples. Journal of based on single case reports or small series. It
Pathology and Translational Medicine, 49(4), 279–287. was first described by Roncaroli et al. (1996),
6 Acinic Cell Carcinoma
and then better delineated by Damiani et al. Macroscopy

(2000). Since then less than 50 cases have
been described in the English literature Macroscopic features are similar to those of
(Foschini et al. 2017). invasive carcinoma NST (▶ Invasive Carcinoma
• Age NST). Specifically ACC presents as a nodule,
ACC usually affects adults, aged from 20 to hard in consistency, with infiltrative margins,
80 years (mean 50). ranging in size from 11 mm to 50 mm. In one
• Sex instance, ACC arose within a fibroadenoma
ACC usually occurs in female patients. One (▶ Fibroadenoma) (Foschini et al. 2017).
case has been described in a male patient
(Shimao et al. 1998) and one case has been
reported in BRCA1 mutated patient
Microscopy
(Ripamonti et al. 2013).
ACC of the breast shows a wide variety of archi-
• Site
tectural patterns, and therefore diagnosis is mainly
Breast ACC affects the parenchyma with no
based on the recognition of the neoplastic cell
specific site; its presentation is similar to breast
features.
carcinoma of no special type (NST).
Breast ACC infiltrates parenchyma with small
• Treatment
glandular structures (Fig. 1 H&E) composed of
Breast ACC is a triple negative tumor, usually
large polygonal cells, with granular, clear, or
showing low aggressive potential. It is treated
amphophilic cytoplasm. The cytoplasm
with radical surgery, and, in most of the reported
contains granules that are seen on H&E stained
cases, radiation and/or chemotherapy are added.
sections, but they can be better evidenced
• Outcome
by PAS after diastase digestion or electron
Prognosis is difficult to assess due to the low
microscopy (Damiani et al. 2000). The
number of reported cases. From a recent
nucleus is centrally located, shows coarse
review (Foschini et al. 2017) most of the
chromatin and well-evident nucleolus (Figs. 2
patients are alive and free of recurrences or
and 3 H&E).
metastases at the time of last follow-up. Length
These cells can be arranged in solid as well as
of follow-up information ranges from 6 to
in microglandular structures devoid of basal
142 months (mean 42 months). Axillary
membrane (Fig. 4 Collagen IV immunostaining).
lymph-node metastases were present in 9/30
In most of the cases a wide range of architectural
cases. Distant metastases (liver, lungs, and
patterns is seen within the same tumor, while in
bone) were reported in three cases, two of
other cases one pattern is predominant. Usually
which died of disease.
the microglandular component is present at the
Acinic Cell Carcinoma,

Fig. 1 Low power view of
ACC with prevalent
microglandular architecture
(H&E)

Fig. 2 At high power the
neoplastic cells show
granular cytoplasm and are A
arranged in small glandular
structures (H&E)

Fig. 3 Neoplastic glands
are small, with irregular
outlines and lined by
multiple layers of neoplastic
cells (H&E)
2000). The microglandular component is char-

acterized by small glands, lined by one or multi-
ple layers of atypical cells, having the same
features of neoplastic cells located in the solid
component. In situ duct carcinoma, composed of
cells with acinic features, can be associated with
the invasive component.
Immunophenotype
Immunohistochemical profile is important to

achieve a correct diagnosis, because it confirms
Acinic Cell Carcinoma, Fig. 4 Basal membrane, the acinic differentiation of cells. Specifically
evidenced by Collagen IV immunostainig, shows small ACC is positive for salivary type amylase
capillary vessels, but it is not present around the neoplastic (Fig. 5), lysozyme, and alpha-1-antichimotrypsin.
glands
Furthermore the majority of ACC cells are
strongly positive for S-100 protein (Fig. 6) and
periphery of the tumor, giving an invasive pat- epithelial membrane antigen (EMA) (Fig. 7) and
tern of growth. Cases with pure microglandular low molecular weight cytokeratins (CK) as CK7
pattern of growth are on record (Damiani et al. and CK8.
8 Acinic Cell Carcinoma

Fig. 5 Salivary type
amylase is strongly positive
in ACC cells
In addition an MLL3 splicing mutation, a TSC2

missense mutation (A289V), and missense muta-
tions in MED12 (D1204E), MLL (K1225 N),
MLL2 (T2017S), TP63 (R594L) together with a
twofold increase in FOXA1 were described in one
case (Conlon et al. 2016).
The molecular profile detected in breast ACC is
quite different from that of salivary gland ACC,
while it is similar to that of breast poorly differenti-
ated carcinoma NST. These observations lead
Piscuoglio et al. (2015) to suggest that breast ACC
is a novel variant of breast triple negative carcinoma.
Acinic Cell Carcinoma, Fig. 6 S-100 antibody stains Differential Diagnosis

most of the ACC neoplastic cells
Several breast carcinomas should be differentiated

Estrogen and progesterone receptors (ER, PR) from ACC, and differential diagnosis is mainly
are usually negative, as well as androgen receptor based on the immunohistochemical profile and on
(AR). No HER2 amplification has been recorded. the architectural pattern of growth.
Basal membrane is absent at the periphery of the ACC with solid growth pattern should be dif-
neoplastic glandular structures (Conlon et al. 2016). ferentiated from breast carcinoma NST (▶ Inva-
On electron microscopy the neoplastic cells are sive Carcinoma NST), oncocytic carcinoma
characterized by intracytoplasmic electron dense (▶ Invasive Oncocytic Carcinoma), and apocrine
granules (Damiani et al. 2000). carcinoma (▶ Apocrine Carcinoma). Breast carci-
noma NST does not express S-100 protein, which
is strongly positive in nuclei and cytoplasms of the
Molecular Features majority of ACC cells. Apocrine carcinoma
shows a strong and diffuse positivity for the apo-
Only few papers dealt with ACC molecular profile, crine marker GCDFP-15, while the same marker
therefore knowledge on this subject is still incom- is only focally positive in ACC. Oncocytic carci-
plete. The following genes were found to be mutated noma is excluded for its intense and diffuse pos-
in ACC: TP53, PIK3CA, KMT2D, ERBB4, ERBB3, itivity for the antimitochondrial marker and, when
NEB, BRCA1, MTOR, CTNNB1, INPP4B, FGFR2 electron microscopy is feasible, it shows numer-
(Guerini-Rocco et al. 2015; Piscuoglio et al. 2015). ous intracytoplasmic mitochondria. Furthermore

Fig. 7 EMA positivity in
ACC
A
and most importantly, none of these latter tumors Damiani, S., Pasquinelli, G., Lamovec, J., Peterse, J. L., &
show serous acinar differentiation, demonstrated Eusebi, V. (2000). Acinic cell carcinoma of the breast:
An immunohistochemical and ultrastructural study.
with anti-lysozyme, anti-salivary type amylase, Virchows Archiv, 437, 74–81.
and anti-alpha-1- antichimotrypsin. Eusebi, V., Ichihara, S., Vincent-Salomon, A., Sniege, A.,
Secretory carcinoma (▶ Invasive Secretory Car- & Sapino, A. (2012). Exceptionally rare types and
cinoma) of the breast can simulate ACC. Differen- variants. In S. R. Lakhani, I. O. Ellis, S. J. Schnitt,
P. H. Tan, & M. van de Vijver (Eds.), WHO classifica-
tial diagnosis is based on the cytological atypias tion of tumours of the breast (4th ed., p. 75). Lyon:
that in secretory carcinoma are quite bland, while IARC Press.
are more marked in ACC. In addition secretory Foschini, M. P., Morandi, L., Asioli, S., Giove, G.,
breast carcinoma is characterized by a typical Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the
ETV6 rearrangement that is absent in ACC. breast. Pathology, 49, 215–227.
Differential diagnosis between ACC with Guerini-Rocco, E., Hodi, Z., Piscuoglio, S., Ng, C. K.,
prominent microglandular pattern and micro- Rakha, E. A., Schultheis, A. M., Marchiò, C., da
glandular adenosis (MGA) (▶ Microglandular Cruz, P. A., De Filippo, M. R., Martelotto, L. G., De
Mattos-Arruda, L., Edelweiss, M., Jungbluth, A. A.,
Adenosis) is a more controversial issue, and Fusco, N., Norton, L., Weigelt, B., Ellis, I. O., & Reis-
recent papers describe similar molecular fea- Filho, J. S. (2015). The repertoire of somatic genetic
tures. According to the original morphological alterations of acinic cell carcinomas of the breast: An
description (Clement and Azzopardi 1983), exploratory, hypothesis-generating study. Journal of
Pathology, 237, 166–178.
MGA is characterized by small glandular struc- Piscuoglio, S., Hodi, Z., Katabi, N., Guerini-Rocco, E.,
tures lined by clear cells with empty cytoplasm, Macedo, G. S., Ng, C. K., Edelweiss, M., De Mattos-
surrounded by basal membrane. On the contrary, Arruda, L., Wen, H. Y., Rakha, E. A., Ellis, I. O., Rubin,
ACC with microglandular pattern is composed B. P., Weigelt, B., & Reis-Filho, J. S. (2015). Are acinic
cell carcinomas of the breast and salivary glands dis-
of cells with eosinophilic cytoplasm, with tinct diseases? Histopathology, 67, 529–537.
intracytoplasmic granules (demonstrated both Ripamonti, C. B., Colombo, M., Mondini, P., Siranoush,
with PAS after diastase digestion and electron M., Peissel, B., Bernard, L., Radice, P., & Carcangiu,
microscopy) and absence of basal membrane. M. L. (2013). First description of an acinic cell carci-
noma of the breast in a BRCA1 mutation carrier: A case
report. BMC Cancer, 13, 46.
Roncaroli, F., Lamovec, J., Zidar, A., & Eusebi, V. (1996).
References and Further Reading Acinic cell-like carcinoma of the breast. Virchows
Archiv, 429, 69–74.
Clement, P. B., & Azzopardi, J. G. (1983). Microglandular Shimao, K., Haga, S., Shimizu, T., Imamura, H.,
adenosis of the breast – A lesion simulating tubular Watanabe, O., Kinoshita, J., Nagumo, H., Utada, Y.,
carcinoma. Histopathology, 7, 169–180. Okabe, T., Kajiwara, T., Oshibe, N., & Aiba,
Conlon, N., Sadri, N., Corben, A. D., & Tan, L. K. (2016). M. (1998). Acinic cell adenocarcinoma arising in the
Acinic cell carcinoma of breast: Morphologic and breast of a young male: A clinicopathological, immu-
immunohistochemical review of a rare breast cancer nohistochemical and ultrastructural study. Breast Can-
subtype. Human Pathology, 51, 16–24. cer, 5, 77–81.
10 Adenoid Cystic Carcinoma
high-grade transformation is characterized by

Adenoid Cystic Carcinoma the presence of high-grade malignant compo-
nent, in addition to the AdCC classical fea-
Maria P. Foschini and Luca Morandi tures. These latter cases can lead to patient’s
Department of Biomedical and Neuromotor death (D’Alfonso et al. 2014; Foschini et al.
Sciences (DIBINEM), Unit of Anatomic 2016, 2017; Shin and Rosen 2002).
Pathology at Bellaria Hospital, University of
Macroscopy
AdCC presents as a lobulated mass, hard in con-

Definition
sistency, whitish in color.
Adenoid cystic carcinoma (AdCC) of the breast is
a low-grade tumor, composed of epithelial, Microscopy
myoepithelial, and basal cells, showing features
similar to the salivary gland counterpart. AdCC can present various morphological features
that reflect the three main categories (Foschini
et al. 2016, 2017).
Clinical Features AdCC classical variant: It is composed of a
mixture of epithelial, myoepithelial, and basal
• Incidence cells, arranged in tubular, cribriform, and solid
AdCC of the breast is a rare tumor, accounting structures. Tubular structures are usually present
for less than 1% of all breast tumors. at the periphery of the neoplastic nodule, thus
• Age giving a peculiar infiltrative pattern of growth
It usually affects elderly female patients, even (Fig. 1 H&E). Tubular AdCC is characterized by
if rare cases have been reported in children. round or elongated tubular structures, lined by
• Sex epithelial, basal, and myoepithelial cells (Fig. 2
AdCC usually affects female patients, rare H&E). The tubular structures contain basal mem-
cases have been reported in males. brane or epithelial type of mucin. The tubular
• Site structures usually infiltrate the fat tissue. The crib-
AdCC is more frequently located in the riform architecture is the most frequently
retroareolar region, but it can affect all the observed (Fig. 3a, b H&E). It shows two types
breast quadrants. It can present as a mass of of glandular spaces. Epithelial cells surround
variable size or as screen detected nodule. luminal spaces containing epithelial-type mucin,
• Treatment which stains blue with Alcian blue pH 2.5.
Radical surgery is the treatment of choice. Myoepithelial and basaloid cells surround
• Outcome pseudoluminal spaces, containing basal mem-
AdCC is a low malignant potential tumor brane evidenced by PAS staining after diastase
therefore prognosis is usually good. Recur- digestion. Cells show little pleomorphism, and
rences and disease progression are rare. To mitoses are rare. No necrosis or perineural or
better predict prognosis, AdCC should be sub- lymphovascular invasion are seen. Sebaceous dif-
divided in three different categories: (i) AdCC ferentiation can be focally encountered.
classical variant shows good prognosis, with AdCC solid-basaloid variant (SB-AdCC): It
no recurrences or metastases, when local com- has been described by Shin and Rosen in 2002.
plete surgical excision is achieved; (ii) AdCC It usually presents as multiple neoplastic foci,
with solid-basaloid features (SB-AdCC) can varying in size from a few millimeters to large
present recurrence and local metastases, but masses (Fig. 4a, b H&E). In addition to the fea-
in most of the cases, long-term follow-up did tures present in the classical variant, it is com-
not show tumor-related deaths; (iii) AdCC with posed of large solid nests of cells with basaloid
Adenoid Cystic Carcinoma 11
Adenoid Cystic
Carcinoma, Fig. 1 AdCC
classical variant, showing
a central part with A
cribriform architecture and
a peripheral part (arrows)
with tubular architecture.
The AdCC with tubular
architecture shows
infiltrative pattern of
growth, invading the fatty
tissue (H&E)
Adenoid Cystic
classical variant with
tubular architecture is
composed of elongated
glands, surrounded by two
or more cell layers. Focally
structures typical of AdCC
with two types of mucins
are visible (H&E)
features and nuclear atypia. Atypical mitotic fig- cells are positive with high molecular weight CK,
ures are frequent; necrosis can be present as well as CK 14 and CK 5\6, p63 (Fig. 7 (a) p63
as perineural invasion (Figs. 5 and 6 H&E). When immunostaining in nuclei of myoepithelial cells in
perineural invasion is present a SB-AdCC variant cribriform and (b) and tubular components).
should always be suspected. Myoepithelial cells are evidenced by myoepithelial
AdCC with high-grade transformation: In rare markers, as smooth muscle actin (SMA), calponin,
cases, in addition to the classical AdCC features, caldesmon. Basal cell markers, as collagen IV and
areas of high-grade tumor of different origin laminin, stain the basal membrane present in the
(melanoma, spindle cell carcinoma, ▶ Invasive pseudoluminal spaces (Fig. 8 immunostaining with
Carcinoma NST, and ▶ Malignant Adenomyoe- Collagen IV). CD117 (cKit) is strongly present in
pithelioma (M-AME)) are present. The presence of all the epithelial components. Proliferative markers,
these high-grade tumor areas has prognostic impact, as Ki67, stain a variable percentage of neoplastic
as metastases and disease progression can occur. cells. High proliferative index is usually encoun-
tered in the SB-AdCC variant or in the areas of
high-grade transformation.
Immunophenotype
Immunohistochemical stainings are useful to high- Molecular Features

light the presence of the different cell types. Spe-
cifically the epithelial cells are positive with low- AdCC of the breast is most frequently a “triple
molecular weight cytokeratins (CKs) as CK7, CK8, negative tumor of low malignancy potential”
and epithelial membrane antigen (EMA). Basal (Foschini and Krausz 2010), as estrogen (ER) and
Adenoid Cystic
classical variant with
cribriform architecture
(a and b) shows neoplastic
nests composed of cells
with mild atypia,
surrounding two types of
spaces. Glandular spaces
contain an epithelial type of
mucin that is weakly
basophilic on H&E stained
sections. Pseudoglandular
spaces contain eosinophilic
basal membrane (H&E)
progesterone receptors (PR) are usually negative Epidermal growth factor receptor 1 (EGFR)
and HER2 protein is not overexpressed (Foschini protein can be overexpressed, even if this over-
et al. 2017). A weak expression for androgen recep- expression is not accompanied by gene amplifica-
tor (AR) has been described (Vranic et al. 2010). tion (Vranic et al. 2010).
Nevertheless, papers, based on large cohorts of MYB-NFIB fusion gene has been detected in
AdCC, report focal ER positivity in a minority of the majority of AdCC (Martelotto et al. 2015); in
cases. In our experience ER positivity can be seen addition it is maintained in SB-AdCC and in
in a minority of epithelial cells in AdCC classical AdCC with high-grade transformation (Fusco
variant, while ER and PR are completely absent et al. 2016; Righi et al. 2011).
in SB-AdCC and in AdCC with high-grade The mutational profile of AdCC has been
transformation. described using whole exome sequencing
A novel isoform of ER, namely ER-alpha36, (Martelotto et al. 2015), which showed a sub-
has been detected in AdCC of the breast. This stantial heterogeneity with lack of recurrent
novel isoform differs from the classical isoform mutations. The mutation rate was found to be
(ER-alpha66) as it does not show the transcrip- very low (0.27 nonsilent mutations/Mb), similar
tional activation domains; in addition, on to that reported for pediatric malignancies and
immunohistochemically stained sections, it is salivary gland AdCCs (0.31 nonsilent mutations/
mainly localized in the cytoplasm and on the cell Mb), and lower than that reported for triple neg-
membrane. It mediates nonclassic (nongenomic) ative breast cancers (TNBCs) (1.38 nonsilent
estrogen signaling, therefore opening the possibil- mutations/Mb). Unlike common TNBCs and
ity of novel therapies (Vranic et al. 2011). basal-like breast cancers, no somatic mutations
Adenoid Cystic Carcinoma, Fig. 4 SB-AdCC variant shows a multinodular type of growth, with neoplastic nodules
varying in size from a few millimeters (a) to larger neoplastic masses (b) (H&E)
Adenoid Cystic
Carcinoma, Fig. 5 SB-
AdCC at higher power
shows cellular atypia,
mitoses, and necrosis
(H&E)
targeting TP53, PIK3CA, RB1, BRCA1, or have been detected. Many of the mutations iden-
BRCA2 were identified in breast AdCCs. The tified were likely clonal with a cancer cell frac-
most frequently mutated genes are: MYB, tion >80%. Evaluating gene copy number
BRAF, FBXW7, SMARCA5, SF3B1, FGFR2, alterations, low level of genetic instability and
TLN2, PRKD1, RASA1, PTPN11, and MTOR. no amplifications or homozygous deletions were
On rare occasions mutations in RAS pathway identified.
When AdCC shows high-grade transformation, firm the morphological hypothesis, that high-grade
progression to high-grade TNBC was found to transformation is related to selected neoplastic
involve clonal shifts with enrichment of mutations clones that acquire additional somatic mutations.
affecting EP300, NOTCH1, ERBB2, FGFR1,
KMT2C, STAG2, KDM6A, CDK12. These data con-
Several differential diagnoses should be carried

out, for the different variants.
AdCC classical variants. At the periphery of
the neoplastic nodules, AdCC usually shows
tubular architecture. Tubular AdCC should be dif-
ferentiated from several entities having a micro-
glandular pattern of growth. Microglandular
adenosis (▶ Microglandular Adenosis) should be
excluded, as this latter entity is composed of glan-
dular structures lined by a single type of cells; on
the contrary in AdCC, tubular structures are
surrounded by epithelial, myoepithelial, and
Adenoid Cystic Carcinoma, Fig. 6 SB-AdCC focal fea- basal cells. In addition, in microglandular
tures reminiscent of AdCC are present (H&E) adenosis, tubular structures are surrounded by a
Adenoid Cystic
Carcinoma, Fig. 7 p63
immunostaining shows the
presence of basal and
myoepithelial cells both in
the cribriform (a) and in the
tubular (b) components
excision, therefore, the most important clue for

the patient’s correct treatment is to identify the
entity and more specific differential diagnosis can A
be referred to postoperative specimens.
AdCC cribriform should be differentiated by
several entities showing glandular spaces, as crib-
riform invasive carcinoma (▶ Invasive Cribriform
Carcinoma), collagenous spherulosis (▶ Collage-
nous Spherulosis), and infiltrating epitheliosis
(▶ Usual Ductal Hyperplasia (UDH)). Cribriform
invasive carcinoma is composed by one cell type
only; it is a pure epithelial cell tumor. The neo-
plastic cells surround glandular spaces, containing
Adenoid Cystic Carcinoma, Fig. 8 AdCC classical var- epithelial type mucin only. Basal membrane is not
iant with cribriform architecture: immunostaining with
collagen IV highlights the presence of basal membrane present inside the neoplastic lumina. All the neo-
inside the pseudoglandular spaces plastic cells stain intensively with ER and with
epithelial markers, as low molecular weight
CK. Basal and myoepithelial markers are negative
layer of basal membrane, while AdCC tubular in the neoplastic cells.
structures contain basal membrane. Collagenous spherulosis is a rare condition,
Sclerosing adenosis (▶ Sclerosing Adenosis) is composed by basal\myoepithelial cells only, sur-
a very common disease, composed of small glan- rounding pseudoglandular spaces filled with basal
dular structures closely packed together, whereas membrane. On immunohistochemistry, basal
AdCC tubular structures are not packed together, \myoepithelial cell markers, such as p63, CK14,
but they show a clear invasive pattern within and CK5\6, are uniformly positive. Collagen IV
the fat tissue. The basal membrane distribution and Laminin stain the luminal content. Similarly,
(outside the glands in sclerosing adenosis and infiltrating epitheliosis, being composed of basal
inside the glands in tubular AdCC) is an addi- \myoepithelial cells only, shows a uniform posi-
tional helpful differential diagnostic criterion. Dif- tivity for basal and myoepithelial markers.
ferential diagnosis is more difficult when we SB-AdCC variant should be differentiated by
compare tubular AdCC with adenomyoepithelioma basaloid carcinomas. The differential diagnosis is
(▶ Adenomyoepithelioma) with tubular architec- mainly based on the detection of classical features
ture. Both tumors share same morphological fea- of AdCC. The differential diagnosis can be diffi-
tures and the same cell composition (epithelial and cult when the solid-basaloid areas compose the
myoepithelial\basal cells), and in addition differen- most of the tumor; in these latter cases, careful
tial diagnosis is complicated by the description of search through the whole tumor is needed. Immu-
cases showing the two tumor types (AdCC and nohistochemistry for CD117 can be helpful, as the
adenomyoepithelioma) merging together. Usually strong and diffuse CD117 positivity is retained in
the typical areas of AdCC or adenomyoepithelioma the SB-AdCC variant also. Differential diagnosis
accompany the tubular type of growth, thus helping is important, as, even if the SB-AdCC variant is
to differentiate the two entities. Differential diagno- more aggressive than that of the classical variant,
sis can be more difficult in preoperative needle core its malignant potential is less than that of other
biopsies. In these latter cases differential diagnosis basaloid breast carcinomas.
could be tempted with the aid of CD117 AdCC with high-grade transformation. These
immunostaining that is usually strong and diffuse cases are characterized by AdCC classical associ-
in AdCC, while it is weak and focal in adenomyoe- ated with highly malignant areas. The detection of
pithelioma. Nevertheless, both entities are of low- the AdCC areas is necessary to achieve the correct
grade malignancy and need complete surgical diagnosis.
16 Adenomyoepithelioma
References and Further Reading EGFR gene amplification. Human Pathology, 41,
1617–1623.
Brill, L. B., Kanner, W. A., Fehr, A., Andrén, Y., Vranic, S., Gatalica, Z., Deng, H., Frkovic-Grazio, S.,
Moskaluk, C. A., Löning, T., Stenman, G., & Frierson, Lee, L. M., Gurjeva, O., & Wang, Z. Y. (2011).
H. F., Jr. (2011). Analysis of MYB expression and ER-a36, a novel isoform of ER-a66, is commonly
MYB-NFIB gene fusions in adenoid cystic carcinoma over-expressed in apocrine and adenoid cystic carci-
and other salivary neoplasms. Modern Pathology, 24, nomas of the breast. Journal of Clinical Pathology,
1169–1176. 64, 54–57.
D’Alfonso, T. M., Mosquera, J. M., MacDonald, T. Y., Wetterskog, D., Wilkerson, P. M., Rodrigues, D. N.,
Padilla, J., Liu, Y. F., Rubin, M. A., & Shin, S. J. (2014). Lambros, M. B., Fritchie, K., Andersson, M. K.,
MYB-NFIB gene fusion in adenoid cystic carcinoma of Natrajan, R., Gauthier, A., Di Palma, S., Shousha, S.,
the breast with special focus paid to the solid variant with Gatalica, Z., Töpfer, C., Vukovic, V., A’Hern, R.,
basaloid features. Human Pathology, 45, 2270–2280. Weigelt, B., Vincent-Salomon, A., Stenman, G., Rubin,
Foschini, M. P., & Krausz, T. (2010). Salivary gland-type B. P., & Reis-Filho, J. S. (2013). Mutation profiling of
tumors of the breast: A spectrum of benign and malig- adenoid cystic carcinomas from multiple anatomical
nant tumors including “triple negative carcinomas” of sites identifies mutations in the RAS pathway, but no
low malignant potential. Seminar in Diagnostic Pathol- KIT mutations. Histopathology, 62, 543–550.
ogy, 27, 77–90.
Foschini, M. P., Rizzo, A., De Leo, A., Laurino, L., Sironi,
M., & Rucco, V. (2016). Solid variant of adenoid cystic
carcinoma of the breast: A case series with proposal of a
new grading system. International Journal of Surgical
Adenomyoepithelioma
Pathology, 24(2), 97–102.
Foschini, M. P., Morandi, L., Asioli, S., Giove, G., Eugenio Maiorano1, Enrica Macorano2 and
Corradini, A. G., & Eusebi, V. (2017). The morpholog- Mauro Giuseppe Mastropasqua2
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Department of Emergency and Organ
breast. Pathology, 49, 215–227.
Fusco, N., Geyer, F. C., De Filippo, M. R., Martelotto, Transplantation, Unit of Pathology, University of
L. G., Ng, C. K., Piscuoglio, S., Guerini-Rocco, E., Bari, Bari, Italy
Schultheis, A. M., Fuhrmann, L., Wang, L., Jungbluth, 2
Department of Emergency and Organ
A. A., Burke, K. A., Lim, R. S., Vincent-Salomon, A.,
Bamba, M., Moritani, S., Badve, S. S., Ichihara, S.,
Transplantation, Universitá degli Studi di Bari
Ellis, I. O., Reis-Filho, J. S., & Weigelt, B. (2016). Aldo Moro – Policlinico, Bari, Italy
Genetic events in the progression of adenoid cystic
carcinoma of the breast to high-grade triple-negative
breast cancer. Modern Pathology, 29, 1292–1305.
Martelotto, L. G., De Filippo, M. R., Ng, C. K., Natrajan, R.,
Definition
Fuhrmann, L., Cyrta, J., Piscuoglio, S., Wen, H. C., Lim,
R. S., Shen, R., Schultheis, A. M., Wen, Y. H., Edelweiss, Adenomyoepithelioma (AME) is a benign tumor of
M., Mariani, O., Stenman, G., Chan, T. A., Colombo, the breast, composed by a biphasic proliferation of
P. E., Norton, L., Vincent-Salomon, A., Reis-Filho, J. S.,
phenotypically distinct myoepithelial cells and
& Weigelt, B. (2015). Genomic landscape of adenoid
cystic carcinoma of the breast. Journal of Pathology, luminal epithelial cells.
237, 179–189. Following the first description by Hamperl
Righi, A., Lenzi, M., Morandi, L., Flamminio, F., De (1970), Tavassoli (1991) identified three histo-
Biase, D., Farnedi, A., & Foschini, M. P. (2011).
Adenoid cystic carcinoma of the breast
logic variants, in which myoepithelial and epithe-
associated with invasive duct carcinoma: A case lial cells are present in variable percentages,
report. International Journal of Surgical Pathology, namely, spindle, tubular, and lobulated AME
19, 230–234. (Tavassoli 1991).
Shin, S. J., & Rosen, P. P. (2002). Solid variant of mam-
AME with malignant features (▶ Malignant
mary adenoid cystic carcinoma with basaloid features:
A study of nine cases. American Journal of Surgical Adenomyoepithelioma (M-AME)) have seldom
Pathology, 26, 413–420. been reported (Hayes 2011) and named AME
Vranic, S., Frkovic-Grazio, S., Lamovec, J., Serdarevic, with carcinoma, when epithelial cells or myoepi-
F., Gurjeva, O., Palazzo, J., Bilalovic, N., Lee, L. M.,
thelial cells show malignant cytomorphological
& Gatalica, Z. (2010). Adenoid cystic carcinomas
of the breast have low Topo IIa expression but fre- features and malignant AME when these are pre-
quently overexpress EGFR protein without sent in both components (Brogi 2014).
Adenomyoepithelioma 17
Clinical Features nodule. Its average size is 2.5 cm, ranging from
0.5 to 8.0 cm, without distinctive discoloration,
• Incidence the cut surface appearing as tan, gray, white, yel- A
AME is an extremely rare tumor, a few small low, or pink (Rosen 1987). Occasionally, a small
case series and single case reports having been multicystic component or multinodulation may
reported so far. (Decorsiere et al. 1988; McLaren be detected (Laforga et al. 1998). Its clinical pre-
et al. 2005; Loose et al. 1992; Rosen 1987; sentations include nipple discharge, pain, or
Tavassoli 1991). AME with carcinoma and tenderness at palpation and, mammographically,
malignant AME are even more infrequent than it appears as a rounded or lobulated, well-
their benign counterpart (Ahmed et al., Ahmed circumscribed dense mass, sometimes showing
and Heller 2000). microcalcifications, while ultrasonography high-
• Age lights a solid or cystic structure (Park et al. 2013;
It mostly occurs in postmenopausal women, Lee et al. 2010). Quite interestingly, strong
with sporadic cases occurring both in younger uptake of 18 F-Fluorodeoxyglucose by Positron
(26 and 27 year old; Loose et al. 1992; Rosen Emission Tomography has recently been reported
1987) and older patients (84 year old; Berna (Oba et al. 2017); this should be taken into
et al. 1997). account as a potential pitfall of clinico-
• Sex instrumental investigations.
Women are far more commonly affected, with
sporadic cases described in males (Berna et al.
1997; Tamura et al. 1993).
Microscopy
• Site
The cytomorphological features of AME have
AME usually is a solitary and unilateral mass,
been described in occasional cases or small case
which more commonly occurs in the peripheral
series (Chang et al. 2002; Hock and Chan 1994;
parts of the breast, and only occasionally may
Kurashina 2002; Mercado et al. 2007; Ng 2002;
be centrally located (Adejolu et al. 2011).
Niemann et al. 1995; Saad et al. 2012; Valente and
• Treatment
Stuckey 1994; Zhang et al. 2004): clusters of
The standard treatment is surgical excision
epithelial and myoepithelial cells represent the
with clear margins (Rosen 1987). Currently,
major finding, the latter also displaying occasional
adjuvant treatments are considered only for
intracytoplasmic vacuolization. Mild to moderate
the management of those exceptional cases of
nuclear atypia was also noted, in the absence of
AME with carcinoma.
necrosis or mitotic activity. Nevertheless, the
• Outcome
diagnosis of AME was not achieved, and based
AME is considered a benign neoplasm; never-
on fine needle aspiration cytology, most cases
theless, local recurrence has been reported in
were interpreted as benign neoplasms but suspi-
sporadic cases, usually more than 2 years after
cion of malignancy was raised in some instances
surgical excision (Loose et al. 1992) and pos-
(Brogi 2014). Proper identification of the
sibly ascribed to incomplete tumor eradication.
myoepithelial cell component, admixed with duc-
AME with carcinoma may present either as
tal cells, seem the most reliable tool to rule out
synchronous or metachronous lesions, follow-
malignancy.
ing recurrence of previously excised AMEs
In histologic preparations, AME usually is
(Tavassoli 1991).
sharply separated from adjacent tissues and may
show discrete fibrous encapsulation. Different
Macroscopy morphological patterns may distinctly or simulta-
neously be present, according to the variable per-
AME generally is a circumscribed, uniformly centage of myoepithelial and epithelial cells in
solid, sometimes lobulated, firm and small individual lesions (Hock and Chan 1994). The
spindle cell growth pattern consists in a predom- infrequently occur, possibly as a consequence of
inant proliferation of myoepithelial cells, some- infarction, while cartilaginous metaplasia is
times showing clear and vacuolated (“soap exceptionally uncommon.
bubble”) cytoplasms, and sparse or hardly visible The detection of infiltrative growth towards the
epithelial-lined spaces (Fig. 1), resembling surrounding tissues, necrosis, prominent cyto-
myoepithelioma (Weidner et al., Weidner and logic atypia, and exuberant mitotic activity in
Levine 1988).
In the tubular pattern, glandular spaces are
far more evident (Fig. 2), oval or rounded in
shape, reminiscent of tubular adenoma. They
are composed by epithelial cells with darkly
stained cytoplasms and slightly hyperchromatic
nuclei. Myoepithelial cells may surround epithe-
lial cells in a basal position or form small
clusters. They appear as small cuboidal cells
with barely visible cytoplasm or as larger cells
with evident cytoplasmic clearing; occasionally,
the exuberant proliferation of myoepithelial cells
may lead to compression of the lumen in tubular
structures.
In the lobulated variant (Fig. 3), the growth Adenomyoepithelioma,Fig.2 Adenomyoepithelioma–
pattern is mostly solid and the tumor nests include tubular variant: duct-like structures are well evident, oval
an admixture of clear, eosinophilic, and or rounded in shape, and composed by epithelial cells, with
plasmacytoid myoepithelial cells along with com- darkly stained cytoplasms and slightly hyperchromatic
nuclei and myoepithelial cells in a basal position. Occa-
pressed epithelial-lined spaces. A fibro-sclerotic sionally, the latter may be assembled in small clusters and
core is at times evident. show either scant cytoplasm or prominent cytoplasmic
Papillary structures may seldom be present and clearing. The exuberant proliferation of myoepithelial
apocrine metaplasia may be detected in such areas cells may lead to compression of the lumen in tubular
structures (H&E 100)
(Eusebi et al. 1987); squamous metaplasia may
Adenomyoepithelioma,Fig.1 Adenomyoepithelioma– Adenomyoepithelioma,Fig.3 Adenomyoepithelioma–

spindle cell variant: the tumor is composed by uniform lobulated variant: clear, eosinophilic, and plasmacytoid
spindle cells, with scant cytoplasm and rounded or myoepithelial cells are widely represented, thus producing
angulated nuclei; duct-like structures represent a minority a predominantly solid growth pattern with only occasional
of the tumor cell population and usually display a small epithelial-lined spaces, which look compressed
lumen (H&E 100) (H&E 100)
either the epithelial or the myoepithelial compo-

nent, are indicative of malignancy (Bult et al.
2000; Chen et al. 1994; Foschini et al. 1995; A
Hegy et al. 2009; Jones et al. 2003; Kihara et al.
2001; Michael et al. 1994; Oka et al. 2007;
Quereshi et al. 2009; Rasbridge and Millis 1998;
Simpson et al. 1998; Trojani et al. 1992); in such
instances, the designation AME with carcinoma
seems appropriate (Brogi 2014). Also, cases have
been described, in which both components show
malignant features, and named malignant AME
(Brogi 2014).
Occasional reports have highlighted the Adenomyoepithelioma, Fig. 4 Low-molecular-weight
simultaneous occurrence of AME in associa- (8–18) cytokeratins immunoreactivity is evident in the
tion with other breast lesions, such as ductal luminal epithelial component (200)
adenoma (▶ Ductal Adenoma) (Guarino et al.
1993), collagenous spherulosis (▶ Collagenous
Spherulosis) (Reis-Filho et al. 2004), adenoid
cystic carcinoma (▶ Adenoid Cystic Carci-
noma) (Van Dorpe et al. 1998), DCIS or inva-
sive NST or lobular carcinoma (Han 2010;
Kuroda et al. 2008; Honda and Lyama 2009),
and phyllodes tumor (▶ Phyllodes Tumor)
(Buch et al. 2006).
Immunophenotype
Immunohistochemistry allows proper identifica-

tion of the distinct, epithelial and myoepithelial, Adenomyoepithelioma, Fig. 5 Smooth muscle actin-
cell components of AME and may be helpful, positivity depicts the basal component of myoepithelial
especially in those cases in which lumen forma- nature (100)
tion is less evident. Luminal epithelial cells are
immunoreactive for low-molecular-weight (8–18)
cytokeratins (Fig. 4), epithelial membrane antigen
(EMA), carcinoembryonic antigen (CEA) (with a
luminal pattern) and, occasionally, for S-100 pro-
tein (McLaren et al. 2005).
Myoepithelial cells show consistent cytoplas-
mic staining for calponin, caldesmon, cytokeratin
14, smooth muscle actin (SMA) (Fig. 5), smooth
muscle myosin heavy chain (SMMHC), and p63
nuclear immunoreactivity (Dewar et al. 2011)
(Fig. 6). Also, cytokeratins 5/6 and CD10 may
be detected at lower rates, estrogen receptors
(ER) are often expressed in the epithelial compo-
Adenomyoepithelioma, Fig. 6 Myoepithelial cells in
nent, while progesterone receptors and HER2 are basal location also show p63 nuclear immunoreactivity
usually negative. (200)
Molecular Features irregular profile and are unevenly distributed

throughout the lesion.
No specific molecular alterations have been iden- In some cases, AME may show a prominent
tified in AME, although cases have been reported papillary pattern, thus prompting to consider
in the literature showing reciprocal translocations, intraductal papillomas (▶ Intraductal Papilloma)
t (8;16) (p23; q21) (Gatalica et al. 2005), micro- with adenosis in the differential diagnosis, in view
satellite instability, and allelic imbalance (Salto- of the presence of obliterated glandular lumens
Tellez et al. 2005). with spindle-shaped appearance. These features
suggested AME could be considered a variant of
ductal papilloma with prominent myoepithelial
Differential Diagnosis hyperplasia.
Tubular adenoma (▶ Tubular Adenoma of the

References and Further Reading
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former usually appears as a more sharply demar- pithelial tumors of the breast: Imaging findings with
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Roentgenology, 197, W184–W190.
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Ahmed, A. A., & Heller, D. S. (2000). Malignant
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Myoepithelial cells also are present in ductal liferation of epithelial and myoepithelial elements:
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Berna, J. D., Arcas, J., & Ballester, A. (1997).
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pithelioma: A potential false positive pitfall and pres- adenosis
ence of intranuclear cytoplasmic inclusions. Diagnostic
Cytopathology, 40, 1005–1009.
Salto-Tellez, M., Putti, t. C., & Lee, C. K. (2005).
Adenomyoepiyhelioma of the breast: Description of Definition
allelic imbalance and microsatellite instability.
Histopatology, 46, 230–231.
Simpson, R. H., Cope, N., & Skalova, A. (1998). Malig- Adenomyoepithelial adenosis: A benign prolifer-
nant adenomyoepithelioma of the breast with mixed ative lesion characterized by the simultaneous
osteogenic, spindle cell, and carcinomatous differenti- hyperplasia in both glandular and myoepithelial
ation. The American Journal of Surgical Pathology, 22, cells of the units of the lobules.
631–636.
Tamura, G., Monma, N., & Suzuki, Y. (1993). Adenosis tumor: A clinically and/or macroscopi-
Adenomyoepithelioma (myoepithelioma) of the breast cally recognizable breast lesion that, histologi-
in a male. Human Pathology, 24, 678–681. cally, primarily consists of sclerosing adenosis
Tavassoli, F. A. (1991). Myoepithelial lesions of the breast. (▶ Sclerosing Adenosis).
Myoepitheliosis, adenomyoepithelioma, and
myoepithelial carcinoma. The American Journal of Tubular adenosis: A very rare benign lesion
Surgical Pathology, 15, 554–568. composed of disorderly growing, noncrowded
Trojani, M., Guiu, M., & Trouette, H. (1992). Malignant narrow tubules that may mimic invasive
adenomyoepithelioma of the breast. carcinoma.
An immunohistochemical, cytophotometric, and ultra-
structural study of a case with lung metastases. Am Simple adenosis: An increase in size and number
J Clin Pathol, 98, 598–602. of lobules.
Valente, P. T., & Stuckey, J. H. (1994). Fine-needle
aspiration cytology of mammary adenomyoe-
pithelioma: Report of a case with intranuclear cyto-
plasmic inclusions. Diagnostic Cytopathology, 10, Clinical Features
165–168.
Van Dorpe, J., De Pauw, A., & Moerman, P. (1998). Adenoid • Incidence
cystic carcinoma arising in an adenomyoepithelioma of Adenomyoepithelial adenosis: In the literature,
the breast. Virchows Archiv, 432, 119–122.
Weidner, N., & Levine, J. D. (1988). Spindle-cell few cases are reported.
adenomyoepithelioma of the breast. A microscopic, Adenosis tumor: Rare.
ultrastructural, and immunocytochemical study. Tubular adenosis: Very rare, only few cases
Cancer, 62, 1561–1567. have been reported.
Zhang, C., Quddus, M. R., & Sung, C. J. (2004). Atypical
adenomyoepithelioma of the breast: Diagnostic prob- Simple adenosis: Incidental finding in surgical
lems and practical approaches in core needle biopsy. specimens.
The Breast Journal, 10, 154–155. • Age
Adenomyoepithelial adenosis: The age range
is from 30 to 52 years (Hamperl 1970; Kiaer
et al. 1984).
Adenosis, Other Types Adenosis tumor: In the 27 cases studied by
Nielsen (1987), all patients were females,
Manuela Lacerda1 and Paulo Figueiredo2 aged 22 to 68 years.
1
Instituto de Patologia e Imunologia Molecular da Tubular adenosis: In the cases reported by Lee
Universidadedo Porto (IPATIMUP), Porto, (Lee et al. 1996), all patients were women aged
Portugal 40 to 82 years.
2
Instituto Português de Oncologia de Coimbra, Simple adenosis: Mainly in the reproductive or
Coimbra, Portugal perimenopausal age group.
Adenosis, Other Types 23
• Sex excluding any focus of in-situ or invasive

These types of adenosis have been described in carcinoma.
female patients. Simple adenosis: No specific treatment is A
• Site required.
No special localization in the breast is known. • Outcome
• Imaging, Clinical Presentation Adenomyoepithelial adenosis: Local recur-
Adenomyoepithelial adenosis: Except in those rences are reported (Kiaer et al. 1984). Tsuda
cases where it is an incidental finding within a et al. (1994) reported a case of multiple foci of
specimen excised for another mammographic obvious carcinoma in the adenomyoepithelial
or ultrasound alteration, the clinical presenta- adenosis and suggest that this lesion may have
tion is a palpable mass. If the clinical presen- progressed to the identified carcinoma. Whether
tation is a mammographically detected mass, it adenomyoepithelial adenosis is associated with
may show an irregularly shaped lesion with an increased risk or is a precursor lesion for
spiculated margins with or without micro- breast carcinoma is not yet known. It is prudent
calcifications. The lesion is classified as to maintain follow-up of these patients.
Bi-RADS 5 (Reston 1998). Adenosis tumor: Adenosis tumors if
Adenosis tumor: In almost all reported cases, completely excised do not recur. None of 18
the clinical presentation was a palpable tumor. pure adenosis tumors described by Nielsen
Mammographic and ultrasound features are treated by excision had recurred at follow-up
often benign-appearing. Occasionally, its 1–9 years later (mean 3.75 years). (Nielsen
appearance may be suggestive of malignancy 1987).
(DiPiro et al. 2000). Tubular adenosis: Tubular adenosis is a benign
Tubular adenosis: In the case series published lesion per se but whether it is a risk or a pre-
by Lee et al. (1996), the clinical presentation cursor lesion remains to be determined (Lee
was a mass lesion but only in one case et al. 1996).
(measuring 3 cm) was the mass produced by Simple adenosis: Since this type of adenosis is
tubular adenosis alone. In the remaining cases, an incidental finding, no specific treatment is
an in-situ ductal carcinoma (DCIS) was found required and it is not a risk factor.
within the tubular adenosis or it was an inci-
dental finding in mastectomy specimens
performed for DCIS or invasive ductal carci- Macroscopy
noma (Lee et al. 1996).
Simple adenosis: No specific imaging charac- Adenomyoepithelial adenosis: When the presen-
teristics have been described. tation is a mass the macroscopic aspect is a
• Treatment firm, irregular area. In the case of incidental
The therapeutic approach and outcome should findings, it may not have been identified
be discussed in the preoperative multi- macroscopically.
disciplinary meeting (Rageth et al. 2016). Adenosis tumor: In the literature, this lesion is
Adenomyoepithelial adenosis: The lesion described as an irregular, ill-defined or nodular
should be completely excised by surgery or mass, with a gray or gray-white cut surface.
by vacuum-assisted systems (VANCB). Local Tubular adenosis: Among the six cases reported
recurrences are reported (Kiaer et al. 1984). by Lee (Lee et al. 1996), one patient presented
Adenosis tumor: The treatment of a pure with a 3 cm breast mass, and the others were found
adenosis tumor is excision (Heller and Fleming in specimens resected for invasive carcinoma
1950). NST (▶ Invasive Carcinoma NST) or DCIS
Tubular adenosis: The treatment of pure tubu- (▶ Ductal Carcinoma In Situ).
lar adenosis is excision. The pathology speci- Simple adenosis: No specific macroscopic appear-
men should be carefully studied with the aim of ance has been described.
24 Adenosis, Other Types
Microscopy cells is pale, vacuolated (cuboidal shaped) or eosin-

ophilic, fibroblastic like (spindle shaped) and may
Adenomyoepithelial adenosis: The lesion can be have a palisading pattern. The glandular epithelium
well circumscribed or consist of sparse multiple is flattened, cuboidal or simple cuboidal. Atypia or
foci located in the terminal duct-lobular units mitotic activity is infrequent.
(Fig. 1). The ducts become incorporated in the Adenosis tumor: Organoid lobular configuration
lesion and may have a distended or obliterated may be seen on low power examination. The
shape. The stroma is sparse, occasionally with glands, rounded or compressed, are organized in
adipose tissue. The glands vary slightly in shape different growth patterns. The luminal cells are
and size and may show apocrine features. cylindrical, cuboidal, or flattened. Myoepithelial
Myoepithelial cells proliferate around the glandular cells are present, may have a spindle shape and are
cells in a centrifugal way or towards the lumen and clearly identified with smooth muscle-actin, p63,
lead to its obstruction. The imbalance of the prolif- and calponin immunohistochemistry. Microcysts,
eration of each component can produce different apocrine metaplasia, or stromal elastosis can also
patterns which must be recognized. Myoepithelial be found (Fig. 3 and Fig. 4).
cells may have a cuboidal or spindle shape. In H&E Tubular adenosis: Proliferation of tubular units
sections (Fig. 2), the cytoplasm of myoepithelial in a haphazard pattern without a lobular
Adenosis, Other Types, Fig. 1 Adenomyoepithelial Adenosis, Other Types, Fig. 3 Adenosis tumor
adenosis (H&Ex50) (H&Ex25)
Adenosis, Other Types, Fig. 2 Adenomyoepithelial Adenosis, Other Types, Fig. 4 Adenosis tumor (p63 IHC
adenosis (H&Ex400) reaction x63)
Adenosis, Other Types 25
arrangement is observed. The tubular units may Differential Diagnosis

show branching. Tubular structures have a
double-layered epithelium (luminal cells and Adenomyoepithelial adenosis: In those cases where A
myoepithelial cells) surrounded by a basement it is an incidental finding, a careful microscopic
membrane. The tubules may contain a basophilic examination is mandatory to exclude an invasive
or granular eosinophilic secretion. The stroma is NST or in-situ carcinoma within the lesion. In
usually fibrous and acellular or edematous (Lee the few published papers, adenomyoepithelial
et al. 1996). adenosis is presented as an individual mass (Kiaer
Simple adenosis: Bonser et al. state that normal et al. 1984; Tavassoli 1991). When a guided needle
lobules may contain from less than 10 to more core biopsy (NCB) is performed, the focus should
than 100 acini. (Bonser et al. 1961). Despite this be on the cytological characteristic of both cell
wide range, some lobules attain a sufficiently components, namely, pleomorphism, overgrowth
large size to be regarded as pathological (Sloane or not of the myoepithelial component, and mitotic
1985). Lee et al. characterize simple adenosis as activity. Immunostaining for epithelial and
an increase in size and number of lobules (Lee myoepithelial components is mandatory in all
et al. 1996). cases. If mitoses or pleomorphism is not identified
in the core biopsy, the case should be classified as
B3 (European guidelines for quality assurance in
Immunophenotype breast cancer screening and diagnosis 2006). The
differential diagnosis is with the other dimorphic
In all these four type of adenosis, immunohisto- lesions where both epithelial and myoepithelial
chemistry is useful to identify both luminal and components are present (e.g., ▶ Adenomy-
myoepithelial cell components. Luminal cells oepithelioma and ▶ Malignant Adenomyoe-
express cytokeratins (CK): both low- and high- pithelioma (M-AME)). Tsuda et al. reported a
molecular weight CKs can be detected (CK8/18, case with multiple foci of an obvious carcinoma
CK5/6, CK14, MNF116) and myoepithelial cells in the adenomyoepithelial adenosis and suggested
express smooth-muscle-actin, p63, and calponin that this lesion may have progressed to malignancy
in addition to high-molecular weight CKs (Erel (Tsuda et al. 1994).
et al. 2008). Adenosis tumor: The most important differential
diagnosis is with tubular carcinoma (▶ Tubular
Carcinoma). Nielsen describes the macroscopic
Molecular Features and histologic features of adenosis tumors, tubular
carcinoma, and tubular adenoma (Nielsen 1987).
Adenomyoepithelial adenosis and Adenosis In needle core biopsies, the focus is on the
tumor: There are no data to date describing the microscopic aspects of the growth pattern and
molecular characteristics of these lesions. shape of the glands (multiple and round or
Tubular adenosis: Da Silva L. et al. (2009) compressed in adenosis tumors, uniform and
described adenoid cystic carcinoma (ACC) angulated in tubular carcinoma) and the presence
(▶ Adenoid Cystic Carcinoma) cases of the of myoepithelial cells in adenosis tumors and its
breast associated with tubular adenosis that pre- absence in tubular carcinoma. Immunohistochem-
sented different molecular genetic alterations istry is often needed to identify the presence of
from those found in the concomitant ACC. myoepithelial cells. Nuclear atypia or epithelial
Tubular adenosis was characterized by gains on hyperplasia are infrequent but when present
1q, 5p, 8q, 10q, 11p, and 11q and losses on 1p, should be reported. In core biopsies adenosis
10q, 11q, 12q, 14q, 15q, and 16q. tumors are classified in the B3 category.
Simple adenosis: There are no published data to Tubular adenosis: Tubular adenosis shows an
date about the molecular features of this type of infiltrative growth similar to microglandular
adenosis. adenosis (▶ Microglandular Adenosis) and
26 Angiosarcoma of the Breast
adenomyoepithelial adenosis but differs from Oberman, H. A. (1984). Benign breast lesions confused
them by the interdigitating tubular configuration; with carcinoma. In R. W. McDivtt, H. A. Oberman,
L. Ozzello, N. Kaufman (Eds.), The breast. Baltimore:
it also differs from microglandular adenosis Williams and Wilkins. United States-Canadian
due to the presence of myoepithelial cells. The Academy of Pathology Monographs in Pathology,
most important differential diagnosis is with 25, 1–33.
tubular carcinoma (▶ Tubular Carcinoma). The Rageth, C. J., O’Flynn, E. A. M., Comstock, C., Kurtz, C.,
Kubik, R., Madjar, H., Lepori, D., Kampmann, G.,
absence of angular shaped tubules with occa- Mundinger, A., Baege, A., Decker, T., Hosch, S.,
sional transverse bars, a lack of prominent lumi- Tausch, C., Delaloye, J. F., Morris, E., & Varga, Z.
nal snouts, a generally acellular collagenous (2016). First International Consensus Conference on
stroma rather than a desmoplastic one and the lesions of uncertain malignant potential in the breast
(B3 lesions). Breast Cancer Research and Treatment,
presence of the myoepithelial cells highlighted 159, 203–213.
by immunostaining, support the diagnosis of Reston, V. A., & American College of Radiology. (1998).
tubular adenosis (Lee et al. 1996). In core biopsy Illustrated breast imaging report and system
this lesion is classified in the B3 category. (BI-RADS), 3rd edn. American College of Radiology
5B 6.
Sloane, J. P. (1985). Non-neoplastic epithelial changes. In
J. P. Sloane (Ed.), Biopsy pathology of the breast,
References and Further Reading Biopsy pathology series (pp. 69–92). London:
Chapman and Hall Medical.
Bonser, G. M., Dossett, J. A., & Jull, J. W. (1961). Human Tavassoli, F. A. (1991). Myoepithelial lesions of the breast.
and experimental breast cancer. London: Pitman Myoepitheliosis, adenomyoepithelioma and
Medical Publications Co. Ltd. myoepithelial carcinoma. American Journal of
Da Silva, L., Buck, L., Simpson, P. T., Reid, L., Surgical Pathology, 15, 554–568.
McCallum, N., Madigan, B. J., & Lakhani, Tsuda, H., Mukai, K., Fukutomi, T., & Hirohashi, S.
S. R. (2009). Molecular and morphological analysis of (1994). Malignant progression of adenomyoepithelial
adenoid cystic carcinoma of the breast with synchronous adenosis of the breast. Pathology International,
tubular adenosis. Virchows Archive, 454, 107–114. 44, 475–479.
DiPiro, P., Gulizia, J. A., Lester, S. C., & Meyer, J. E. (2000).
American Journal of Radiology, 175, 31–34.
Erel, S., Tuncbilek, I., Kismet, K., Kilicoglu, B., Ozer, E.,
& Mehmet, A. A. (2008). Adenomyoepithelial
adenosis of the breast: Clinical, radiological and path- Angiosarcoma of the Breast
ological findings for differential diagnosis. Breast
Cancer, 3, 427–430.
European guidelines for quality assurance in breast Alberto Pisacane
cancer screening and diagnosis. (2006). European Unit of Pathology, Candiolo Cancer Institute
Commission, 4th edn 6a (pp. 221–256). FPO-IRCCS, Candiolo, TO, Italy
Hamperl, H. (1970) The myoepithelia (myoepithelial cells)
normal state; regressive changes; hyperplasia; tumors.
In H-W. Altmann, et al., (Eds.), Current topics in
pathology (Vol. 53, pp. 161–213). Berlin/Heidelberg: Definition
Springer.
Heller, E. L., & Fleming, J. C. (1950). Fibrosing A tumor composed of malignant cells with endo-
adenomatosis of the breast. American Journal of
Clinical Pathology, 20, 141–146. thelial differentiation.
Kiaer, H., Nielsen, B., Paulsen, S., Sørensen, I. M.,
Dyrebog, U., & Blichert-Tft, M. (1984). Adenomyoe-
pithelial adenosis and low-grade malignant Clinical Features
adenomyoepithelioma of the breast. Virchows Archive
(A), 405, 55–67.
Lee, K. C., Chan, J. K., & Gwi, E. (1996). Tubular adenosis • Incidence
of the breast: A distinctive lesion mimicking invasive Angiosarcoma (AS) of the breast is a rare dis-
carcinoma. American Journal of Surgical Pathology, ease accounting for about 1% of all soft tissue
20, 46–54.
breast tumors.
Nielsen, B. B. (1987). Adenosis tumor of the breast – a
clinic – pathological investigation of 27cases. It may present as primary AS, without pre-
Histopathology, 11, 1259–1275. vious history of mammary carcinoma or any
Angiosarcoma of the Breast 27
associated factor, or as secondary AS, most Low-grade tumors confer better outcomes
commonly associated with previous breast in terms of disease-free survival interval.
irradiation. Conversely, no statistically significant corre- A
Primary AS represents <0.05% of all pri- lation between tumor size and likelihood of
mary breast cancers. local recurrence has been identified in pri-
Secondary AS presents a median of mary AS, as far as no correlation seems to
10.5 years after radiotherapy for breast cancer. exist between tumor grade and the rate of
In those patients undergoing breast conserving local recurrence, distant metastases and
surgery with adjuvant radiotherapy, the esti- death owing to disease.
mated incidence of radiation-induced AS is
0.05–0.3%.
Macroscopy
AS rarely occurs after mastectomy with
axillary dissection without irradiation and dur-
In secondary AS single or multiple erythematous-
ing pregnancy.
violaceous nodules and/or papules may be present
• Age
on the breast skin. On gross examination AS
Primary AS more frequently affects young and
appear as poorly circumscribed, brown and hem-
middle-aged women (median age 30–55 ys).
orrhagic masses, friable, spongy or firm in breast
Secondary AS presents in older women
parenchyma.
(median age 67–71 ys) after radiotherapy for
breast cancer.
• Sex
Microscopy
Rare cases of AS have been described in male
breast.
Microscopic spectrum ranges from tumors dem-
• Site
onstrating well-formed vessels with mild cyto-
Primary AS arises within the breast paren-
logic atypia, to morphologically atypical and
chyma and usually presents with fullness or
undifferentiated pleomorphic sarcoma
swelling, which can rapidly grow forming pal-
(Nascimento et al. 2008).
pable mass or masses, without skin changes.
Tumors are histologically graded using
Secondary AS arises in the cutaneous tissue
Rosen’s three-tier system into low (I), intermedi-
and might secondarily invade breast
ate (II), or high (III) grade.
parenchyma.
Low-grade AS (Fig. 1 H&E) are composed of
• Treatment
complex anastomosing vascular channels. The
Because of rarity of AS, few data are available
endothelium is flat with minimal nuclear atypia
to support treatment decisions. Surgical resec-
tion is key, with mastectomy preferred over
breast-conserving therapy. Lymph node dis-
section is not routinely recommended.
The role of adjuvant radiotherapy and che-
motherapy is poorly defined, with many agents
showing activity and varying clinical benefit. It
is generally agreed that multimodality therapy
is the best for this aggressive tumor.
• Outcome
The 5-year survival rate of secondary AS
patients is in the range of 27%–48%. The
5-year disease-free survival rate is 35%.
Tumor size, grade, and number of foci are Angiosarcoma of the Breast, Fig. 1 Low-grade AS:
important prognostic factors. neoplastic vessels dissect mammary parenchyma (H&E)
28 Angiosarcoma of the Breast
and no cellular stratification. Tumor dissects the channels, often with prominent areas of hemor-
stroma, causing distortion with little destruction rhage (so called “blood lakes”). Tumor cells are
of the preexisting lobules and ducts. The mitotic mostly spindled or epithelioid and show diffuse
rate is low (median 2/10 HPF). Necrosis is gener- and prominent nuclear atypia. Mitotic figures are
ally absent. easily observed. Necrosis is frequent, and the
Intermediate-grade AS (Fig. 2 H&E) are more tumor growth is infiltrating with dissection of
cellular and are characterized by intermingled adjacent breast parenchyma. High-grade AS may
areas of low and moderate nuclear atypia. The contain low- or intermediate-grade elements,
endothelial cells lining neoplastic vessels are gen- especially at the periphery of the lesion.
erally plump, multilayered, frequently arranged in
papillary structures. Solid areas are not present.
Immunophenotype
Mitotic rate is low (median 3/10 HPF). Necrosis
may be present.
Fli-1, FactorVIII, CD31, CD34, and ERG used in
High-grade AS (Fig. 3) show a generally solid
combination have the greatest sensitivity (94%)
growth pattern with very poorly defined vascular
and specificity (up to 100%).
Molecular Features
MYC gene amplification and protein over-

expression has been demonstrated in secondary
AS, and more rarely in primary AS.
The most challenging differential diagnoses of
breast AS are represented by low-grade pseudo-
angiomatous and angiomatous proliferations.
Above all, hemangiomas, pseudoangiomatous
stromal hyperplasia (PASH), and atypical vascu-
Angiosarcoma of the Breast, Fig. 2 Intermediate-grade lar lesions (AVLs) must be kept in mind (Bowman
AS: cellular area of moderate nuclear atypia; an entrapped et al. 2012; Rosen et al. 1988).
duct is in the center (H&E)
Hemangiomas and other benign vascular
tumors are generally well-circumscribed lesions
composed of well-formed vascular channels and
lack a dissecting growth pattern within breast
parenchyma (▶ Hemangioma of the Breast).
PASH is a benign proliferation of stromal
myofibroblasts, which express CD34 and focally
smooth muscle actin or desmin, but not other
more specific endothelial markers (CD31, Factor
VIII, or ERG) (▶ Pseudoangiomatous Stromal
Hyperplasia).
AVLs, typically develop 2–5 years after
radiotherapy and is histologically characterized
by a focal proliferation of dilated, sometimes
anastomosing, vascular channels lined by a sin-
Angiosarcoma of the Breast, Fig. 3 High-grade AS:
cellular area of solid growth with very poorly defined gle layer of endothelial cells in the papillary and
vascular channels (H&E) reticular dermis. Although AVLs lack cytologic
Apocrine Carcinoma 29
atypia, their exact nature is not fully elucidated Definition

(▶ Atypical Vascular Lesions).
Immunohistochemical staining combined with Carcinoma with apocrine differentiation A
fluorescence in situ hybridization for MYC are help- (invasive apocrine carcinoma) is defined by
ful in distinguishing post-radiation atypical vascular “WHO Classification of Tumours of the Breast”
lesions from low-grade secondary AS. Amplifica- as “any invasive carcinoma in which cells show
tion of MYC have been described in secondary AS the cytological features of apocrine cells”
and are absent in AVLs (Mentzel et al. 2012). (O’Malley and Lakhani 2012). More strictly, it
is a breast cancer characterized by apocrine mor-
phology (abundant eosinophilic and granular
References and Further Reading cytoplasm, centrally/eccentrically located nuclei
with prominent nucleoli and distinct cell bor-
Bowman, E., Oprea, G., Okoli, J., Gundry, K., et al. (2012).
Pseudoangiomatous stromal hyperplasia (PASH) of the ders) and a distinct steroid receptor profile:
breast: A series of 24 patients. Breast Journal, 18(3), Estrogen receptor (ER)-negative and androgen
242–247. receptor (AR)-positive cells (Vranic et al. 2013)
Lucas, D. R. (2009). Angiosarcoma, radiation-associated
angiosarcoma, and atypical vascular lesion. Archives of
(Fig. 1a–c).
Pathology & Laboratory Medicine, 133, 1804–1809. On the basis of gene expression profiling stud-
Mentzel, T., Schildhaus, H. U., Palmedo, G., Buttner, R., & ies, several investigators defined “molecular apo-
Kutzner, H. (2012). Postradiation cutaneous crine groups” including “molecular apocrine
angiosarcoma after treatment of breast carcinoma is
breast cancer” [MABC] and “Luminal Androgen
characterized by MYC amplification in contrast to
atypical vascular lesions after radiotherapy andcontrol Receptor” [LAR] breast cancer, all of which are
cases: Clinicopathological, immunohistochemical and characterized by increased AR signaling, lack of
molecular analysis of 66 cases. Modern Pathology, ER, and absence of basal differentiation. It should
25, 75–85.
be noted here that “molecular apocrine groups”
Nascimento, A. F., Raut, C. P., & Fletcher, C. (2008).
Primary angiosarcoma of the breast, clinicopathologic (as defined by microarray studies) are not fully
analysis of 49 cases, suggesting that grade is not equivalent to apocrine carcinoma differentiation
prognostic. The American Journal of Surgical defined by morphology and steroid receptor
Pathology, 32, 1896–1904.
Rosen, P. P., Kimmel, M., & Ernsberger, D. (1988). Mam-
profile.
mary angiosarcoma, the prognostic significance of
tumor differentiation. Cancer, 62, 2145–2151.
Clinical Features
• Incidence
Apocrine Carcinoma Invasive apocrine carcinoma is a rare special
type of breast cancer constituting 0.3–4% of all
Semir Vranic1,2 and Zoran Gatalica3 breast cancers (depending on the criteria used
1
Department of Pathology, Clinical Centre and for its definition). When strictly defined as
School of Medicine, University of Sarajevo, above, it constitutes ~1% of all breast cancers.
Sarajevo, Bosnia and Herzegovina • Age
2
College of Medicine, Qatar University, Typically affects postmenopausal women.
Doha, Qatar A recent comprehensive analysis based on the
3
Caris Life Sciences, Phoenix, AZ, USA SEER [The Surveillance, Epidemiology, and
End Results] data confirmed the prevalence of
apocrine carcinomas among the elderly women
Synonyms (Zhang et al. 2017).
• Sex
Carcinoma with apocrine differentiation; Invasive Invasive apocrine carcinoma predominantly
apocrine carcinoma affects women although rare cases of apocrine
30 Apocrine Carcinoma
carcinoma (both in situ and invasive) among due to encysted (encapsulated) lesions with pap-
males have also been described (Vranic illary architecture and apocrine morphology
et al. 2013). (Vranic et al. 2013).
• Site
The tumor location of invasive apocrine carci-
noma does not differ from that of invasive Microscopy
carcinoma of no special type (NST) (▶ Inva-
sive Carcinoma NST). Apocrine cells have abundant eosinophilic/granu-
• Treatment lar cytoplasm (called “type A” cells), with cen-
Current therapeutic approach to the patients trally/eccentrically located nuclei and prominent
with invasive apocrine carcinoma is similar to nucleoli (positive for Periodic Acid Schiff
that of breast carcinoma NST. A subset of staining, PAS). The tumor cells usually show dis-
invasive apocrine carcinomas (30–50%) are tinct cell borders (Fig. 1a). Another, less common
HER-2/neu positive (amplified) and are ame- type of apocrine cells (called “type B” cells)
nable for anti-HER2 treatment modalities. exhibits foamy and vacuolated cytoplasm resem-
Consistent AR expression and activation of bling histiocytes (O’Malley and Lakhani 2012;
AR signaling pathways may represent a new Vranic et al. 2013). The tumor cells show marked
avenue for the anti-AR treatment modalities of nuclear pleomorphism and atypia while the num-
patients with advanced and/or metastatic apo- ber of mitotic figures (easily appreciated by light
crine carcinomas. microscopy) may vary. Invasive apocrine carcino-
• Outcome mas are typically grade 2 or 3 carcinomas (graded
Clinical studies reporting outcome (overall by the Elston-Ellis modification of the Bloom and
survival and disease-free survival) of the Richardson grading system). Apocrine ductal car-
patients with invasive apocrine carcinoma cinoma in situ (DCIS) is commonly seen in asso-
are contradictory due to the lack of consistent ciation with its invasive counterpart. Apocrine
criteria for its definition (O’Malley and DCIS is usually high-grade DCIS with
Lakhani 2012; Vranic et al. 2013). A recent comedonecrosis and calcifications. Similar to
SEER analysis, based on 840 patients with its ductal counterpart, a subset of apocrine
invasive apocrine carcinoma, revealed that carcinomas may develop through a multistep pro-
apocrine carcinomas tend to behave more gression process (“linear progression model”):
aggressively in comparison with NST carci- Apocrine hyperplasia (metaplasia)!apocrine
nomas. However, the worse outcome was atypia!apocrine DCIS!invasive apocrine
significantly diminished after matching for carcinoma) (Fig. 2) (Costa et al. 2013; Gromov
demographic and clinicopathologic character- et al. 2015). This model has also been confirmed
istics (Zhang et al. 2017). by a molecular study that revealed common
mutations in both preinvasive (e.g., apocrine
DCIS) and invasive apocrine carcinomas (Costa
Macroscopy et al. 2013).
Gross and radiologic characteristics of invasive

apocrine carcinomas are not specific and are sim- Immunophenotype
ilar to those of breast carcinomas NST (O’Malley
and Lakhani 2012). Apocrine carcinomas usually Breast apocrine cells including invasive apocrine
present as a firm, whitish mass with infiltrative carcinomas show a characteristic steroid receptor
borders. Mammography may reveal micro- profile: no expression of estrogen receptor-alpha-
calcifications, particularly if apocrine in situ 66 (ER-alpha66) and progesterone (PR) receptors
component is present. Exceptionally, apocrine and strong expression of androgen receptor
carcinomas may present with nipple discharge (AR) (Fig. 1b, c). Apocrine cells express
Apocrine Carcinoma 31
Apocrine Carcinoma, Fig. 1 Hematoxylin and Eosin positively for androgen receptor (AR). Her-2/neu protein
(H&E) staining of a case of invasive carcinoma of the was overexpressed exhibiting a complete, intense mem-
breast with a characteristic apocrine morphology; the brane positivity in the majority of neoplastic apocrine cells
tumor cells are negative for ER-a66 (ER), but stain (HER2).
Apocrine Carcinoma, Fig. 2 A concept of apocrine carcinoma progression and development: Apocrine hyperplasia
(metaplasia)!apocrine atypia!apocrine DCIS!invasive apocrine carcinoma.
ER-alpha36 variant that locates to the cytoplasm [acyl-CoA synthetase medium-chain family mem-
and cytoplasmic membrane (Vranic et al. 2011). ber 1]), and negative biomarkers (ER, PR, Bcl-2,
Apocrine cells are also positive for gross cystic GATA-3) (Gromov et al. 2015). Recently, additional
disease fluid protein-15 (GCDFP-15) and novel biomarkers of apocrine differentiation have
negative for Bcl-2 (Gatalica 1997). Celis et al. been identified (HMGCS2 and FABP7) (Gromov
defined a specific “apocrine protein signature” et al. 2015).
that includes positive biomarkers AR, CD24, HER-2 protein is overexpressed (with under-
15-PDGH [prostaglandin dehydrogenase], ACMS1 lying HER-2/neu gene amplification) in 30–50%
32 Apocrine Carcinoma
of invasive apocrine carcinomas (Fig. 1d) (Vranic factor receptor 1 (IGF-1R) expression appears to
et al. 2013). be downregulated in apocrine carcinomas.
Invasive apocrine carcinomas typically stain for
luminal cytokeratins including CK7, CK8/18, and
CK9/19. CK20 expression has also been described Differential Diagnosis
in one study (Shao et al. 2012). Basal markers
(basal cytokeratins [CK5/6, CK14, CK17], p63, Apocrine differentiation may be seen in invasive
P-cadherin, S-100, CD10, vimentin) are usually carcinomas NST (▶ Invasive Carcinoma NST) as
absent or positive in only small subset of invasive well as some special types such as pleomorphic
apocrine carcinomas, while EGFR protein is pre- lobular carcinoma (▶ Pleomorphic Lobular Carci-
sent in ~50–60% of cases (with uncommon EGFR noma) with which apocrine carcinoma shares some
gene alterations) (Vranic et al. 2013). morphologic and molecular characteristics; anti-
body to E-cadherin can aid diagnosis in such
cases as apocrine carcinomas predominantly
Molecular Features (>80%) retain E-cadherin expression in contrast
to pleomorphic lobular carcinomas. Primary breast
“Molecular apocrine breast cancers” exhibit a oncocytic carcinoma (▶ Invasive Oncocytic Carci-
poor prognostic gene signature with a high-risk noma) and a subset of lipid-rich and secretory car-
recurrence score and overall poor outcome. If cinomas (▶ Invasive Secretory Carcinoma) may
strictly defined by morphology and ER-/AR+ ste- also pose diagnostic dilemmas as well as metaplas-
roid receptor profile, invasive apocrine carcino- tic carcinomas (▶ Invasive Metaplastic Carci-
mas are either triple-negative (50–70%) or HER2- noma), which latter also may have morphologic
positive breast carcinomas (30–50%). characteristics similar to apocrine carcinomas
Several comprehensive molecular studies (e.g., eosinophilic cytoplasm in squamous cells).
revealed common mutations of TP53 and Apocrine carcinomas may be occasionally con-
PIK3CA/PTEN/AKT genes. Interestingly, patients fused with a granular cell tumor (▶ Granular Cell
with germline PTEN mutations (Cowden syn- Tumor) (S-100 and pancytokeratins may help),
drome, OMIM #158350) are prone to develop while apocrine carcinomas composed of “type B”
breast carcinomas with apocrine differentiation. cells may resemble a benign histiocytic
Mutations within the mitogen-activated protein (inflammatory) lesion (CD68, CD163, and
kinase [MAPK] pathway (KRAS, NRAS, BRAF) pancytokeratins are helpful).
may also be occasionally seen in a subset of In addition, metastatic neoplasms to the breast
invasive apocrine carcinomas. Other targetable exhibiting eosinophilic cytoplasm may mimic apo-
mutations are much less common (Vranic et al. crine carcinoma. These include metastatic malig-
2013, 2017). nant melanoma and oncocytic carcinomas. In such
HER-2/neu gene is amplified in 30–50% of cases, a comprehensive immunohistochemical
invasive apocrine carcinomas, while HER-2/neu workup along with the clinical history may help
gene mutations are rare. EGFR protein expression render the correct diagnosis.
is common while underlying EGFR gene alter-
ations are uncommon: EGFR gene amplification
is present <10% of the cases and EGFR gene
References
mutations have not been described so far. Simi- Costa, L. J., Justino, A., Gomes, M., Alvarenga, C. A.,
larly, cMET overexpression is present in ~25% of Gerhard, R., Vranic, S., Gatalica, Z., Machado, J. C., &
the cases without cMET gene alterations (Vranic Schmitt, F. (2013). Comprehensive genetic characteri-
et al. 2017). Growth hormone-releasing hormone zation of apocrine lesions of the breast. Cancer
Research, 73, 2013.
(GHRH) and its receptors (GHRH-R) are also
Gatalica, Z. (1997). Immunohistochemical analysis of apo-
overexpressed in vast majority of invasive apocrine breast lesions. Consistent over-expression of
crine carcinomas. In contrast, insulin-like growth androgen receptor accompanied by the loss of estrogen
Atypical Ductal Hyperplasia 33
and progesterone receptors in apocrine metaplasia and micropapillae, arcades, Roman bridges, bars
apocrine carcinoma in situ. Pathology Research and crossing the glandular space, and finally full-
Practice, 193, 753–758.
Gromov, P., Espinoza, J. A., & Gromova, I. (2015). blown lesions with solid or cribriform growth A
Molecular and diagnostic features of apocrine breast (Fig. 1). As discussed below, the definition of
lesions. Expert Review of Molecular Diagnostics, 15, ADH has undergone remarkable changes. It is
1011–1022. the great achievement of Azzopardi who shifted
O’Malley, F., & Lakhani, S. R. (2012). Carcinoma with
apocrine differentiation. In S. R. Lakhani, I. O. Ellis, our view from usual ductal hyperplasia to ductal
S. J. Schnitt, P. H. Tan, & M. J. van de Vijver (Eds.), in situ microcancer as the decisive step in early
World Health Organization classification of tumours of breast cancer development.
the breast (4th ed., pp. 53–54). Lyon: International In rare cases, atypical ductal proliferation
Agency of Research and Cancer (IARC).
Shao, M. M., Chan, S., Yu, A., Lam, C., Tsang, J., Lui, P., (ADH/DCIS) may evolve from primarily benign
Law, B., Tan, P. H., & Tse, G. (2012). Keratin expres- proliferative breast lesions, or they may show
sion in breast cancers. Virchows Archiv, 461, 313–322. apocrine features (see below).
Vranic, S., Gatalica, Z., Frkovic-Grazio, S., Deng, H.,
Lee, L. M. J., Gurjeva, O., & Wang, Z. Y. (2011).
ER-a36 a novel isoform of ER-a66 is commonly over-
expressed in apocrine and adenoid cystic carcinoma of Clinical Features
the breast. Journal of Clinical Pathology, 64, 54–57.
Vranic, S., Schmitt, F., Sapino, A., Costa, J. L., Castro, M., • Incidence
Reddy, S., & Gatalica, Z. (2013). Apocrine carcinoma
of the breast: A comprehensive review. Histology and The frequency of ADH diagnosis has multi-
Histopathology, 28, 1393–1409. plied with the advent of mammographic
Vranic, S., Feldman, R., & Gatalica, Z. (2017). Apocrine screening with figures of 12–17% of cases
carcinoma of the breast: A brief update on the molec- performed due to the presence of micro-
ular features and targetable biomarkers. Bosnian
Journal of Basic Medical Sciences, 17, 9–11. calcifications. In biopsies from mass lesions
Zhang, N., Zhang, H., Chen, T., & Yang, Q. (2017). Dose identified in screening programs, ADH is
invasive apocrine adenocarcinoma has worse prognosis only found in 2–4% of specimens.
than invasive ductal carcinoma of breast: Evidence • Age
from SEER database. Oncotarget, 8, 24579–24592.
Late 40s, screening programs.
• Sex
Atypical Ductal Hyperplasia Female
• Site
Werner Boecker Either breast, any quadrant, probably prefer-
Gerhard Domagk-Institute of Pathology, ence of upper outer quadrant.
University of Münster, Münster, • Clinic, Treatment, and Core Biopsy
North-Rhine Westphalia, Germany ADH, generally, is asymptomatic. Clustered
microcalcifications (Fig. 2) are thought to be
the most common findings on a screening
Synonyms mammogram that usually require minimal
invasive biopsy (MIB) techniques such as
Atypical intraductal hyperplasia; Ductal vacuum-assisted core biopsy. However, due
intraepithelial neoplasia 1B (DIN 1B) to the limited amount of tissue in core biopsies,
ADH cannot be reliably diagnosed with
these techniques because the atypical epithelial
Definition foci in these biopsies may form part of an
established in situ neoplastic lesion, with or
Atypical ductal hyperplasia (ADH) is defined as a without associated invasion. For this reason,
local proliferation of evenly spaced monotonous the European Working Group for Breast Screen-
cells with an atypical architecture, characterized ing Pathology (EWGBSP) recommended to
by smooth geometrical growth patterns as abandon the term ADH in core biopsies in
34 Atypical Ductal Hyperplasia
favor of “atypical epithelial proliferation, ductal categorized as B3, and an indication for a
type” (AEPDT) (Wells et al. 2006). In the diagnostic biopsy to exclude a DCIS should
five category reporting system of core needle be made. Nevertheless, the number of foci of
biopsies, which was initially proposed by the atypical ductal proliferation and the number
UK National Coordinating Group for Breast of cores involved may help in making a clin-
Screening Pathology and later adopted and ical decision about a surgical diagnostic exci-
recommended by the EWGBSP, “atypical epi- sion. In the study of Sneige et al. (2003) on
thelial proliferation, ductal type,” is listed as B3 61 cases of vacuum-assisted biopsy atypical
which includes lesions with uncertain malignant ductal proliferations, the lesions were con-
potential. This explains why in the literature fined to an average of 1.5 large ducts or lob-
“upstaging” of excisions after stereotactic breast ular units and were associated with
core biopsies of patients with nonpalpable sus- microcalcifications in all cases. Surgical spec-
picious microcalcifications and/or lesions of imens showed ADH in 15 cases, no residual
AEPDT to DCIS or invasive carcinoma are lesion in 24 cases, and ductal carcinoma in
found in 12–52%; likewise, using vacuum- situ only in 3 cases. It was found that micro-
assisted biopsy devices, which reveal more con- calcifications that contain atypical ductal pro-
tiguous tissue than core biopsy needles, the liferations in less than three lobules or ducts
reported rate of “upstaging” of AEPDT to and/or that are removed completely do not
breast cancers ranges from 0% to 28%. reveal higher-risk lesions on excision; thus,
Recently Weigel et al. (2011) analyzed the it was concluded removal in such cases to be
rate and the histological spectrum for malig- unnecessary. Similar results were published
nancy of minimally invasive biopsies with by Wagoner et al. (2009). In practice, we
“uncertain malignant potential (B3)” in digital therefore modify the NHSBSP and EWGBSP
mammography screening. One hundred forty- guidelines for cases in which sufficient mate-
eight of 979 MIBs (15.1%) were categorized as rial is available and in which the mammogram
B3. Among these B3 lesions, calcifications shows only minor changes that have been
(61.5%) were the most important screening removed by the procedure and finally where
abnormalities. In agreement with several ana- the atypical epithelial proliferation is con-
log studies, the authors found AEPDT to be the fined to single terminal duct-lobular units
most frequent entity (35%), followed by radial (TDLUs) and spares the ducts. Follow-up of
scars (28%) and papillary lesions (20%). these patients with annual control mammog-
Furthermore, with 40.4% AEPDT was the sub- raphy seems a reasonable management
type with the highest rate of finally detected option. The same holds true for ADH in diag-
malignancy (DCIS n = 16, invasive cancer nostic biopsies. In contrast, if ducts or several
n = 3) in surgical excision biopsies (19/47). TDLU areas are involved by atypical prolif-
The lesion-specific positive predictive value erations in core biopsies or in cases in which
(PPV) was highest for AEPDT compared to the mammogram shows more extended
other B3-lesions with a PPV of 0.40, similar changes, which usually indicates grade
to the respective PPVs of 0.32 to 0.59 reported 1 DCIS, we prefer further diagnostic and, if
from analog screening settings (see also Menes necessary, therapeutic procedures.
et al. 2017). • Outcome
The NHSBSP guidelines (2001) suggest Dupont and Page (1989) proposed the term
that if a low- or intermediate-grade atypical ADH for lesions in which “some but not all
epithelial proliferation is found in a vacuum- the features of DCIS” are present and demon-
assisted biopsy that is lacking in extent or strated that the subsequent general risk of inva-
degree of ductal/lobular involvement to be sive breast carcinoma for these lesions is about
classified as DCIS, the lesion should be four to five times that of the general population.
Macroscopy ductules or acini and the relationship to ducts is

easily appreciated (Fig. 1). The atypical archi-
ADH is not associated with any specific macro- tecture includes micropapillae, rigid bars, A
scopic features. Roman bridges, and cribriform patterns. The
key features of ADH are shown in Fig. 3 and
Table 1.
Microscopy
Demarcation of ADH at the Lower and Upper
The presence of a focal proliferation (usually less Limits
than 3 mm) of atypical uniform ductal-type cells At the lower limit, “flat epithelial atypia” (FEA)
with rounded or oval slightly hyperchromatic (▶ Columnar Cell Lesions) and ADH are cur-
nuclei and with an atypical architecture with rently recognized as members of the low-grade
even spacing of cells is now universally recog- carcinogenesis pathway. Any form of atypical
nized as indicating ADH. In most cases, architectural growth pattern (micropapillae, bars,
this atypical proliferation is confined to a Roman bridges, etc.) is regarded as the essential
TDLU. At low magnification, the lobular criterion for ADH and for the distinction between
architecture with its moderately “unfolded” FEA and ADH.
Atypical Ductal Hyperplasia, Fig. 1 (H&E) Atypical in a. (b) ADH with monotonous atypical cells with atypical
ductal hyperplasia. (a) Scanning view showing unfolded architecture characterized by cribriform growth. (c)
TDLU with atypical ductal hyperplasia (center) with two Columnar cell change with psammomatous type micro-
foci of columnar cell change (arrows) and lobular hyper- calcification. (d) Atypical lobular hyperplasia
plasia (asterisks); (b–d) higher magnification of the lesions
It must be acknowledged that the extension of

an otherwise classic low-grade DCIS into lob-
ules (lobular cancerization) should be regarded
as part of the DCIS and thus should be included
into any size considerations of a DCIS. This
suggestion is based on observations of several
studies who found that DCIS with “ADH” at the
periphery of the excision was associated with
recurrences at the same location. In this context,
the additional diagnosis of “ADH” may be mis-
leading to the clinician and hence may be dan-
gerous for the patient.
Rare Types of Atypical Ductal Proliferations

In rare cases, atypical ductal proliferation
(ADH/DCIS) may evolve from primarily benign
proliferative breast lesions, such as col-
umnar cell change (▶ Columnar Cell Lesions),
papilloma (▶ Intraductal Papilloma) mucocele-
like lesions (▶ Mucocele-like Lesion), radial
scar (▶ Radial Scar), sclerosing adenosis
(▶ Sclerosing Adenosis), and fibroadenoma
(▶ Fibroadenoma). In such instances, identify-
ing the underlying benign lesion is important for
an appropriate diagnosis. It should be empha-
sized that the same cytological and architectural
Atypical Ductal Hyperplasia, Fig. 2 Mammographic criteria used for the identification of the benign
microcalcification (a) and corresponding picture in histo- background lesion are also applied in this con-
logic section (b) (H&E) text as discussed in the corresponding chapters.
There are two main problems in this setting.
At the upper limit, we are concerned with These are related (1) to the extent of the atypical
distinguishing ADH from low-grade DCIS proliferation and (2) to the clinical impact of
(▶ Ductal Carcinoma In Situ). Although some such findings. At the time of writing, there was
pathologists incorporate an assessment of the no generally accepted solution to these problems.
size of a lesion in their analysis of ductal pro- The author defines ADH in benign lesions as par-
liferations (two glandular spaces or aggregate tial involvement of atypical ductal proliferation,
diameter of 2 mm), the reliance on quantitative having features of low-grade DCIS, in an otherwise
findings does not have a strong foundation. typically benign lesion, most important, without
Rather, it should be emphasized that such size DCIS outside the benign lesion.
considerations do provide guidelines rather Another rare morphological variation of
than precise biological definitions. We propose this theme includes cases with apocrine type
a pragmatically founded definition of ADH as a morphology (▶ Benign and Atypical Apocrine
focal atypical ductal-type proliferation (usually of Lesions). O’Malley and colleagues (2004) use
about 2–5 mm in diameter) involving TDLU cytological criteria (usual apocrine, borderline
structures, but with no, or only minor ductal features, and “as in DCIS”) and extension
involvement, in contrast with DCIS which is char- criteria (<4 mm, 4–8 mm, >8 mm) to distinguish
acterized by its spread into the ductal system in a between benign, borderline, and malignant
segmental manner (Fig. 4). categories. According to Raju et al. (1993), the
Atypical Ductal Hyperplasia, Fig. 3 Cellular algorithm low-grade intraepithelial neoplasias (LG-IEN), including
of ductal-type lesions of the breast. Usual ductal hyperpla- flat epithelial atypia, atypical ductal hyperplasia, low-grade
sia (UDH) contains phenotypically the whole set of lumi- DCIS, and lobular neoplasia. (From Boecker et al. 2017)
nal cells contrasting with the robust CK8/18+ phenotype of
Atypical Ductal Hyperplasia, Table 1 Key features of benign apocrine cells, and moderately stained
atypical ductal hyperplasia regular nuclei with usually small nucleoli and a
ADH Monomorphic epithelial proliferation with higher nucleus-to-cytoplasm ratio. In contrast,
regular placement of cells and atypical high-grade apocrine lesions are defined by pleo-
architecture with smooth geometrical growth morphic, hyperchromatic nuclei, coarse chroma-
patterns such as micropapillae, arcades, Roman
bridges, bars crossing the glandular space, and tin, and prominent nucleoli.
in full-blown lesions with cribriform growth
The cells contain eosinophilic to pale cytoplasm
and round to oval monotonous nuclei Immunophenotype
Confined to individual TDLU(s), lacking the
ductal segmental spread of low-grade DCIS
Several groups demonstrated that the epithelial
Often associated with lamellar
microcalcifications cells in the putative low-grade ductal pathway
precursors, including classical ADH, were posi-
tive for glandular keratins CK7, CK19, and CK8/
criteria of atypical apocrine hyperplasia are met CK18 but negative for basal keratins CK5
whenever a lesion shows features of low-grade (Fig. 5) and CK14 and myoepithelial markers.
apocrine DCIS and is of small size. There is Strong E-cadherin membranous staining has
good reason to believe that the same fundamen- been used to define ductal-type carcinomas,
tal extension criteria used to define classical both in situ and invasive. Overexpression of
atypical ductal proliferations (distinguishing HER2 is rare with only weak basal expression
such lesions from low-grade DCIS) also in ADH, in contrast to high expression and
apply to lesions with low-grade atypical apo- amplification rates in high-grade DCIS (▶ Duc-
crine proliferations. Among the cytological hall- tal Carcinoma In Situ). The cellular constituents
marks of low-grade apocrine lesions are a of ADH demonstrate increased expression rates
smaller cell size, cytoplasmic eosinophilia or with Ki-67 (usually <5%), ERa, the anti-
pallor with less coarse granularity than in classic apoptotic proto-oncogene bcl-2, and the cell
Atypical Ductal Hyperplasia, Fig. 4 (H&E) Growth crossing the lumen in the background of FEA. The nuclei
patterns of ADH. High-power views. (a) Ductule are round and hyperchromatic. (d) Ductule showing pro-
highlighting the proliferation of the same cell type both liferation of cells forming irregular bars and an abortive
in the periphery and within a single micropapilla. The cribriform pattern and micropapillae with psammomatous
tumor cells in the micropapilla, however, tend to be smaller microcalcifications. (e) In this ductule, many rigid bars
with more darkly staining nuclei with slight variation in cross the lumen forming a cribriform growth pattern.
size and spacing. (b) Ductule with multiple micropapillae Same case as c. (f–g) Proliferation of a single cell type
in a background of FEA. Same case as a. (c) Ductule with forming many arcades resembling the pillars supporting
proliferation of a single cell type forming a rigid bar Roman bridges
cycle regulator cyclin D1, compared with adja- Molecular Features and Tumorigenesis
cent normal breast lobular units. The
myoepithelial cells stain strongly for p63, CK5/ The traditional tumorigenesis model of linear
14, and myoepithelial markers such as smooth- progression implies a cascade from benign duc-
muscle actin, calponin etc. tal proliferations to invasive breast carcinoma.
supported by immunohistochemical studies of

several groups demonstrating CK5/CK14 mosai-
cism in UDH lesions in contrast to robust nega- A
tivity for basal keratins CK5 and CK14 and
positivity for glandular keratins (CK7+
CK8/CK18+ CK19+) of ductal proliferations of
the low-grade pathway. Recently, precision
immunofluorescence studies showed that usual
ductal hyperplasia represents a heterogeneous epi-
thelial lesion of the luminal lineage, including
CK5+/CK14+ progenitor cells. In contrast, low-
grade intraepithelial neoplasia of the breast, based
on their key characteristic of a robust CK18-
positive phenotype, is thought to originate from
the CK18+ cell population of normal breast epi-
thelium. These findings support the view that
usual ductal hyperplasia and low-grade
intraepithelial neoplasia are different entities
rather than a spectrum of the same disease
(Table 2). As discussed above, the findings of
“clinging carcinoma” of Azzopardi have intro-
duced profound changes in the conception of
early tumorigenesis of ductal breast carcinoma.
Atypical Ductal Hyperplasia, Fig. 5 (H&E) ADH and Later on, several studies have demonstrated that
low-grade DCIS. (a) ADH. Enlarged TDLU with FEA commonly coexists on the same microscopic
distended ductules which contain a monomorphous cell slides as ADH, lobular neoplasia (LN), or low-
population with a cribriform growth pattern with a normal grade DCIS and losses at 16q and 17p were the
duct on the left side. (b) Low-grade DCIS with cribriform
growth pattern in ducts and distended lobules most frequent changes in ADH, similar to the
other early lesions of the low-grade pathway
(FEA and low-grade DCIS) and tubular and
This concept resolves around usual ductal hyper- grade 1 invasive (no special type) breast carci-
plasia (▶ Usual Ductal Hyperplasia (UDH)) as noma. In line with these observations, Aulmann
the central and initial event in the tumorigenesis et al. (2009) and colleagues examined the relation-
process and has at the same time its reflection in ships between tubular carcinoma (▶ Tubular Car-
the notion of the ADH definition of Jensen and cinoma), low-grade DCIS (▶ Ductal Carcinoma
Page that “The lower boundary of ADH is In Situ), and FEA (▶ Columnar Cell Lesions)
defined by examples of florid hyperplasia and concerning the mitochondrial DNA mutation pat-
focal areas of cellular uniformity and even place- terns and found that most cases of low-grade
ment.” However, this concept is in contrast to the DCIS and FEA were directly related to tubular
concept of J. Azzopardi, relating to the relation- cancer with a possible precursor role. The current
ship between ductal microcancer and usual duc- prevailing view is that FEA and ADH may repre-
tal hyperplasia, that “one of the more striking sent an initial morphologic nonobligate precursor
findings was the absence of any evidence of of the low-grade ER-dependent pathway to carci-
transition from areas of epitheliosis (usual ductal noma. Concerning high-grade neoplasias, given
hyperplasia, the author) to cancer except perhaps the high number of individual genetic alterations
in a single case.” As early as in 1987, Azzopardi, including high-level amplifications in high-grade
therefore, suggested a de novo evolution of DCIS and their invasive counterparts, it seems
breast cancer from glandular cells of the normal unlikely that a relevant fraction of high-grade
lobular breast epithelium. This view was DCIS derive from these low-grade ductal lesions.
Atypical Ductal Hyperplasia, Table 2 Comparison of histological features of UDH, ADH, and low-grade DCISa
Histological Low-nuclear-grade
features UDH ADH DCIS
Size Variable size but rarely extensive Small More extensive,
ductal-lobular
involvement
Cellular Mixed epithelial cells with Monotonous cell population with Identical to ADH
composition variations in size and shape regular spacing
Myoepithelial cells usually around Myoepithelial cells around the ductal
the ductal periphery periphery
Architecture Fenestrating growth pattern with Atypical with well-delineated Identical to ADH
irregular lumina: Streaming pattern geometric structures
common with long axes of nuclei (micropapillae, bars, Roman bridges,
arranged parallel to the direction of arcades, and cribriform pattern) or
cellular bridges, which often have a solid growth
“tapering” appearance
Lumina Irregular lumina, often ill-defined Usually well-formed rounded Identical to ADH
peripheral slit-like spaces are spaces
common and useful distinguishing
features
IH Mosaicism of CK5- (CK14-) CK8-/CK18-positive cells, lacking Identical to ADH
positive cells. Myoepithelial cells CK5 and CK14. Residual normal
around the periphery CK5- and/or CK14-positive cells
usually attenuated or in a luminal
position
Focal ER positivity Uniformly and strongly ER+ cells
Nuclear Uneven Even, occasionally uneven Identical to ADH
spacing
Nucleoli Indistinct Single, small Identical to ADH
Mitoses Infrequent with no abnormal forms Infrequent, abnormal forms rare Identical to ADH
Necrosis Rare Rare If present, confined
to small particulate
debris in luminal
spaces
Major diagnostic features are shown in bold type
a
Modified version of the table in “European Guidelines for Quality Assurance in Mammography Screening – Fourth
Edition,” Office for Official Publications of the European Communities
Differential Diagnosis UDH (▶ Usual Ductal Hyperplasia (UDH)) is

one of the differential diagnoses (Fig. 6). The
Concerning the decision-making of epithelial pro- key here is to recognize the heterogeneous cell
liferations of ductal type is fraught with two main proliferation of UDH contrasting with the
problems: (1) the lesion cannot be easily classified monotonous single-type neoplastic cell prolifer-
as either neoplastic or hyperplastic in nature, or ation in ADH. UDH shows a robust CK5/CK14
(2) the distinction between FEA on the one hand mosaicism, whereas ADH is strongly positive
and low-grade DCIS on the other hand may be a for CK8/CK18 and ER and negative for
problem. Whenever a definitive diagnosis cannot CK5/CK14. Importantly, Jain et al. (2011)
be reached, this should be indicated, rather than found an 8% decrease in the number of lesions
prematurely diagnosing the lesion as ADH. classified as atypical ductal hyperplasia in favor
Pathologists should refrain from using ADH as a of usual hyperplasia using in an interobserver
blanket term for indecisive findings and should study a ADH-5 cocktail (cytokeratins (CK) 5,
instead seek external consultation. 14, 7, 18, and p63) by immunohistochemistry;
Atypical Ductal Hyperplasia, Fig. 6 Atypical ductal CK5/CK14-positive myoepithelial cells in the periphery in
hyperplasia versus usual ductal hyperplasia. H&E stain of (b). Usual ductal hyperplasia showing the fenestrating
ADH showing monomorphous cell proliferation with crib- growth pattern in H&E routine section in (c) and strong
riform growth pattern in (a) and CK5/CK14 immunostain immunostaining for CK5/CK14 in proliferating cells with
with CK5/CK14-negative neoplastic cells contrasting with the typical CK5/CK14þ mosaicism (d)
in clinical practice, this could lead to a decrease challenges. In the authors’ experience, the typi-
in the number of surgeries carried out for cal CK5/CK14 staining pattern usually helps to
intraductal proliferative lesions. One important solve the problem as intermediate malignant
problem remains: as intermediate-grade neoplas- ductal-type proliferations usually fail to stain
tic intraepithelial proliferations, ductal type, may for keratins CK5 and CK14. Finally, micro-
exhibit more variability in cytological and archi- papillary ductal growth patterns of epithelial
tectural characteristic than classical prolifera- proliferations may occasionally also pose prob-
tions of the low-grade ductal pathway, the lems in the differential diagnosis in which, again,
differentiation of these lesions from conven- CK5/CK14 immunohistochemistry may help to
tional ductal hyperplasia is one of the greatest solve the problem.
42 Atypical Vascular Lesions
Occasionally cells with more advanced cellular Moinfar, F., Man, Y. G., Bratthauer, G. L., Ratschek, M., &
atypia may grow in just one or two layers. Tavassoli, F. A. (2000). Genetic abnormalities in mam-
mary ductal intraepithelial neoplasia-flat type (“cling-
Currently, most experts in the field agree that flat ing ductal carcinoma in situ”): A simulator of normal
epithelial lesions with high-nuclear-grade mor- mammary epithelium. Cancer, 88, 2072–2081.
phology should be termed high-grade DCIS O’Malley, F. P., & Bane, A. L. (2004). The spectrum of
irrespective of their size. apocrine lesions of the breast. Advances in Anatomic
Pathology, 11, 1–9.
The most important distinguishing feature of Page, D. L., & Rogers, L. W. (1992). Combined histologic
ADH to lobular neoplasia (▶ Lobular In Situ Neo- and cytologic criteria for the diagnosis of mammary
plasia) is its cohesive growth; the latter, by its atypical ductal hyperplasia. Human Pathology, 23,
discohesive growth and typical change of cell 1095–1097.
Raju, U., Zarbo, R. J., Kubus, J., & Schultz, D. S. (1993).
shape from polygonal to round tumor cells, is The histologic Spectrum of apocrine breast prolifera-
usually easily recognizable on H&E sections. tions: A comparative study of morphology and DNA
Molecularly the presence or loss of the adhesion content by image analysis. Human Pathology, 24,
molecule E-cadherin may be helpful in 1973–1981.
Sneige, N., Lim, S. C., Whitman, G., Krishnamurthy, S.,
distinguishing between growth patterns of ductal Sahin, A. A., Smith, T. L., & Stelling, C. B. (2003).
and lobular type. Atypical ductal hyperplasia diagnosis by directional
vacuum-assisted stereotactic biopsy of breast micro-
calcifications. Considerations for surgical excision.
American Journal of Clinical Pathology, 119, 218–243.
References and Further Reading Wagoner, M. J., Laronga, C., & Acs, G. (2009). Extent and
histologic pattern of atypical ductal hyperplasia present
Aulmann, S., Elsawaf, Z., Penzel, R., Schirmacher, P., & on core needle biopsy specimens of the breast can
Sinn, H. P. (2009). Invasive tubular carcinoma of the predict ductal carcinoma in situ in subsequent excision.
breast frequently is clonally related to flat epithelial American Journal of Clinical Pathology, 131, 112–121.
atypia and low-grade ductal carcinoma in situ. Weigel, S., Decker, T., Korsching, E., Biesheuvel, C.,
The American Journal of Surgical Pathology, 33, Wöstmann, A., Böcker, W., Hungermann, D.,
1646–1653. Roterberg, K., Tio, J., & Heindel, W. (2011). Minimal
Azzopardi, J. (1979). Problems in breast pathology. invasive biopsy results of “uncertain malignant poten-
London: W.B. Saunders. tial” in digital mammography screening: High preva-
Boecker, W., Stenman, G., Schroeder, T., Schumacher, U., lence but also high predictive value for malignancy.
Loening, T., Stahnke, L., Löhnert, C., Siering, R. M., Fortschritte auf dem Gebiet der Röntgenstrahlen und
Kuper, A., Samoilova, V., Tiemann, M., Korsching, E., der bildgebenden Verfahren, 183, 743–748.
& Buchwalow, I. (2017). Multicolor immunofluores- Wells, C. A., Amendoeira, I., Apostolikas, N., et al. (2006).
cence reveals that p63- and/or K5-positive progenitor Quality assurance guidelines for pathology.
cells contribute to normal breast epithelium and usual In N. M. Perry, M. Broeders, & C. de Wolf (Eds.),
ductal hyperplasia but not to low grade intraepithelial European guidelines for quality assurance in breast
neoplasia of the breast: New concepts on the cellular cancer screening and diagnosis (p. 219). Luxembourg:
hierarchy using in-situ multicolour experiments. Office for Official Publication of the European
Virchows Archiv, 470, 493–504. Communities.
Dupont, W. D., & Page, D. L. (1989). Relative risk of
breast cancer varies with time since diagnosis of atyp-
ical hyperplasia. Human Pathology, 20, 723–725.
Jain, R. K., Mehta, R., Dimitrov, R., Larsson, L. G.,
Musto, P. M., Hodges, K. B., Ulbright, T. M.,
Atypical Vascular Lesions
Hattab, E. M., Agaram, N., Idrees, M. T., & Badve, S.
(2011). Atypical ductal hyperplasia: Interobserver and Lauren E. Rosen and Thomas Krausz
intraobserver variability. Modern Pathology, 24(7), Department of Pathology, University of Chicago,
917–923.
Chicago, IL, USA
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., &
van de Vijver, M. J. (2012). WHO-classification of
tumours of the breast. Lyon: IARC.
Menes, T. S., Kerlikowske, K., Lange, J., Jaffer, S., Synonyms
Rosenberg, R., & Miglioretti, D. L. (2017). Subsequent
breast cancer risk following diagnosis of atypical
ductal hyperplasia on needle biopsy. JAMA Oncology, Cutaneous atypical vascular lesions (AVLs) of
3, 36–41. the breast have been described using a variety
Atypical Vascular Lesions 43
of terms including post-mastectomy lymph- • Treatment

angiomatosis, benign lymphangiomatous pap- AVLs are treated by excision with free margins
ules, benign lymphangioendothelioma, acquired and close clinical follow-up to monitor for devel- A
lymphangiectasis, and lymphangioma circum- opment of new lesions (Baker and Schnitt 2017).
scriptum (Baker and Schnitt 2017; Weaver and • Outcome
Billings 2009). In approximately 10–20% of cases, AVLs can
recur or new lesions can arise within the radi-
ation field following complete excision (Baker
and Schnitt 2017). Rare cases of progression to
Definition
angiosarcoma (▶ Angiosarcoma of the Breast)
have been reported, but it is unclear if these
AVLs are benign vascular proliferations of the
represent cases of angiosarcoma with AVL-like
skin that occur following radiation therapy for
areas which were misdiagnosed on biopsy, or
breast cancer within the field of radiation. The
an angiosarcoma developing in the same area
term AVL was proposed by Fineberg and
as an AVL (Brenn and Fletcher 2005). It has
Rosen in 1994 to reflect the fact that these
been suggested that vascular type AVLs have a
lesions were occasionally mistaken for
higher risk of progression to angiosarcoma
angiosarcoma, and because their relationship
than the lymphatic type; however, this claim
to post-irradiation angiosarcomas (PIAS) is
has not been well supported (Patton et al.
not fully understood (Fineberg and Rosen
2008). While few reports raise the possibility
1994).
that AVLs have the potential to progress to
angiosarcoma in rare circumstances, overall
the current evidence suggests that AVLs follow
Clinical Features a benign course (Ginter et al. 2017).
• Incidence
Macroscopy
AVLs occur in the field of radiation after radi-
ation therapy for breast cancer, with a latency
AVLs typically present as discrete flesh-toned to
period of 1 month to 20 years, occurring most
reddish or bluish papules arising in the field of
frequently between 3 and 6 years post-
radiation, and less frequently as vesicles, cystic
treatment (Ginter et al. 2017).
lesions, or erythematous plaques (Brenn and
• Age
Fletcher 2005; Koerner 2014). The lesions are
AVLs are seen in a population ranging in age
generally less than 5 mm in size (range
from 29 to 95 years, most occurring in the fifth
1–20 mm), and can be single or multiple, with
and sixth decades (Ginter et al. 2017).
up to half of patients developing multiple lesions
• Sex
either at the time of initial diagnosis or subse-
All reported cases of AVLs of the breast have
quently (Baker and Schnitt 2017; Ginter et al.
occurred in females, likely reflecting the higher
2017; Flucke et al. 2013).
incidence of breast cancer in this population
(Weaver and Billings 2009).
• Site
AVLs occur most commonly in mammary or Microscopy
axillary skin, and can rarely involve the breast
parenchyma. AVLs also occur in sites other On low power, AVLs are frequently circum-
than the breast following radiation therapy for scribed lesions located within the superficial der-
various malignancies, such as gynecologic mis. AVLs can be wedge-shaped with their base
tumors and multiple myeloma (Brenn and oriented toward the dermal-epidermal junction
Fletcher 2005). (Baker and Schnitt 2017). The lesions are
generally flat, but may appear as exophytic pap- and rare mitotic figures; however, endothelial
ules that project from the skin surface. The over- multilayering and necrosis are absent. The adja-
lying epidermis is usually normal or mildly cent stroma may contain sparse to dense chronic
acanthotic (Koerner 2014). When AVLs involve inflammatory infiltrate composed of lymphocytic
the breast parenchyma, they are usually encased aggregates with occasional germinal centers, or
within fibrous tissue without involvement of the there may be adjacent hemorrhage or hemosiderin
mammary glandular tissue (Brenn and Fletcher (Ginter et al. 2017; Patton et al. 2008).
2005). AVLs are composed of ectatic, angulated,
and variably anastomosing thin-walled vascular
channels lined by a single layer of monomorphous Immunophenotype
endothelial cells (Baker and Schnitt 2017; Weaver
and Billings 2009) (Fig. 1a: H&E). While in Lymphatic type AVLs are positive for CD31,
most cases the lesions are limited to the superficial D2-40, ERG, and positive or negative for CD34
dermis, in some cases the vessels extend into (Fig. 1b: CD34 immunostaining; 1C: D2-40
the deep dermis where they are often smaller, immunostaining; 1D: CD31 immunostaining). Vas-
compressed, and infiltrative with focal dissection cular type AVLs are positive for CD31, CD34, and
of collagen and infiltration of adnexal structures ERG, but negative for D2-40 (Baker and Schnitt
(Brenn and Fletcher 2005). More rarely, the 2017). The pericytes surrounding the vessels in
lesions can extend into the subcutis. Two distinct vascular type AVLs are positive for smooth muscle
morphologic subtypes of AVL have been actin (Brenn and Fletcher 2005).
described, lymphatic type and vascular type.
Both patterns are often seen within the same
lesion (Patton et al. 2008; Ginter et al. 2017). Molecular Features
The lymphatic type is the most common sub-
type of AVL, and is comprised of variably-sized Amplification of MYC has been implicated in
anastomosing vascular channels lined by a mono- the development of PIAS (Fernandez et al.
layer of attenuated to hobnail endothelial cells 2012; Fraga-Guedes et al. 2015; Mentzel et al.
reminiscent of lymphangioma (Gengler et al. 2012). The MYC oncogene is a transcription fac-
2007; Koerner 2014). Endothelial-lined stromal tor that has a role in cell proliferation, cellular
projections can be seen within the vascular differentiation, apoptosis, and angiogenesis.
lumens, which are characteristically devoid of Dysregulated MYC expression due to gene ampli-
erythrocytes (Flucke et al. 2013; Patton et al. fication promotes cell proliferation through inap-
2008). The vessels are typically tightly clustered propriate progression to S-phase from G1 phase
within the superficial dermis; however, in a minor- of the cell cycle. Amplification of MYC occurs
ity of cases, they extend into the deep dermis in other sarcomas, such as high-grade chon-
where they have a more infiltrative appearance. drosarcomas, proximal type epithelioid sarcomas,
The lining endothelium is commonly hyper- and myxoid liposarcomas (Fraga-Guedes et al.
chromatic, but lacks significant nuclear atypia, 2015). Many studies have found high-level ampli-
prominent nucleoli, and mitoses (Patton et al. fications of MYC by fluorescence in situ hybridi-
2008; Requena et al. 2002). zation (FISH) in the majority of post-radiation and
Vascular type AVLs are composed of round to lymphedema associated angiosarcomas, but not
elongated capillary sized vessels that grow irreg- in primary cutaneous angiosarcomas or AVLs
ularly within the superficial or deep dermis, rem- (Fernandez et al. 2012; Fraga-Guedes et al.
iniscent of a capillary hemangioma (Patton et al. 2015; Mentzel et al. 2012). Interestingly in one
2008). In contrast to lymphatic type AVLs, these study, two patients had AVLs lacking MYC ampli-
lesions show intraluminal red cells and the vessels fication adjacent to MYC amplified PIAS (Fraga-
are surrounded by a layer of pericytes. Vascular Guedes et al. 2015). Amplification of MYC by
type AVLs can show mild random nuclear atypia FISH has a strong correlation with MYC
Atypical Vascular Lesions, Fig. 1 (a) AVL composed of cytologic atypia [H&E, 40X], (b) AVL with variable pos-
irregular thin-walled dilated vascular spaces dissecting itivity for CD34 [20x], (c and d) AVL with strong diffuse
through collagen. The nuclei are widely spaced and lack positivity for D2-40 (c) and CD31 (d) [20x]
expression by immunohistochemistry (IHC). (Weaver and Billings 2009). The majority of PIAS
FLT4 is a gene that encodes for VEGFR3 and are high grade, but low and intermediate grade
plays a role in lymphatic differentiation. FLT4 tumors have been described in which there is
gene amplification is detected by FISH in 25% morphologic overlap with AVLs. AVLs may be
of PIAS, and is absent in AVLs, but the gene is multiple but are usually small pink papules (<
co-amplified with MYC limiting its utility in this 1 cm) while PIAS are often larger (>2 cm) and
setting (Cornejo et al. 2015; Guo et al. 2011). One present as violaceous or erythematous plaques
study demonstrated TP53 mutations in the major- with ulceration (Weaver and Billings 2009;
ity of AVLs studied, and hypothesized that TP53 Brenn and Fletcher 2005). AVLs are relatively
mutations may occur early in neoplastic develop- circumscribed and limited to the superficial der-
ment of AVL (Santi et al. 2011). mis, however can invade into the deep reticular
dermis and rarely into the subcutis; while PIAS
often invade through the dermis and into the sub-
Differential Diagnosis cutis (Weaver and Billings 2009; Brenn and
Fletcher 2005). The nuclei of AVLs are hyper-
The main differential diagnosis for AVL is chromatic and can show mild random atypia
angiosarcoma (▶ Angiosarcoma of the Breast), (Fig. 2a: H&E), while the nuclei in PIAS are
particularly those that arise following radiation, uniformly enlarged with prominent nucleoli
termed PIAS. Both AVL and PIAS arise in the (Weaver and Billings 2009; Brenn and Fletcher
skin of the breast or chest wall following radia- 2005). Features that favor a diagnosis of AVL
tion, occur in middle aged to elderly women, and include circumscription, vessels lined by a single
are characterized by anastomosing vascular chan- layer of endothelial cells, bloodless spaces, deli-
nels. PIAS have a latency period of 5–6 years, cate projections of endothelial lined stroma into
which overlaps with the 3–6 year interval of AVLs the vascular spaces, and associated chronic
Atypical Vascular Lesions, Fig. 2 (a) AVL with irregu- (dissecting collagen), irregular vascular channels lined by
larly shaped, dilated vascular channels and random cyto- focally multilayered neoplastic endothelium with marked
logic atypia with variably enlarged and hyperchromatic diffuse nuclear atypia and extravasated red blood cells
nuclei [H&E, 40x]. (b and c) AVL with low Ki-67 prolif- [H&E, 40x]. (e and f) Post-radiation angiosarcoma
eration index (b) and negativity for c-myc (c) [40x]. (d) with high Ki-67 proliferation index (e) and c-myc positiv-
Post-radiation angiosarcoma is composed of invasive ity (f) [40x]
inflammation. Proliferation activity evaluated by (Fig. 2e and f: Ki67 immunostaining and cMYC
Ki67 is low and cMYC is negative (Udager et al. immunostaining, respectively). AVLs can very
2016; Requena et al. 2002) (Fig. 2b and c: Ki67 rarely show more worrisome features such as
immunostaining and cMYC immunostaining, scattered variably enlarged nuclei with prominent
respectively); (Table 1). Findings that favor nucleoli, an occasional mitosis, focal, limited
PIAS include infiltration of the subcutis, promi- multilayering (usually not more than a double
nent dissection of dermal collagen, hemorrhage layer of endothelium), poor circumscription, and
and extravasated red blood cells, marked cyto- extension into subcutis (Weaver and Billings
logic atypia, mitotic figures, necrosis, and multi- 2009). In addition, AVLs and PIAS can coexist,
layering of the endothelial cells (Fig. 2d: H&E). and PIAS may exhibit AVL-like areas, which can
Proliferation activity evaluated by Ki67 is be indistinguishable from a true AVL in a limited
high and cMYC is overexpressed in nuclei biopsy. For this reason, it is recommended that a
(Udager et al. 2016; Requena et al. 2002) diagnosis of AVL should not be made on a small
Atypical Vascular AVL AS

Lesions,
Histology
Table 1 Histologic,
immunohistochemical, and Relative circumscription +++ A
molecular features of AVL Anastomosing vessels ++ +++
versus post-radiation Dissection of dermal collagen + +++
angiosarcoma. (Adapted Infiltration into subcutis /+ +++
from Fineberg and Rosen
Stromal projections into lumen +++ +
(1994) and Flucke et al.
(2013)) Multilayered endothelium /+ +++
Hyperchromatic endothelial nuclei +++ ++
Significant cytologic atypia +++
Enlarged nuclei /+ +++
Prominent nucleoli /+ +++
Mitotic figures /+ +++
Extravasated red blood cells or blood lakes ++
Chronic inflammation +++ +
Immunohistochemistry
CD34 ++ +
CD31 +++ +++
ERG +++ +++
D2-40 ++ +
Molecular
MYC amplification/expression +++
FLT-4 amplification/expression +
AVL, atypical vascular lesion; AS, post radiation angiosarcoma; , absent; /+ rare focal
finding; +, occasionally present; ++, present in most cases; +++, present in all cases
biopsy, with preferred classification as an atypical acquired progressive lymphangioma, reactive

vascular proliferation with the definitive diagnosis angioendotheliomatosis, and diffuse dermal
deferred to excision (Baker and Schnitt 2017). angiomatosis. Clinicopathologic correlation is
Immunohistochemistry can be useful in mandatory to distinguish these entities from
distinguishing AVL from PIAS. The endothelial AVLs, and history of radiotherapy to the region
markers CD31, CD34, and ERG are generally is very important in solving the differential diag-
positive in both AVLs and angiosarcoma. While nostic dilemma. Hemangiomas are small and
positive in most AVLs, D2-40 is less frequently often incidental superficial lesions composed of
positive in angiosarcomas (Flucke et al. 2013). dilated vascular channels lined by bland endothe-
Ki-67 may be useful in distinguishing between lial cells (Ginter et al. 2017). Microvenular hem-
the two, as it is high (>20%) in PIAS, and low angiomas typically occur on the trunk, but can
or absent in most AVLs (Requena et al. 2002). involve the breast and are characterized by a
Prospero homeobox 1 (Prox-1) is a lymphatic well-circumscribed proliferation of thin-walled
endothelial marker that is strongly expressed in vessels with attenuated endothelial cells, which
angiosarcomas but only focally positive in AVLs dissect through the dermal collagen, mimicking
(Flucke et al. 2013). The majority of PIAS show vascular type AVLs (Baker and Schnitt 2017).
MYC protein expression by IHC or amplification Hobnail hemangiomas preferentially involve the
by FISH, while AVLs do not. However, AVLs can trunk and thighs, and are characterized by dilated
very rarely show rare MYC positive endothelial vessels lined by hobnail endothelial cells within
cells by IHC (Udager et al. 2016). the superficial dermis with stromal papillary pro-
Benign lesions that can mimic AVLs include jections and thin narrow vascular channels in the
hemangioma (▶ Hemangioma of the Breast), deep dermis, mimicking lymphatic type AVLs.
However, hobnail hemangiomas contain extrava- Histologically, diffuse dermal angiomatosis is

sated red blood cells, hemorrhage, and hemosid- characterized by an extravascular endothelial cell
erin deposition, which distinguish the lesion from proliferation involving the dermal stroma. In a
lymphatic type AVLs (Flucke et al. 2013). In small biopsy, diffuse dermal angiomatosis may
addition, atypical hemangiomas can show be difficult to distinguish from an atypical vascu-
increased vascular anastomoses, infiltration, and lar lesion, or even a low-grade angiosarcoma
nuclear hyperchromasia, similar to AVLs (Ginter (Requena et al. 2002; Baker and Schnitt 2017).
et al. 2017).
Acquired progressive lymphangioma, also
known as benign lymphangioendothelioma pre- References
sents as slowly enlarging erythematous papules
with a mean size of 1.5 cm that predominately Baker, G. M., & Schnitt, S. J. (2017). Vascular lesions
involve the limbs and rarely also the breast. It is of the breast. Seminars in Diagnostic Pathology, 34,
410–419.
comprised of dilated, irregular, and anastomosing Brenn, T., & Fletcher, C. D. M. (2005). Radiation-
vascular spaces containing red blood cells involv- associated cutaneous atypical vascular lesions
ing the superficial dermis. The dermis is often and angiosarcoma. Clinicopathologic analysis of
hyalinized with a band of acellular collagen sep- 42 cases. American Journal of Surgical Pathology,
29, 983–996.
arating the lesion from the overlying epidermis. Cornejo, K. M., Deng, A., Wu, H., et al. (2015). The
Similar to AVLs, benign lymphangioen- utility of MYC and FLT4 in the diagnosis and treat-
dotheliomas show endothelial lined papillary stro- ment of postradiation atypical vascular lesion and
mal projections, hobnailing of bland endothelial angiosarcoma of the breast. Human Pathology, 46,
868–875.
cells, and lack intraluminal red blood cells. With Fernandez, A. P., Sun, Y., Tubbs, R. R., et al. (2012). FISH
extension into the deep dermis, lymphangioen- for MYC amplification and anti-MYC immunohisto-
dotheliomas have a pseudomalignant appearance chemistry: Useful diagnostic tools in the assessment of
with prominent dissection of collagen and wrap- secondary angiosarcoma and atypical vascular prolifera-
tions. Journal of Cutaneous Pathology, 39, 234–242.
ping of vascular channels around collagen bun- Fineberg, S., & Rosen, P. P. (1994). Cutaneous angiosarcoma
dles and dermal adnexae (Flucke et al. 2013). and atypical vascular lesions of the skin and breast after
Reactive angioendotheliomatosis is a rare radiation therapy for breast carcinoma. American Journal
vascular disorder that occurs in the setting of of Clinical Pathology, 102, 757–763.
Flucke, U., Requena, L., & Mentzel, T. (2013). Radiation-
co-existent systemic disease, such as renal and induced vascular lesions of the skin: An overview.
cardiac disease. It presents as multifocal erythem- Advance in Anatomic Pathology, 20, 407–415.
atous macules, papules, plaques, or ecchymoses Fraga-Guedes, C., Andre, S., Mastropasqua, M. G., et al.
typically involving the limbs; however, rare (2015). Angiosarcoma and atypical vascular lesions of
the breast: Diagnostic and prognostic role of MYC
cases with breast involvement have been reported. gene amplification and protein expression. Breast Can-
Reactive angioendotheliomatosis is characterized cer Research Treatment, 151, 131–140.
histologically by a proliferation of closely packed Gengler, C., Coindre, J. M., Leroux, A., et al. (2007).
capillaries predominately involving the dermis Vascular proliferation of the skin after radiation therapy
for breast cancer: Clinicopathologic analysis of a series
with occasional extension into the subcutis. The in favor of a benign process: A study from the French
capillaries lack endothelial atypia and multi- sarcoma group. Cancer, 109, 1584–1598.
layering, and are often accompanied by stromal Ginter, P. S., McIntire, P. J., & Shin, S. J. (2017). Vascular
hemosiderin, a mild chronic inflammatory infil- tumours of the breast: A comprehensive review with
focus on diagnostic challenges encountered in the core
trate, microthrombi, and extravasated red blood biopsy setting. Pathology, 49, 197–214.
cells (Weaver and Billings 2009). Guo, T., Zhang, L., Change, N. E., et al. (2011). Consistent
Diffuse dermal angiomatosis is a rare vas- MYC and FLT4 gene amplification in radiation-
cular lesion of the breast which presents as non- induced angiosarcoma but not in other radiation-
associated atypical vascular lesions. Genes, Chromo-
healing painful plaques or ulcers on the breast skin somes & Cancer, 50, 25–33.
surrounded by prominent vessels and occurs most Koerner, F. C. (2014). Sarcoma. In S. A. Hoda, E. Brogi,
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pathology (pp. 1143–1148). Philadelphia: Lippincott Requena, L., Kutzner, H., Mentzel, T., et al. (2002). Benign
Williams & Wilkins. vascular proliferations in irradiated skin. American
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Postradiation cutaneous angiosarcoma after treatment Santi, R., Cetica, V., Franchi, A., et al. (2011). Tumour A
of breast carcinoma is characterized by MYC amplifi- suppressor gene TP53 mutations in atypical vascular
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B
Benign and Atypical Apocrine Atypical apocrine change within sclerosing

Lesions adenosis (atypical apocrine adenosis): Generally
seen in postmenopausal women, these cases are
Reena Khiroya and Clive Wells defined as having a 3 variation in nuclear size.
University College London Hospital, London, UK They have no necrosis and few mitoses.
Atypical apocrine hyperplasia: This is a rare
lesion within ducts which shows complex bridg-
Synonyms ing and a 3 variation in nuclear size but which
does not have the periductal inflammation, peri-
Apocrine adenosis; Apocrine atypia; Apocrine ductal fibrosis, and mitotic activity associated
change; Apocrine metaplasia; Atypical apocrine with apocrine ductal carcinoma in situ. There is
adenosis not a universal agreement on the upper size cutoff
to differentiate this lesion from apocrine DCIS.
Definition
Clinical Features
Apocrine metaplasia: This is a change of native
breast ductal epithelial cells into cells showing • Incidence
eosinophilic granular cytoplasm, a large open Microscopic apocrine change is frequent in the
nucleus with a single nucleolus, and decapitation female breast after the age of 30, is uncommonly
secretion. Apocrine metaplasia can be subtyped observed in women younger than 19, and
into simple, papillary, and complex depending on increases with age, persisting postmenopausally.
architectural complexity. Apocrine metaplasia can Atypical apocrine lesions are uncommon, and
coexist with columnar cell change (▶ Columnar the precise incidence is unknown.
Cell Lesions), sometimes even involving the same • Age
duct spaces. 19–90
Apocrine adenosis: This is apocrine change • Sex
in sclerosing adenosis (▶ Sclerosing Adenosis). Female
Some authors use a different definition, as • Site
a haphazard proliferation of bland glands Breast parenchyma, no specific localizations
with apocrine differentiation and use this • Treatment
term as synonymous with adenomyoepithelial Benign apocrine changes and apocrine cell meta-
adenosis. plasia: Apocrine metaplasia is quite common
https://doi.org/10.1007/978-3-319-62539-3
52 Benign and Atypical Apocrine Lesions
within the breast, is not premalignant and hence but when found in the ducts and lobules within the
does not require surgical intervention. breast, these appear to be a consequence of meta-
Atypical apocrine change within sclerosing plasia, possibly related to columnar cell change
adenosis (atypical apocrine adenosis): Insufficient (▶ Columnar Cell Lesions) and hormonal stress.
cases have been studied to determine if surgical Apocrine cells have eosinophilic granular cyto-
excision is warranted or not (in view of the clin- plasm due to secretory vacuoles, a large open
ical concern of concurrent apocrine DCIS or nucleus with a single nucleolus, and decapitation
invasive apocrine carcinoma (▶ Apocrine Carci- secretion. Apocrine cells carry androgen receptor,
noma). Atypical apocrine change in a papilloma: as do some examples of columnar cell change and
Complete surgical excision recommended. therefore this may be a response to androgenic
Atypical apocrine hyperplasia: Complete stimulation. Although some authors believe that
surgical excision recommended. apocrine cells are a normal constituent of the
• Outcome breast, they can sometimes be seen as partial
Benign apocrine lesions pose no long-term risk metaplasia within a duct, the rest of the lining of
to the patient. which is columnar cell change (Fig. 1 (H&E)).
Regarding atypical apocrine lesions, Apocrine cells often form the lining of type
Fuehrer et al. (2012) showed that the rate of 1 cysts. Type 1 cysts have a high concentration of
breast cancer diagnosis in follow-up of patients potassium relative to sodium and chloride
diagnosed with atypical apocrine change
within sclerosing adenosis (8.1%) was not
appreciably different from that of the cohort
overall (7.8%). Calhoun and Booth (2014)
showed that out of seven patients diagnosed
with atypical apocrine change within scleros-
ing adenosis, none of these diagnoses were
upgraded to ductal carcinoma in situ (▶ Ductal
Carcinoma In Situ) or invasive carcinoma fol-
lowing surgical excision; hence it remains
unclear whether a diagnosis of atypical apo-
crine change within sclerosing adenosis in iso-
lation requires surgical excision or not.
Macroscopy
Apocrine lesions of the breast can present as

cystic or solid breast lesions, which may be
associated with microcalcification (calcium phos-
phate or calcium oxalate/Weddellite micro-
calcifications). They can form macroscopically
visible cystic spaces. Juvenile papillomatosis
shows a “Swiss cheese”-like appearance due to
the formation of multiple cysts.
Microscopy
Benign and Atypical Apocrine Lesions,
Fig. 1 Columnar cell change and apocrine metaplasia
Apocrine cells are a normal constituent of the occurring within same duct spaces, with associated micro-
sweat glands around the nipple and in the axilla, calcifications (H&E)
Benign and Atypical Apocrine Lesions 53
concentration (K/Na ratio greater than 1.5). They

also contain high concentrations of androgens,
estrogen conjugates, and epidermal growth fac-
tor. Conversely, type 2 cysts have high concen-
trations of sodium and chloride relative to B
potassium concentration (K/Na ratio less than
1.5). Type 2 cysts also have lower concentrations
of sex hormones and epidermal growth factor
receptor.
As type 1 cysts have been shown to contain
androgens and, given their nuclear androgen
receptors (AR), they may be subject to
continuous stimulation leading to proliferation.
This may lead to papillary proliferation unless
the cyst becomes extremely tense when the
lining becomes attenuated. Apocrine metaplasia
is a major component of fibrocystic change
(▶ Fibrocystic Breast Changes) and is a diagnos-
tic feature of this condition.
Metaplastic change within many organs is
related to the development of cancer, for example,
in the lung and cervix, but is not a sine qua non.
Apocrine metaplasia is quite common within the Benign and Atypical Apocrine Lesions,
Fig. 2 Apocrine metaplasia and apocrine cysts (H&E)
breast and usually is not premalignant. There are,
however, some examples where apocrine change
may well form the precursor of certain types of
carcinoma. The common benign apocrine lesions Apocrine Cells in Other Lesions
will be described below. Apocrine cells can also be seen associated
with sclerosing adenosis (▶ Sclerosing Adenosis)
Apocrine Cysts and also in other lesions such as complex
Grossly palpable cysts lined by apocrine fibroadenomas (▶ Fibroadenoma), hamartomas
epithelium usually contain cyst fluid with a (▶ Hamartoma), and papillomas (▶ Intraductal
high K+/Na+ ratio, which is characteristic of Papilloma) and are the major constituent of other
the type 1 cyst. Apocrine cells form the lesions such as apocrine adenoma. They are not a
lining of type 1 cysts (Fig. 2 (H&E)) and may constituent of phyllodes tumors as these appear to
be seen as a flattened lining if the cyst is be monoclonal lesions unless in extremely rare
extremely tense precluding the development of examples; the phyllodes tumor (▶ Phyllodes
papillary apocrine metaplasia. It is often, how- Tumor) may have developed within a complex
ever, seen as papillary apocrine metaplasia, fibroadenoma.
which has been classified by Page (Page et al.
1996) into simple (Fig. 3 (H&E)), complex Fibroadenoma and Hamartoma with Apocrine
(Figs. 4 and 5 (H&E)), and highly complex. In Change
his study of premalignant conditions, the simple Dupont and Page (1994) identified a group of
and complex forms were not related to subse- fibroadenomas (▶ Fibroadenoma) with features
quent malignancy. There were too few of the leading to a slightly increased risk of subsequent
highly complex variety as defined in the study carcinoma of 2.17. These lesions had either
to comment on the possible premalignant con- apocrine metaplasia (Fig. 6 (H&E)), sclerosing
notation of these. adenosis (▶ Sclerosing Adenosis), or epithelial

Benign and Atypical Apocrine Lesions, Fig. 3 Simple
Fig. 4 Papillary apocrine metaplasia (H&E)
apocrine metaplasia (H&E)
Papilloma with Apocrine Change

hyperplasia. It is unclear which of these compo- Most large duct papillomas (▶ Intraductal Papil-
nents would be responsible for greater risk, and loma) have a simple columnar lining around a
also nowadays some of these so-called complex papillary core, which may be associated with reg-
fibroadenomas may better be classified as ular hyperplasia. Some, however, may develop
hamartomas (▶ Hamartoma), especially those for- apocrine change (Fig. 7 (H&E)), and this may
merly called pericanalicular where there is little appear rather solid in some cases. Atypical apo-
lobular stromal proliferation. Much of this distinc- crine change (Fig. 8 (H&E)) can be seen in papil-
tion is semantic as fibroadenomas in general lomas and is discussed below. Encapsulated
appear to be a special type of hamartoma rather papillary carcinomas (▶ Encapsulated Papillary
than a clonal lesion. Carcinoma) do not have apocrine elements within
Of note, some benign fibroepithelial lesions may them. Apocrine change within papillary lesions is
occasionally show apocrine cysts and apocrine generally regarded as a sign of benignity, but
metaplasia with attenuated or absent myoepithelial atypical apocrine proliferation within a papilloma
cells (Cserni 2008). In these rare cases, further may cause difficulty in distinguishing these atyp-
immunohistochemistry as well as careful assess- ical papillomas from apocrine ductal carcinoma in
ment for other accompanying features of malig- situ developing in the papilloma.
nancy (significant cytological atypia, desmoplastic
stromal response, mitotic activity, loss of the normal Apocrine Change within Sclerosing Adenosis
lobular architecture) is essential in order to avoid This is a relatively uncommon lesion where apo-
misclassification of a benign lesion. crine cells form the majority of the epithelial

Benign and Atypical Apocrine Lesions, Fig. 6 Apocrine metaplasia within a fibroadenoma (H&E)
Fig. 5 Complex apocrine metaplasia (H&E)
subsequent carcinoma; however too few are

component in a background of sclerosing reported to quantify the absolute risk.
adenosis (▶ Sclerosing Adenosis) (Fig. 9
(H&E)). It has also been called apocrine Atypical Apocrine Lesions
adenosis, but this term has also been used for Atypia in apocrine cells is difficult to quantify as
an unusual change in adenomyoepitheliomas apocrine cells have large nuclei, and in standard
(▶ Adenomyoepithelioma). Unless there is clear 3–5 mm sections the nuclear size can appear quite
atypia within this, the consequences are unclear. variable due to the plane of the section of each
However, there are some worrying features of nucleus. However, benign apocrine cells can
cases of apocrine atypia within sclerosing often appear quite pleomorphic even in cytolog-
adenosis which demand further investigation ical preparations where the actual nuclear size
(see below). can be more readily appreciated. Currently the
accepted definition of atypia in apocrine prolif-
Apocrine Adenoma erations is a variation in nuclear size of greater
This is an unusual apocrine proliferation, which than three times. Atypical apocrine lesions are
resembles a tubular adenoma (▶ Tubular Ade- rare but fall mainly into two types: atypical apo-
noma of the Breast) but composed entirely of crine change within sclerosing adenosis
apocrine cells. These lesions are extremely rare (atypical apocrine adenosis) and atypical apo-
and are not thought to have an increased risk of crine hyperplasia.

Fig. 8 Atypical apocrine change within a papilloma
(H&E)
Fig. 7 Apocrine change within a benign papilloma (H&E)
inflammation, periductal fibrosis, and mitotic
Atypical Apocrine Change Within Sclerosing activity associated with apocrine ductal carci-
Adenosis (Atypical Apocrine Adenosis) noma in situ. Necrosis, if present, indicates that
This was investigated by Seidman et al. (1996) the lesion is apocrine ductal carcinoma in situ.
who discovered a 5.5 increased relative risk of Size cutoffs for defining a lesion as apocrine duc-
subsequent breast cancer in postmenopausal tal carcinoma in situ rather than atypical apocrine
women. These cases are defined as having a hyperplasia have been suggested at 2 mm or
3 variation in nuclear size. They have no necro- 4 mm, but there is not a universal agreement
sis and few mitoses. If necrosis is present or on this.
mitotic activity is prominent, the possibility of
cancerization of lobules by high-grade apocrine Apocrine Change in Core Biopsies
ductal carcinoma in situ (▶ Ductal Carcinoma In Apocrine metaplasia may be responsible for
Situ) should be considered. Some of these lesions microcalcification on mammography as it may
appear to arise in the context of a complex scle- contain Weddellite calcification. This is a reflec-
rosing lesion (▶ Complex Sclerosing Lesion), and tion of fibrocystic change. If no other lesion
occasional cases have an association with is present and there is no atypia, the patient
established apocrine ductal carcinoma in situ. can be reassured and discharged from the
clinic. Similarly patients with apocrine change
Atypical Apocrine Hyperplasia within fibroadenomas or hamartomas can also be
This is a rare lesion within ducts, which shows reassured. Papillomas (▶ Intraductal Papilloma)
complex bridging and a 3 variation in nuclear with apocrine change are currently recommended
size but which does not have the periductal to require excision, which may be performed by

Fig. 9 Apocrine change within sclerosing adenosis
(H&E)
Fig. 10 Atypical apocrine hyperplasia in a core biopsy
(H&E)
vacuum excision biopsy unless clear atypia is
identified on the core biopsy. Apocrine change
within sclerosing adenosis is controversial. If seen in patients up to 60 years old. The lesion
there is no apocrine atypia within this, some usually presents as a single discrete mass although
pathologists would regard this as a benign multifocal and bilateral lesions have been
(B2) lesion. As the relative risk of these lesions described. The lesion is composed of multiple
is still controversial, some pathologists would still cysts, hence its alternative name of “Swiss
call these atypical (B3) even without cytological cheese disease.” The lining of the cysts is usually
atypia of the apocrine cells. Clearly atypical apo- apocrine metaplasia with a marked papillary com-
crine change should be subject to further interven- ponent. The original description (Rosen et al.
tion and given a B3 designation. Many of these 1985) also cited regular hyperplasia, sclerosing
cases will, however, be associated with sclerosing adenosis, and abundant foamy macrophages as
lesions which will qualify for a B3 designation in associated features (Fig. 11 (H&E)). The risk of
their own right. Atypical apocrine hyperplasia subsequent carcinoma is not dissimilar to that of
(Fig. 10 (H&E)) should always raise the possibil- the general population at approximately one in ten
ity of associated apocrine ductal carcinoma in situ women although cases with bilateral disease or a
and excision undertaken. positive family history are stated to be at increased
risk. In essence, therefore, this lesion can be
Juvenile Papillomatosis thought of as a localized area of fibrocystic change
Juvenile papillomatosis is a term given to a local- (▶ Fibrocystic Breast Changes) and it should not
ized area of fibrocystic change which generally be confused with true papillary proliferations such
occurs in young women but which can also be as papillary hyperplasia of young adults (Rosen
progesterone receptor (PR) negative, because in

the breast they are metaplastic, some cells may be
seen which are intermediate between columnar
cells and fully differentiated apocrine cells. In
this case they may have both ER and PR. HER2
staining can be a little controversial in that occa-
sionally some otherwise normal apocrine cells
lining cysts may show membrane staining on the
basal and lateral aspects of the cell but not on the
luminal surface. The significance and function of
this are unknown.
Atypical apocrine lesions: Apocrine carcino-
mas (▶ Apocrine Carcinoma) are interesting in
that they carry AR but may also be positive for
ER and PR and are often HER2 positive. Some,
however, may be triple negative. Atypical apo-
crine lesions also have this variability in that
they may lose functional markers of apocrine dif-
ferentiation such as GCDFP 15, 24, and 44. The
Benign and Atypical Apocrine Lesions, use of p53 and Ki-67 immunohistochemistry has
Fig. 11 Juvenile papillomatosis showing multiple cyst
been suggested to help differentiate between
formation (H&E)
benign and malignant apocrine lesions (Collins
et al. 2011).
1985) or multiple papilloma syndrome (Papotti A proportion of atypical apocrine lesions show
et al. 1984), the latter having an increased propen- intermediate overexpression of HER2 (2+)
sity for the development of in situ carcinoma. The (Fig. 12 (IHC)) but no amplification of the gene.
proliferation is not papillary in the sense of the Immunostaining for HER2 can help in the assess-
two above conditions and is not exclusively in ment of atypical apocrine lesions as, if there is
juveniles. This terminology appears to have led strong positivity for HER2 and amplification, it is
to confusion between the three conditions, and the likely that one is dealing with cancerization of
authors would prefer that this lesion is referred to lobules by apocrine ductal carcinoma in situ, and
as localized fibrocystic change (“Swiss cheese further sections should be taken to try to identify
disease”) rather than given the designation of a more typical in situ carcinoma.
“papillary” lesion. It is therefore included in this
chapter instead of being linked with true papillary
lesions. Molecular Features
Gromov et al. (2015) and Celis et al. (2007)

Immunophenotype propose that carcinomas with apocrine features
arise from atypical and benign precursors. It has
Benign apocrine metaplasia: Apocrine cells con- been demonstrated that malignant lesions acquire
tain AR and a number of proteins designated as mutations as they become more aggressive. Celis
gross cystic disease fluid proteins (GCDFP) such et al. studied cases of sclerosing adenosis with
as GCDFP 15, GCDFP 24, and GCDFP 44. They apocrine metaplasia and identified non-obligate
are positive for cytokeratin (CK) 8/18 and nega- putative apocrine precancerous lesions as defined
tive for CK 5 and hence represent fully differen- by the expression of p53 and/or MPR14 (S100A9)
tiated epithelial cells. Although normal apocrine which is a marker highly overexpressed in pure
cells are AR positive and estrogen (ER) and invasive apocrine carcinomas.
Atypical apocrine change within sclerosing

adenosis (▶ Sclerosing Adenosis) (atypical apo-
crine adenosis) can be misdiagnosed as B
invasive apocrine carcinoma (▶ Apocrine Carci-
noma). Atypical apocrine hyperplasia could also
potentially be diagnosed as DCIS (▶ Ductal Car-
cinoma In Situ) if the size or extent of the lesion is
overestimated.
Calhoun, B. C., & Booth, C. N. (2014). Atypical apocrine

adenosis diagnosed on breast core biopsy: Implications
for management. Human Pathology, 45, 2130–2135.
Celis, J. E., Moreira, J. M. A., Gromova, I., Cabezón, T.,
Gromov, P., Shen, T., Timmermans, V., & Rank, F.
(2007). Characterization of breast precancerous lesions
and myoepithelial hyperplasia in sclerosing adenosis with
apocrine metaplasia. Molecular Oncology, 1, 97–119.
Collins, L. C., Cole, K. S., Marotti, J. D., Hu, R.,
Benign and Atypical Apocrine Lesions, Schnitt, S. J., & Tamimi, R. M. (2011). Androgen
Fig. 12 Atypical apocrine change within a papilloma receptor expression in breast cancer in relation to
showing intermediate expression of HER2 protein molecular phenotype: Results from the Nurses’ Health
Study. Modern Pathology, 14, 924–931.
Cserni, G. (2008). Lack of myoepithelium in apocrine
glands of the breast does not necessarily imply malig-
nancy. Histopathology, 52, 253–255.
Selim et al. (2002) showed that cases of apo- Fuehrer, N., Hartmann, L., Degnim, A., Allers, T.,
crine cell metaplasia showed loss of heterozygos- Vierkant, R., Frost, M., & Visscher, D. (2012). Atypical
apocrine adenosis of the breast: Long-term follow-up
ity (LOH)/allelic instability (AI), most frequently
in 37 patients. Archives of Pathology and Laboratory
involving 11q (INT2), 1p (MYCL1), and 13q Medicine, 136, 179–182.
(D13S267). In their study, one case of apocrine Gromov, P., Espinoza, J. A., & Gromova, I. (2015).
metaplasia was associated with DCIS. In this Molecular and diagnostic features of apocrine breast
lesions. Expert Review of Molecular Diagnostics, 15,
case, one area of DCIS showed allelic alterations
1011–1022.
at 11q (INT2) and 17p (TP53), as did the area of Page, D. L., Dupont, W. D., & Jensen, R. A. (1996).
apocrine metaplasia in the same case. This area Papillary apocrine change of the breast: Associations
also showed LOH at 17q (D17S250). The other with atypical hyperplasia and risk of breast cancer.
Cancer Epidemiology, Biomarkers and Prevention, 5,
focus of DCIS, however, also showed allelic loss
29–32.
at 16q. Papotti, M., Gugliotta, P., Ghiringhello, B., & Bussolati, G.
A proportion of atypical apocrine lesions (1984). Association of breast carcinoma and multiple
show intermediate overexpression of HER2 intraductal papillomas: An histological and immu-
nohistochemical investigation. Histopathology, 8,
(2+) but no amplification of the gene. A possible
963–975.
scenario is that continued stimulation by andro- Rosen, P. P. (1985). Papillary duct hyperplasia of the breast
gen may lead to the development of established in children and young adults. Cancer, 56, 1611–1617.
neoplasia in these cases, and continued stimula- Rosen, P. P., Holmes, G., Lesser, M. L., Kinne, D. W., &
Beattie, E. J. (1985). Juvenile papillomatosis and breast
tion of the overexpressed receptor may lead to
carcinoma. Cancer, 55, 1345–1352.
amplification of the gene and hence uncontrolled Seidman, J. D., Ashton, M., & Lefkowitz, M. (1996).
proliferation. Atypical apocrine adenosis of the breast:
60 Breast Fat Necrosis
A clinicopathologic study of 37 patients with 8.7-year Sometimes, the cause of fat necrosis is unknown
follow-up. Cancer, 77, 2529–2537. (Tan et al. 2006; Kaplan et al. 2005).
Selim, A. G. A., Ryan, A., El-Ayat, G., & Wells, C. A.
(2002). Loss of heterozygosity and allelic imbalance in Fat necrosis of the breast may be a challenging
apocrine metaplasia of the breast: Microdissection diagnosis on mammography, ultrasound, CT,
microsatellite analysis. The Journal of Pathology, PET-CT, and MRI. The extent of associated fibro-
196, 287–291. sis, liquefied fat, and calcifications determine the
imaging findings of fat necrosis. The diagnosis of
fat necrosis using fine needle aspiration cytology
(FNAC) is limited by inadequate samples. Core
Breast Fat Necrosis biopsy is more sensitive.
Clinical presentation of fat necrosis is variable
Inta Liepniece-Karele and Sergejs Isajevs (Chala et al. 2004) ranging from an incidental
Riga East University Hospital, benign finding (indolent single or multiple round
Centre of Pathology/Faculty of Medicine, oil cysts or nodules on imaging) to a lump highly
University of Latvia, Riga, Latvia suggestive of cancer (palpable and radiologically
visible irregular masses with overlying skin
retraction). It can be associated with pain, skin or
Synonyms nipple retraction, erythema and lymphadenopa-
thy. The lesion characteristically is situated near
Adipose tissue necrosis the skin or areola, since these are the sites within
the breast that are most vulnerable to trauma. The
average period for patients to present with a breast
Definition lump from time of trauma is 68.5 weeks (Tan et al.
2006; Kaplan et al. 2005).
Breast fat necrosis is a benign nonsuppurative
inflammatory process of adipose tissue usually • Incidence
complicating breast trauma, breast surgery, or The incidence of the disease is estimated to be
radiation treatment. It was initially described in up to 0.6% in the breast, representing 2.75% of
1920 by Lee, BE & Munzer, JT. all benign lesions. Fat necrosis is found in
0.8% in surgical specimens of breast tumors
and in 1% of breast reduction surgery cases
Clinical Features (Tan et al. 2006; Kaplan et al. 2005).
• Age
The etiological factors include trauma or micro- Variable, the average age of clinical presenta-
trauma, radiotherapy, biopsy, anticoagulation tion is 50 years.
(warfarin), surgery, duct ectasia (▶ Duct Ectasia • Sex
and Periductal Mastitis), and breast infections Mainly described in female breast.
(Tan et al. 2006; Kaplan et al. 2005). The breast • Site
can be injured in a motor vehicle accident, which Variable.
occurs in 16% of cases of seat belt-restrained • Treatment
victims. Fat necrosis was observed secondary In patients with a new palpable finding, the
to the direct injection of silicone or paraffin into history of a traumatic event can be helpful in
the breast. Transplantation of a large amount of making the diagnosis of fat necrosis. Manage-
autologous fat can result in fat necrosis, because ment includes short-term follow-up with imag-
fat cells are not nourished adequately until neo- ing and physical examination, including
vascularization occurs. Other rare causes mammographic follow-up. Fat necrosis often
include polyarteriitis nodosa, Weber-Christian resolves on its own. If the lump does not dis-
disease, and granulomatous angiopanniculitis. appear over time, or increase in size, operation
Breast Fat Necrosis 61
may be recommended to remove the affected

area. Excisional biopsy is required when the
clinical and radiological features resemble
carcinoma.
• Outcome B
Edema is characteristic in the hyperacute
inflammatory phase. Fat cell necrosis releases
cytoplasmic triglycerides into the interstitial
space leading to a fat-containing cavity called
“oil cyst”. The fatty acids can react with cal-
cium ions, which accumulate around the cavity
forming “calcified oil cyst.” Non-encapsulated
fatty acids or granulation tissue can be attacked
by the immune system and reabsorbed leaving Breast Fat Necrosis, Fig. 1 Magnification 200, H&E
staining
a fibrous scar (Tan et al. 2006; Kaplan et al.
2005; Taboada et al. 2009).
Macroscopy
Initially fat necrosis appears as an area of hemor-

rhage in fat. After several weeks, the affected area
becomes bright yellow (saponification), chalky
white (calcification) or yellow-gray (fibrosis).
Cystic degeneration may occur.
Microscopy
Microscopic appearance of the fat necrosis

depends on the age of the lesion. Initial changes Breast Fat Necrosis, Fig. 2 Magnification 40, H&E
staining
are disruption of fat cells accompanied by hemor-
rhage and lipid laden histiocytes (Figs. 1, 2, and 3
H&E). Progression of the lesion is marked by the
formation of multinucleated histiocytes, hemosid-
erin deposits, and calcification. Variable amount
of lymphocytes, plasma cells, sometimes with
eosinophils is present at this stage. Fibrosis
develops peripherally as the demarcation. In
some cases, the area of necrotic fat and cellular
debris may become cystic. Dystrophic calcifica-
tion may occur in older lesions.
Immunophenotype
In rare cases, immunohistochemical stains for Breast Fat Necrosis, Fig. 3 Magnification 100, H&E
cytokeratin may be necessary to exclude an staining
62 Breast Fat Necrosis
underlying carcinoma. Foamy histiocytes may be metaplasia in terminal portion of lactiferous

confirmed by positive CD68 and negative ducts.
pancytokeratin immunostains (Tan et al. 2006;
Kaplan et al. 2005). Breast Infarction
Breast infarction (▶ Infarct of Breast Tissue)
(Kaplan et al. 2005) most frequently occurs dur-
Differential Diagnosis ing pregnancy or postpartum (Tan et al. 2006).
The lesion presents clinically as a discrete mass
Breast Tuberculosis that usually is asymptomatic, but sometimes pain
Breast tuberculosis (▶ Granulomatous Mastitis) and tenderness are reported. The breast infarction
(tuberculous mastitis) is more frequent in pre- usually occurs in women less than 35 years. The
menopausal women. In younger patients, the gross appearance of the infarcted tissue is vari-
lesion is more likely to have signs and symptoms able: hemorrhage in acute onset and pallor or
of an abscess, whereas in older women tuberculo- yellow discoloration in older infarcts similar to
sis tends to cause a mass that simulates carcinoma. fat necrosis. Microscopic findings depend on the
The patients usually have ipsilateral axillary gran- duration of the infarct. Early lesions are charac-
ulomatous lymphadenitis. The most common terized by hemorrhage. Ischemic changes involve
form of tuberculous mastitis is nodular mastitis glandular tissues, a feature not seen in fat necrosis.
with slowly growing solitary mass. Macroscopi- Infarction is demarcated by a zone of granulation
cally, the lesion consists of nodular, indurated tissue with variable inflammatory reaction, hemo-
gray or tan tissue with yellow-to-white foci of siderin deposits, and fibrosis.
caseous necrosis, which may simulate non-
infective fat necrosis. Microscopically granulo- Lupus Mastitis
matous lesions are present with Langhans giant Lupus mastitis can occur in 2% of patients with
cells and caseous necrosis containing typical bac- systemic lupus erythematosus. Lupus mastitis is a
teria detected by Ziehl Neelsen stain. The granu- form of lupus panniculitis characterized by nodu-
lomas tend to be associated with ducts (Tan et al. lar lesions clinically and by fat necrosis in various
2006; Kaplan et al. 2005), while fat necrosis is not stages of evolution histologically. It can present as
specifically associated to glandular structures. palpable nodules accompanied by calcifications
Similarly to fat necrosis, the chronic evolution is on mammography reflecting the evolution from
fibrosis. local panniculitis to fat necrosis (Tan et al. 2006;
Kaplan et al. 2005).
Abscess
Breast abscess (▶ Abscess) commonly seen in Breast Lipoma
lactating women, frequently caused by Staphylo- Breast lipoma with central necrosis is uncommon;
coccus aureus that penetrates through a nipple just few cases have been reported. Lipoma appears as
fissure (Tan et al. 2006; Kaplan et al. 2005). Lac- a round or oval radiolucent mass with a thin capsule.
tational mastitis and abscess formation develop as Mammography shows eggshell calcifications.
a result of obstruction to the flow in one or more
major lactiferous ducts. The histologic appear- Mondor’s Disease or Superficial
ance varies from acute inflammation that may be Thrombophlebitis
accompanied by focal necrosis, to organized The cause of this lesion is trauma, physical exer-
chronic abscesses. tion, operations performed on the breast or chest
Subareolar abscesses usually occur in non- wall (Tan et al. 2006; Kaplan et al. 2005). At
lactating premenopausal women. The process difference with fat necrosis, physical examination
is characterized by repeated episodes of shows a subcutaneous cord. Microscopically, the
abscess formation in subareolar region as the characteristic feature is thrombophlebitis (Tan
result of duct obstruction caused by squamous et al. 2006; Kaplan et al. 2005).
Breast Implant-Associated Malignant Lymphoma 63
References and Further Reading types of ALCLs already recognized (Oishi

2018). While the morphological and
Bowman, E., Oprea, G., Okolo, J., Rizzo, M., Garram- immunophenotypical features of BI-ALCL are
Mendola, S., Manne, U., Smith, G., Pambuccian, S.,
indistinguishable from those of systemic ALK-
& Bumpers, H. L. (2012). Pseudoangiomatous stromal
hyperplasia (PASH) of the breast: A series of negative ALCL, the specificity of the newly B
24 patients. Breast, 18, 242–247. described entity is its clinical presentation in
Chala, L. F., de Barros, N., de Camargo Moraes, P., association with and the vicinity of a breast
Endo, E., Kim, S. J., Pincerato, K. M.,
implant.
Carvalho, F. M., & Cerri, G. G. (2004). Fat necrosis
of the breast: Mammographic, sonographic, computed
tomography, and magnetic resonance imaging findings.
Current Problems in Diagnostic Radiology, 33, Clinical Features
106–126.
Kaplan, V., Kelley, C. J., & Babu, E. D. (2005). Fat necro-
sis of the breast – A review. The Breast, 15, 313–318. • Incidence
Lee, B. E., & Munzer, J. T. (1920). Fat necrosis of the A nationwide study based on the pathology
female breast and its differentiation from carcinoma. registry in the Netherlands established that BI
Annals of Surgery, 37, 188–195.
are associated with a markedly increased risk
Taboada, J. L., Stephens, T. W., Krishnamurthy, S.,
Brandt, K. R., & Whitman, G. J. (2009). The many (400 times) of developing ALCL, but the abso-
faces of fat necrosis in the breast. American Journal of lute risk remains very small, estimated to one
Roentgenology, 192, 815–825. case for every 50,000 women with BI by the
Tan, P. H., Lai, L. M., Carrington, E. V., Opaluwa, A. S.,
age of 50 years, one per 12,000 by the age of
Ravikumar, K. H., Chetty, N., Kaplan, V., Kelley, C. J.,
& Babu, E. D. (2006). Fat necrosis of the breast – 70, and one per 7,000 by the age of 75. The
A review. The Breast, 15, 313–318. mean interval between implant insertion and
lymphoma diagnosis is 10–13 years in differ-
ent studies, but wide variations (1–32 years)
are observed. There is no clear-cut association
Breast Implant-Associated with the type of implant (silicone, saline, tex-
Malignant Lymphoma tured or not).
• Age
Laurence de Leval and Dina Milowich The mean age of patients is 50 years.
Institute of Pathology, University Hospital • Sex
Lausanne, Lausanne, Switzerland All reported cases have occurred in women.
• Site
BI-ALCL is by definition a neoplasm arising in
Synonyms the vicinity of a mammary prosthesis.
• Treatment
Breast implant-associated anaplastic large cell Surgical management with complete surgical
lymphoma (BI-ALCL) resection (total capsulectomy and implant
removal) is essential to achieve optimal
event-free survival in patients with BI-ALCL.
Definition In cases restricted to the seroma cavity, the
addition of chemotherapy does not appear to
Breast implant-associated anaplastic large cell affect outcome.
lymphoma (BI-ALCL) is a very rare form of • Outcome
T-cell lymphoma that arises in association with While most patients have excellent outcome,
various kinds of breast implants. In the recently several studies have highlighted an association
revised WHO classification of hematological between the clinical pattern and disease
malignancies, BI-ALCL is introduced as a new aggressiveness, i.e., most cases presenting as
provisional disease entity, distinct from the other a seroma appear to be cured with surgery alone
64 Breast Implant-Associated Malignant Lymphoma
and infrequently experience recurrences,

while the presence of a solid tumor mass is
an adverse prognostic factor. Clemens MW
et al. conducted a clinical follow-up study of
87 patients (median follow-up time
45 months): the overall survival rate was
93% at 3 years and 89% at 5 years, respec-
tively. Patients with lymphoma confined to
the fibrous periprosthetic capsule had a better
outcome than those with lymphoma spread
beyond the capsule, and patients who
underwent complete surgical excision (total
capsulectomy and breast implant removal)
had a better overall survival than those who
received partial excision, chemotherapy, or
radiation therapy only. A detailed longitudinal
analysis of patients who died of BI-ALCL
showed locoregional dissemination of the dis-
ease to the breast, locoregional lymph nodes,
chest wall, and mediastinum but no systemic
dissemination typical of other lymphomas. It
was therefore suggested to use a staging sys-
tem for BI-ALCL similar in its principles to Breast Implant-Associated Malignant Lymphoma,
those applied to solid tumors (Clemens Fig. 1 (H&E) Caspulectomy specimen in a case of BI-
ALCL presenting as a seroma, showing a lymphoid prolif-
et al. 2016). eration embedded in fibrinous material at the surface of the
periprosthetic capsule (A) with mild infiltration into the
capsule (B, arrow)
Macroscopy
Most cases present as a periprosthetic effusion presentation was found to correlate with an infe-
(seroma or “in situ” lymphoma) as illustrated in rior overall survival (Ferrufino-Schmidt et al.
Fig. 1. Figure 1a shows a lymphoid proliferation 2018). Rare cases present with disseminated
embedded in fibrinous material at the surface of disease.
the periprosthetic capsule; panel 1b shows an
area of mild infiltration into the capsule
(arrow). Only a minority of cases present as a Microscopy
tumor mass infiltrating into the adjacent breast
parenchyma (Fig. 3a), with or without an In cases with seroma-associated presentation,
associated effusion (Clemens et al. 2016). tumor cells may be identified in cytological
A significant proportion of the patients samples from pericapsular effusions or on
(around 30%) may present with axillary lymph- capsulectomy specimens. The tumor cells are
adenopathy, which is not proven involved large and pleomorphic, with large nuclei and
by lymphoma in all instances. Lympho- abundant cytoplasm (Fig. 2). Cells with
matous involvement of axillary lymph nodes horseshoe-shaped nuclei and a paranuclear
is usually characterized by a low-tumor cytoplasmic inclusion (“hallmark cells”)
burden and can feature a sinusoidal, perifollicular, typically encountered in all forms of ALCL are
diffuse, or Hodgkin-like pattern, often associated also found in BI-ALCL (Fig. 2, arrows). The
to fibrosis. Lymph node involvement at initial neoplastic cells may resemble Hodgkin-like
Breast Implant-Associated Malignant Lymphoma, Breast Implant-Associated Malignant Lymphoma,

Fig. 2 (H&E) Cytological features of BI-ALCL composed Fig. 3 (H&E) Breast tumorectomy specimen in a case of
of large pleomorphic cells, including several “hallmark cells“, BI-ALCL presenting as a tumor mass diffusely infiltrating
with eccentric horseshoe-shaped nuclei and a prominent para- the breast tissue, with focal necrosis (A). Higher power
nuclear Golgi region (arrows) (A and B) examination shows diffuse cohesive sheets of large pleo-
morphic lymphoid cells (B)
Reed-Sternberg cells. In capsulectomy speci-

mens, the tumor cells are embedded within a show strong expression of CD30 with a membrane
proteinaceous and fibrinous meshwork at the and paranuclear dot-like pattern of staining
surface of the capsule and may show varying (Fig. 4a), incomplete expression of T-cell antigens,
degrees of capsular infiltration (Figs. 1b and 2). and no ALK expression (Fig. 4b). BI-ALCL fre-
In the minority of cases characterized by a mass- quently expresses EMA (Fig. 4c) but is negative for
forming lesion (Fig. 3), the tumor cells cytokeratins, and features activated cytotoxic
infiltrate into the adjacent breast tissue and may immunophenotype (expression of TIA-1,
be accompanied by a pronounced inflammatory granzyme B (Fig. 4d), and/or perforin (Fig. 4f)).
component including prominent eosinophilia; CD45 is expressed in most cases. CD15 is weakly
necrosis is frequent and sclerosis is sometimes positive in a significant proportion of cases.
observed. Regarding T-cell antigens, CD43 is almost con-
stantly expressed, CD4 expression is frequent,
and positivity for CD2 and CD3 is more common
Immunophenotype than for CD5. CD8 expression is unusual, but rare
cases may coexpress CD4 and CD8. MUM1 is
Images A–D on Fig. 4 are from a tumoral BI-ALCL consistently positive and EBV is consistently neg-
and images E–F from a seroma-associated case. ative. Ki67 stains a very high proportion of the
The tumor cells have an immunophenotype similar nuclei indicating a high proliferation fraction
to that of systemic ALK-negative ALCL: they (Fig. 4e).
Breast Implant-Associated Malignant Lymphoma, a very high proportion of the nuclei indicating a high
Fig. 4 Immunohistochemical findings in BI-ALCL: the proliferation fraction (E) and perforin, another marker of
tumor cells are strongly positive for CD30 with a mem- activated cytotoxic phenotype, produces fine granular pos-
brane and paranuclear dot-like pattern (A), negative for itivity in a subset of the tumor cells (F). Images A-D are
ALK (B), positive for EMA (C), and positive for granzyme from the tumoral BI-ALCL and images E-F from the
B indicating an activated cytotoxic profile (D); Ki67 stains seroma-associated case
Molecular Features of BI-ALCL and its molecular pathogenesis.

Conventional cytogenetics and/or sequencing ana-
T-cell receptor genes are rearranged in most cases. lyses have been reported in a small number of cell
Limited information is available on the genetic lines established from BI-ALCL or from primary
lesions underlying the development and progression lymphoma specimens.
Three IL2-dependent TLBR (T-cell breast origin of the neoplasm may be questioned. Stag-
lymphoma) cell lines established from seroma- ing and clinical history are therefore critical to
associated BI-ALCL had clonally abnormal establish the correct diagnosis.
complex karyotypes with a modal number – Other types of lymphomas have been reported to
of 47 chromosomes in one cell line (TLBR-1) occur in association with breast implants: mycosis B
and a hypertriploid pattern in TLBR-2 and fungoides/Sézary syndrome, extranodal NK/T-
TLBR-3. Functional studies on these three cell cell lymphoma, nasal type, and different types
lines showed evidence of STAT3 activation, of B-cell lymphomas (diffuse large B-cell lym-
while pharmacological inhibition of STAT3 inhi- phoma, follicular lymphoma, lymphoplasmacytic
bition induced in vitro cell death. lymphoma, primary effusion lymphoma, mar-
Seven cases of BI-ALCL were successfully ginal zone B-cell lymphoma). These lymphomas
analyzed by whole exome or targeted next- differ from BI-ALCL both by their morphology
generation sequencing using a large panel of and immunophenotype.
465 cancer-associated genes, and of these only – Hodgkin lymphoma is an entity with
four showed somatic variants (reviewed in significant overlapping morphological and
Letourneau et al. 2018). The STAT3 S614R variant immunophenotypical features with BI-ALCL.
was detected by whole exome sequencing or The Hodgkin/Reed-Sternberg cells of Hodgkin
targeted sequencing in two cases (including the lymphoma are typically scarce in a prominent
primary tumor from which TLBR-1 cell line was inflammatory background, coexpress CD30
derived), as the sole abnormality in the latter and in and CD15, and have a B-cell genotype with
combination with pathogenic mutations in TP53 expression of a markedly attenuated B-cell
and SOCS1 in the other case. One somatic variant immunophenotype. They are usually negative
was detected in the other two cases, affecting JAK1 for T-cell antigens. Although Hodgkin lym-
(G1097 V) or DNMT3A (W176X). In one case of phoma very rarely occurs in extranodal locali-
BI-ALCL which presented as a solid tumor mass zations, an exceptional case of Hodgkin
and recurred as an in situ capsular lesion, dual gain- lymphoma arising adjacent to a breast implant
of-function mutations in JAK1 and STAT3 were has been reported in a woman who had a his-
identified in both specimens, suggesting pathoge- tory of follicular lymphoma, and the Hodgkin
netic mechanisms overlapping with those of sys- lymphoma was shown to represent transforma-
temic ALK-negative ALCLs (Letourneau et al. tion from the preexisting follicular lymphoma.
2018) However, rearrangements of the IRF4/ – Chronic inflammatory lesions associated to a
DUSP22 locus at 6p25 and of TP63 (frequently breast implant may contain occasional CD30+
observed in systemic or primary cutaneous ALCL) activated lymphoid cells and must be distin-
have not been found in any of the cases tested so far guished from BI-ALCL.
(Oishi et al. 2018).

Clemens, M. W., Medeiros, L. J., Butler, C. E., Hunt, K. K.,
– Primary breast implant-associated ALCL is cyto- Fanale, M. A., Horwitz, S., Weisenburger, D. D.,
logically and by immunophenotype indistin- Liu, J., Morgan, E. A., Kanagal-Shamanna, R.,
Parkash, V., Ning, J., Sohani, A. R., Ferry, J. A.,
guishable from systemic ALK-negative ALCL.
Mehta-Shah, N., Dogan, A., Liu, H., Thormann, N.,
Although rarely, systemic ALCL in patients with Di Napoli, A., Lade, S., Piccolini, J., Reyes, R.,
breast implants may manifest in the breast with a Williams, T., McCarthy, C. M., Hanson, S. E.,
presentation mimicking BI-ALCL. Likewise, Nastoupil, L. J., Gaur, R., Oki, Y., Young, K. H., &
Miranda, R. N. (2016). Complete surgical excision is
primary cutaneous ALCL involving the breast
essential for the management of patients with breast
in women harboring breast implants may grow implant-associated anaplastic large-cell lymphoma.
near the breast implant, and in that situation the Journal of Clinical Oncology, 34(2), 160–168.
Ferrufino-Schmidt, M. C., Medeiros, L. J., Liu, H., Clemens, Letourneau, A., Maerevoet, M., Milowich, D., Dewind, R.,
M. W., Hunt, K. K., Laurent, C., Lofts, J., Amin, M. B., Bisig, B., Missiaglia, E., & de Leval, L. (2018, 2018).
Ming Chai, S., Morine, A., Di Napoli, A., Dogan, A., Dual JAK1 and STAT3 mutations in a breast implant-
Parkash, V., Bhagat, G., Tritz, D., Quesada, A. E., Pina- associated anaplastic large cell lymphoma. Virchow
Oviedo, S., Hu, Q., Garcia-Gomez, F. J., Jose Borrero, J., Archiv. https://doi.org/10.1007/s00428-018-2352-y.
Horna, P., Thakral, B., Narbaitz, M., Hughes, R. C., 3rd, Oishi, N., Brody, G. S., Ketterling, R. P., Viswanatha, D. S.,
Yang, L. J., Fromm, J. R., Wu, D., Zhang, D., Sohani, He, R., Dasari, S., Mai, M., Benson, H. K., Sattler, C. A.,
A. R., Hunt, J., Vadlamani, I. U., Morgan, E. A., Ferry, Boddicker, R. L., McPhail, E. D., Bennani, N. N.,
J. A., Szigeti, R., C Tardio, J., Granados, R., Dertinger, S., Harless, C. A., Singh, K., Clemens, M. W., Medeiros,
Offner, F. A., Pircher, A., Hosry, J., Young, K. H., & L. J., Miranda, R. N., & Feldman, A. L. (2018). Genetic
Miranda, R. N. (2018). Clinicopathologic features and subtyping of breast implant-associated anaplastic large
prognostic impact of lymph node involvement in patients cell lymphoma. Blood, 132(5), 544–547.
with breast implant-associated anaplastic large cell lym- Rupani, A., et al. (2015). Lymphomas associated with
phoma. The American Journal of Surgical Pathology, breast implants: A review of the literature. Aesthetic
42(3), 203–305. Surgery Journal, 35(5), 533–544.
C
Collagenous Spherulosis Clinical Features
Alena Skalova • Incidence

Department of Pathology, Faculty of Medicine Collagenous spherulosis (CS) is very rare, with
in Plzen, Charles University, Plzen, Czech an estimated incidence of less than 1% in exci-
Republic sional specimens (Resetkova et al. 2006) and
Biopticka laborator s.r.o, Pilsen, Czech Republic about 0.2% in cytology material (Sola Perez
et al. 1993). CS may go unrecognized in about
48% of cases or may be misdiagnosed as atyp-
Synonyms ical hyperplasia in 17% of cases or as in situ
and/or invasive carcinoma in 11% of cases
Adenoid cystic hyperplasia; Mucinous (Mooney et al. 1999).
spherulosis; Spherulosis • Age and sex
The patients were all women ranging in age
from 36 to 90 years (mean age, 52 years;
Definition median age, 50 years) in the largest published
study (Resetkova et al. 2006).
Collagenous spherulosis (CS) of the breast is a • Treatment and outcome
benign lesion most frequently associated with Although rare, CS is a distinct, morphologi-
other benign proliferative processes, including cally well-defined entity most often reported in
papilloma (▶ Intraductal Papilloma), papillary association with benign proliferative changes.
duct hyperplasia, radial sclerosing lesions Processes most frequently associated with col-
(▶ Radial Scar and ▶ Complex Sclerosing lagenous spherulosis lesions include columnar
Lesion), sclerosing adenosis (▶ Sclerosing cell hyperplasia (▶ Columnar Cell Lesions),
Adenosis), and atypical ductal hyperplasia radial scar (▶ Radial Scar), sclerosing adenosis
(▶ Atypical Ductal Hyperplasia). Originally (▶ Sclerosing Adenosis), papillomas (▶ Intra-
reported by Clement et al. in 1987, the lesion ductal Papilloma), ductal hyperplasia without
was first described as an incidental microscopic atypia (▶ Usual Ductal Hyperplasia (UDH)),
finding of intraluminal clusters of collagen-rich, and adenomyoepithelioma (▶ Adenomyoe-
eosinophilic, or star-shaped fibrillar spherules pithelioma) (Reis-Filho et al. 2004). Less fre-
(Clement et al. 1987). quently, CS has been observed in specimens

https://doi.org/10.1007/978-3-319-62539-3
70 Collagenous Spherulosis
with a concurrent malignant process, most

commonly lobular carcinoma in situ (LCIS)
(▶ Lobular In Situ Neoplasia) (Resetkova
et al. 2006; Mooney et al. 1999). Association
of CS with LCIS and other benign and malig-
nant breast lesions is interpreted as most
likely coincidental. CS could present as a
mammographically suspicious mass or den-
sity and could be associated with micro-
calcifications. Treatment of the patient and
clinical outcome of CS is dependent on
accompanying breast lesion.
Collagenous Spherulosis, Fig. 2 The eosinophilic
spherules of CS have a concentric fibrillary pattern with
Macroscopy darker peripheral staining (H&E)
CS is an incidental finding in breast samples

variable thickness and staining intensity (Fig. 2
removed for other reasons, and it is not visible at
H&E). The hyaline material present within the
macroscopy.
intraluminal space is rich in collagen type IV of
the basement membrane origin.
Microscopy
Immunophenotype
CS is characterized by presence of eosinophilic
intraluminal collagen-rich spherules measuring
The myoepithelial cells surrounding the basement
20–100 mm in diameter, surrounded by flattened
membrane deposits in CS express myoepithelial
myoepithelial cells (Fig. 1 H&E). Most frequently,
markers, such as smooth muscle actin, smooth
it shows a central floccular aggregate with radiating
muscle myosin heavy chain, calponin, p63
spikes that merge with the scalloped projections at
(Fig. 3a P63 immunostaining), and cytokeratin
the periphery. The material may also be finely
14 (CK14) (Fig. 3b CK14 immunostaining).
granular and more evenly distributed in concentric
onion skin-like pattern. The periphery of the sphere
may be marked by an eosinophilic cuticle of Differential Diagnosis
Cribriform architecture characterizes, in addition

to CS, a broad spectrum of benign and malignant
proliferations in the breast, chiefly invasive crib-
riform carcinoma (▶ Invasive Cribriform Carci-
noma), ductal carcinoma in situ (▶ Ductal
Carcinoma In Situ), and adenoid cystic carcinoma
(AdCC) (▶ Adenoid Cystic Carcinoma). The dif-
ferential diagnosis can be especially challenging
in needle core biopsies (Rabban et al. 2006).
AdCC of the breast is a rare, special type
of invasive breast carcinoma, accounting for
0.05–0.10% of all primary carcinomas of the
Collagenous Spherulosis, Fig. 1 Collagenous breast. The myoepithelial immunophenotypic
spherulosis (CS) associated with benign columnar cell overlap between cribriform pattern AdCC of
hyperplasia (H&E) the breast and CS could lead to diagnostic
Columnar Cell Lesions 71
Collagenous Spherulosis, Fig. 3 Immunostainings with p63 (a) and CK 14 (b) highlight myoepithelial cells, which
form incomplete lining of the spherules
pitfalls in evaluating cribriform lesions of the

breast, especially in core needle biopsies. While Columnar Cell Lesions
smooth muscle actin and p63 are expressed by
both entities, other myoepithelial markers, Margaret C. Cummings1,2, Peter T. Simpson1 and
calponin and smooth muscle myosin heavy Sunil R. Lakhani1,2
1
chain, are expressed only by CS and thus can Centre for Clinical Research, Faculty of
be used to distinguish it from AdCC (Reis-Filho Medicine, The University of Queensland,
et al. 2004). In contrast, the staining for c-kit and Brisbane, QLD, Australia
2
EMA may facilitate identification of the ductules Pathology Queensland: The Royal Brisbane and
characteristic for AdCC. Women’s Hospital, Brisbane, QLD, Australia
References and Further Reading Synonyms

Clement, P. B., Young, R. H., & Azzopardi, J. G. (1987).
Collagenous spherulosis of the breast. American For columnar cell lesions: Columnar cell change,
Journal of Surgical Pathology, 11, 411–417. Columnar cell hyperplasia, Columnar alteration
Mooney, E. E., Kayani, N., & Tavassoli, F. A. (1999). with prominent apical snouts and secretions
Spherulosis of the breast. A spectrum of mucinous
(CAPSS), Atypical cystic ducts, Atypical cystic
and collagenous lesions. Archives of Pathology &
Laboratory Medicine, 123, 626–630. lobules, Blunt duct adenosis, Columnar alteration
Rabban, J. T., Swain, R. S., Zaloudek, C. J., Chase, D. R., & of lobules, Columnar cell metaplasia, Enlarged
Chen, Y. Y. (2006). Immunophenotypic overlap between lobular units with columnar alteration, Hyperplas-
adenoid cystic carcinoma and collagenous spherulosis of
tic enlarged lobular units, Hyperplastic unfolded
the breast: Potential diagnostic pitfalls using myoepithelial
markers. Modern Pathology, 19, 1351–1357. lobules
Reis-Filho, J. S., Fulford, L. G., Crebassa, B., et al. (2004). For flat epithelial atypia (FEA): Columnar cell
Collagenous spherulosis in an adenomyoepithelioma of change with atypia, Columnar cell hyperplasia
the breast. Journal of Clinical Pathology, 57, 83–86.
with atypia, Columnar cell lesion with atypia,
Resetkova, E., Albarracin, C., & Sneige, N. (2006).
Collagenous spherulosis of breast: Morphologic study Columnar alteration with prominent apical snouts
of 59 cases and review of the literature. American and secretions with atypia, Atypical columnar cell
Journal of Surgical Pathology, 30, 20–27. lesions, Atypical cystic duct, Atypical cystic
Sola Perez, J., Perez-Guillermo, M., Bas Bernal, A., et al.
lobules, Atypical cystic lobules type A, Clinging
(1993). Diagnosis of collagenous spherulosis of the
breast by fine needle aspiration cytology: A report of carcinoma (monomorphic type), Ductal
two cases. Acta Cytologica, 37, 725–728. intraepithelial neoplasia of the flat monomorphic
72 Columnar Cell Lesions
type (Flat DIN 1), Hypersecretory hyperplasia • Clinical Presentation

with atypia, Pretubular hyperplasia, Small ectatic Columnar cell lesions are most commonly
ducts lined by atypical cells with apocrine snouts identified on core needle biopsy taken
because of microcalcification which has
been identified on screening mammography.
Definition
The microcalcification has been variably
described as indistinct, amorphous, fine,
Columnar cell lesions refers to a group of prolif-
irregular, and pleomorphic. Calcification
erative lesions in the breast which have a charac-
such as this can also be seen in more signifi-
teristic cystic dilatation of acini of terminal duct
cant breast diseases, hence the need for core
lobular units such that they appear enlarged and
needle biopsy. There are no mammographic
unfolded, and which are lined by cells showing a
features that can be used to distinguish colum-
columnar morphology. Columnar cell lesions that
nar cell lesions showing atypia from those
display cytological atypia are referred to as flat
without atypia. Columnar cell lesions may
epithelial atypia (FEA).
also be identified histologically when a core
needle biopsy has been taken for another rea-
Clinical Features son, such as a nonspecific density and they
may also be found incidentally in surgical
• Incidence excision specimens.
As a typical feature of columnar cell lesions is • Treatment
the presence of calcification, they have been For columnar cell change and columnar cell
increasingly identified through the use of hyperplasia diagnosed on core needle biopsy,
screening mammography and have been no further treatment is required.
described as occurring in up to 50% of core The situation with regards to the manage-
needle biopsies that are performed for micro- ment of patients in whom FEA is diagnosed on
calcification. A frequency of 1.9% has been core needle biopsy is not so straightforward.
reported for FEA in reduction mammoplasty A contributing factor to this uncertainty is the
specimens (Desouki et al. 2013) and between not insignificant frequency of FEA in the
2.4% and 4.5% in core needle biopsies derived screening population. A related factor is the
from breast screening programs (Said et al. difficulty of making the diagnosis of FEA his-
2015; Yu et al. 2015). For FEA, excluding tologically. Pathologists concerned about the
those cases which coexist with higher grade possibility of underdiagnosis and the implica-
lesions, such as atypical hyperplasia, in situ tions of missing an atypical lesion tend to over-
or invasive carcinoma, an incidence of up to diagnose the condition, which of course makes
12.2% has been reported (Berry et al. 2016). the most appropriate management difficult to
• Age determine. And for the instances where FEA is
Reflecting the general age distribution of accurately diagnosed, another confounding
women undergoing screening mammography, factor is the possible pathology upgrade on
an age range in the 40s–60s has been described surgical excision, and this is of the most imme-
for women with columnar cell lesions diate concern, considerations of long-term risk
including FEA. reduction being less relevant. The most com-
• Sex monly described treatment for FEA identified
Columnar cell lesions, including FEA, have on core needle biopsy is surgical excision. If no
only been reported in females, no doubt higher grade lesion, such as in situ or invasive
because of the lack of lobular units in male carcinoma is identified initially in the excision
breast tissue. specimen, all the material should be blocked
• Site thoroughly and levels performed as required.
These lesions occur only in breast tissue. However, the presence of FEA at the margin of
a surgical excision specimen is not an indica- and Collins 2009). An association with tubular
tion for further surgery. carcinoma (▶ Tubular Carcinoma), which
If FEA is found to coexist with atypical together with columnar cell lesions and lobular
ductal hyperplasia, in situ or invasive carci- neoplasia forms the eponymously named
noma, then naturally the treatment recommen- Rosen’s triad, was first described in 1999
dation is dictated by the higher grade lesion. (Rosen 1999). Whether or not columnar cell
Other treatment recommendations for lesions constitute a direct precursor lesion or C
FEA found on core needle biopsy include radi- are an indicator of a more general increased
ology and pathology correlation with multi- risk of subsequent breast cancer has not been
disciplinary team discussion. Some may established. The time course of possible pro-
recommend using vacuum-assisted biopsy to gression to in situ or invasive carcinoma and
excise any residual tissue showing micro- actual upgrade rates are also contentious areas.
calcification or other areas of radiological con- There is probably sufficient evidence to sup-
cern, instead of advocating surgical excision. port columnar cell lesions being at least one
If no further microcalcification is identified early feature of the low-grade breast neoplasia
radiologically, if the extent of involvement of pathway, but the data are difficult to compare
the terminal duct lobular units by FEA is small and analyze because of the range of methodol-
and the patient does not have a personal history ogies the various studies have used. In some
of breast cancer, ongoing radiological surveil- follow-up studies it is not clear if the subse-
lance instead of surgical excision has been quent carcinoma has been in the same area as
suggested as the preferred management the initial columnar cell lesion. When colum-
(Berry et al. 2016; Acott and Mancino 2016). nar cell lesions are removed at core biopsy it is
However, long-term follow-up studies of generally not known how much, if any, lesional
women with FEA diagnosed on core needle tissue remains. It is difficult to then interpret
biopsy for whom the management has been the significance of subsequent cancers as it
prolonged surveillance are not yet available, would not be known from precisely what tissue
and some use this lack of definitive informa- they may have arisen.
tion to support the use of surgical excision as An association between columnar cell
the primary treatment recommendation. lesions and carcinoma has also been investi-
• Outcome gated by assessing whether columnar cell
The clinical outcomes of the various colum- lesions are present in breast tissue adjacent to
nar cell lesions have not been precisely in situ and invasive carcinomas. Another way
defined, and while some generalizations to explore this association is to retrospectively
can be made, there is still a lack of clarity study biopsies taken previously from women
with respect to the long-term significance of with invasive carcinomas to see if columnar
these lesions. A lower level of risk has been cell lesions, including FEA, might have been
attributed to columnar cell change and present earlier. Follow-up studies have investi-
columnar cell hyperplasia compared with gated whether cancers arising subsequent to
that for FEA. columnar cell lesions have occurred in the
The biological importance of columnar cell same area or somewhere else in the ipsilateral
lesions is underscored by their association with breast or indeed in the contralateral breast, the
other breast lesions such as atypical ductal latter, of course, not being used to support any
hyperplasia (▶ Atypical Ductal Hyperplasia) direct precursor role (Boulos et al. 2008).
and lobular neoplasia, including atypical lobu- Another confounding factor is that many of
lar hyperplasia and lobular carcinoma in situ the studies have not been able to provide infor-
(▶ Lobular In Situ Neoplasia), which have mation as to the size or possible multifocality
been noted to coexist with them, sometimes of the columnar cell lesions although
in the same terminal duct lobular unit (Schnitt pathology-radiology correlation as to the
extent of residual calcification has been very had atypical ductal hyperplasia (Verschuur-
helpful in this regard. Maes et al. 2012b).
Overall, the long-term relative risk of carci-
noma for those women with nonatypical
Macroscopy
columnar cell lesions diagnosed in isolation
appears to be very low, similar to that seen for
Columnar cell lesions, including FEA are diag-
nonatypical proliferative breast disease in gen-
nosed microscopically, and except for occasional
eral, around the order of a 1.5-fold increase
floridly cystic examples, are not able to be identi-
(Verschuur-Maes et al. 2012b).
fied macroscopically.
A closely related issue with columnar cell
lesion is that of the potential upgrade to more
significant lesions, particularly in situ and
Microscopy
invasive carcinoma, which occurs when there
is an immediate surgical excision taken on
A distinctive feature of columnar cell lesions on
the basis of a columnar cell lesion identified
low power examination is the cystic dilatation of
on core biopsy. A very wide range of upgrade
enlarged terminal duct lobular units, and for
rates (between 0% and 67%) has been
columnar cell change and columnar cell hyperpla-
described in the literature, and this consider-
sia, these gland spaces often have an irregular
able variation partly reflects the very different
contour (Fig. 1). The lesions may also be conspic-
ways in which the upgrade rate has been cal-
uous on low power examination because of a
culated. The numerator is generally those who
basophilic appearance, partly due to the regular
have had a malignancy in the subsequent exci-
arrangement of the cells, which are generally uni-
sion specimen, while the denominator can
form, columnar to cuboidal in shape, and mostly
include all women who have had a columnar
orientated perpendicular to the basement mem-
cell lesion on core biopsy, or only those who
brane. Quite frequently, small apical cytoplasmic
have gone on to surgical excision. This of
blebs or snouts are seen, projecting into the lumen
course would give a higher upgrade rate. In
of some glandular spaces, but these are not usually
this latter group too, other clinical and radio-
prominent. Thin, pale proteinaceous secretions
logical features may have also contributed to
which may be pink or blue are commonly seen
the decision to recommend surgical excision,
in the gland lumina (Fig. 2). Luminal micro-
thus confounding the analysis of columnar cell
calcification, often the reason for these lesions
lesions. Some studies have reviewed columnar
cell lesions when there is also atypical ductal or
lobular hyperplasia present, while others have
specifically excluded cases with concomitant
atypical lesions. Many more studies have
addressed upgrade rates from FEA than from
pure columnar cell change or columnar cell
hyperplasia. The problem of correctly diagnos-
ing these lesions histologically only adds to
the difficulty of obtaining meaningful outcome
data. Verschuur-Maes in a comprehensive
meta-analysis of 24 papers concerning the
risk of carcinoma in women with columnar
cell lesions derived pooled underestimation
risks of 1.5% for columnar cell lesions without
atypia, 9% for columnar cell lesions with Columnar Cell Lesions, Fig. 1 Columnar cell lesion.
atypia compared with 20% for those who also Cystic dilatation of terminal duct lobular unit. (H & E)
Columnar Cell Lesions, Fig. 2 Columnar cell Columnar Cell Lesions, Fig. 4 Columnar cell hyperpla-
lesion. dilated gland lumina containing watery secretions. sia. irregularly dilated gland spaces with some overlapping
(H & E) of cells. (H & E)
Columnar Cell Lesions, Fig. 3 Columnar cell lesion and Columnar Cell Lesions, Fig. 5 Columnar cell hyperpla-
columnar cell hyperplasia. Luminal microcalcification. sia. Luminal tufting of cells and small micropapillae. (H & E)
(H & E)
being detected radiologically, may be seen and micropapillae, and luminal secretions can occur
these range from being fine to granular or coarse (Fig. 5).
and even sometimes psammomatous (Fig. 3). The Enlarged or dilated acini of terminal duct lob-
nuclei of columnar cell change or hyperplasia are ular units, often appearing rounded or distended
generally oval or elongated, with smooth nuclear (Fig. 6) rather than the more convoluted contours
membranes and fine chromatin. Nucleoli usually of columnar cell change, characterize lesions of
are not seen and mitoses are rarely identified. FEA and these are lined by 3–5 layers of cells.
Occasionally the underlying myoepithelial cells With a loss of polarity, the cells have a more
become cuboidal and even relatively prominent. haphazard overlapping arrangement. “Flat” refers
For columnar cell change, 1–2 layers of cells are to the absence of complex architectural features
seen above the basement membrane, with greater such as Roman bridges or well-developed rigid
numbers seen for columnar cell hyperplasia micropapillae. Apical cytoplasmic projections,
(Fig. 4), where stratification of cells can occur characteristic of columnar cell change, may on
within dilated acini, often giving an impression occasion be more pronounced. The lining epithe-
of hyperchromasia. Luminal tufting of cells, blunt lial cells are usually rounded, with a low-grade
can also be seen in gland lumina and this may be

granular or irregular (Schnitt and Collins 2009).
Immunophenotype
Columnar cell lesions, including columnar cell

change, columnar cell hyperplasia, and FEA,
show an immunoprofile similar to that seen in
atypical ductal hyperplasia (▶ Atypical Ductal
Hyperplasia) and low-grade ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ), reflecting the
clonality of these entities. Diffuse expression of
Columnar Cell Lesions, Fig. 6 Flat epithelial atypia. the low molecular weight cytokeratins CK7,
Rounded dilated acini of terminal duct lobular unit. (H & E)
CK8/18, and CK19 can be seen in the luminal
cells, with complete absence of expression of
high molecular weight cytokeratins such as
CK14, CK5/6, and 34bE12. Unlike the cells of
the normal terminal duct lobular units which show
a heterogeneous pattern of staining, columnar cell
lesions show diffuse, intense staining with anti-
bodies to both estrogen and progesterone receptor
proteins. This is also in contrast with the cells of
apocrine metaplasia which are usually uniformly
negative for hormone receptor proteins and some-
times can be confused with those of columnar cell
lesions. The proliferation rate of columnar cell
lesions as indicated by Ki67 staining is generally
low, with less than 10% of cells staining, and
Columnar Cell Lesions, Fig. 7 Flat epithelial atypia.
Overlapping cells with monomorphic atypia and occa- while it may be increased compared with that of
sional nucleoli visible. (H & E) the adjacent noninvolved breast tissue, it is not a
reliable discriminating feature and nor can it be
used to distinguish between FEA and nonatypical
monomorphic appearance (Fig. 7) unlike that seen columnar cell lesions. The immunoprofile of
in columnar cell change or hyperplasia. The nuclei columnar cell lesions also includes Bcl2 positiv-
are enlarged, with an increased nuclear to cyto- ity, with strong diffuse cytoplasmic staining, pos-
plasmic ratio and hyperchromasia, making the itive E-cadherin, and absence of staining with
lesions appear distinctive on low-power examina- HER2 immunohistochemistry.
tion. The cellular crowding, loss of polarity, and
increased nuclear to cytoplasmic ratio all contrib-
ute to a basophilic appearance. Nuclear mem- Molecular Features
branes may be irregular, the chromatin relatively
dense, and nucleoli can generally be seen. Stromal Prompted by morphological similarities with
changes, such as a chronic inflammatory infiltrate more advanced lesions, potential molecular
and a fibrinous or myxoid change can be found in changes in columnar cell lesions have been inves-
the intralobular stroma, surrounding glandular tigated to try to determine the clinical significance
spaces involved by FEA. Microcalcification, as of these entities as possible (even nonobligate)
occurs in columnar cell change and hyperplasia, precursors of atypical ductal hyperplasia or
in situ and invasive carcinoma, as part of the low- Twenty-five percent of invasive breast carcino-
grade breast neoplasia pathway. A variety of mas have been demonstrated to contain an acti-
methods of analysis have been used, and while vating mutation in the catalytic subunit of
the findings so far are suggestive of a causal rela- phosphatidylinositol-3-kinase (PIK3CA), and the
tionship, rather than just co-occurrence, the evi- presence of these mutations have been investi-
dence currently available is relatively scanty. gated in columnar cell lesions, with one study
A loss of heterozygosity study of clinging ductal showing them to be present in 13/24 (54%) cases C
carcinoma in situ, also called ductal intraepithelial (Troxell et al. 2012) and in 31/62 (50%) of colum-
neoplasia (DIN) flat type, one of the earlier names nar cell/usual ductal hyperplasia lesions in another
for what is now referred to as FEA, demonstrated (Ang et al. 2014). However, the same point muta-
changes at chromosomes 11q21-23.2, 16q23.1- tions were not consistently identified in the
24.2, and 3p14.2 in 50%, 45%, and 41% of infor- corresponding carcinoma, sometimes with differ-
mative cases, respectively, with corresponding ent mutations identified, or wild-type PIK3CA in
changes identified in the in situ and invasive carci- the carcinoma with mutations in the columnar cell
noma also present in these cases (Moinfar 2009). lesions, or vice versa, wild-type in the columnar
These findings were later supported by the work of cell lesions and point mutations identified in the
Aulman in a study of FEA, tubular carcinoma, and carcinomas making the association less certain.
low-grade ductal carcinoma in situ where loss of Promoter methylation of the tumor suppressor
heterozygosity was noted for 16q in up to 80% of genes ID4, CCND2, and CDH13 has been dem-
cases, 8p21 (26% of cases) 3p14 (20% of cases), onstrated in columnar cell lesions with increasing
1p35 (20% of cases), and 11q14 (24% of cases), levels shown to occur in parallel with progression
with many comparable losses seen in the adjacent to invasive carcinoma (Verschuur-Maes et al.
low-grade ductal carcinoma in situ and tubular 2012a) supporting a precursor role for these
carcinoma (Aulmann et al. 2009). lesions, although atypia was not associated with
Using comparative genomic hybridization increased levels. Other changes identified as
Simpson was able to demonstrate chromosomal linked to the early phase of the low-grade pathway
losses (6q, 11q, 12q, 16q, 17p, 19q, and 22) and include, in columnar cell hyperplasia, down-
gains (3p, 3q, 7, 8q, 12p, 15q, 16p, 19, and 20) in regulation of the let-7c microRNA in the epithelial
columnar cell lesions, with increasing chromo- compartment and upregulation of miR-132 in the
somal changes seemingly occurring in parallel stroma surrounding columnar cell hyperplasia
with increasing cytological and architectural (Bjorner et al. 2014) possibly reducing some con-
atypia, particularly the recurrent loss of 16q trols on anti-proliferative activity.
(Simpson et al. 2005).
Gains and losses of 17 breast cancer-related
genes were documented for columnar cell lesions Differential Diagnosis
with accompanying ductal carcinoma in situ and
invasive carcinoma. Copy number gains were The diagnosis of columnar cell change, columnar
identified for C11orf30, MYC, CPD, MTDH, cell hyperplasia, and FEA can be difficult to be
CCND1, CCNE1, ESR1, and TOP2A, while losses certain about, particularly on a core needle biopsy
were seen for CDH1 and TOP2A in a small num- where there may be only limited material for
ber of cases, the copy number changes increasing evaluation; however, distinguishing FEA is par-
from columnar cell lesions through to invasive ticularly important as it is associated with a dif-
carcinomas. The relative infrequency of the ferent management outcome for the patient.
changes in the columnar cell lesions compared Similar to columnar cell lesions, apocrine
with those for the in situ and invasive carcinomas metaplasia (▶ Benign and Atypical Apocrine
suggested that they may represent relatively late Lesions) can also be seen in cystically dilated
events in the presumed low-grade pathway acini and the lining cells may also show apical
(Verschuur-Maes et al. 2014). snouts. The cytoplasm of apocrine cells is more
eosinophilic and granular than that of columnar References

cell lesions, the apical snouts are usually quite
inconspicuous, and the nuclei of apocrine cells Acott, A. A., & Mancino, A. T. (2016). Flat epithelial
atypia on core needle biopsy, must we surgically
tend to be more round and to have a central prom-
excise? American Journal of Surgery, 212, 1211–1213.
inent nucleolus. Subtle, refractile calcium oxalate Ang, D. C., Warrick, A. L., Shilling, A., Beadling, C.,
crystals can be associated with apocrine metapla- Corless, C. L., & Troxell, M. L. (2014). Frequent
sia rather than the darker blue calcium phosphate phosphatidylinositol-3-kinase mutations in prolifera-
tive breast lesions. Modern Pathology, 27, 740–750.
seen with columnar cell lesions. Immunostaining
Aulmann, S., Elsawaf, Z., Penzel, R., Schirmacher, P., &
for both hormone receptors and Bcl-2 is usually Sinn, H. P. (2009). Invasive tubular carcinoma of the
negative in apocrine lesions. breast frequently is clonally related to flat epithelial
Cystic columnar cell lesions may contain lumi- atypia and low-grade ductal carcinoma in situ. The
American Journal of Surgical Pathology, 33,
nal mucin, and this may calcify and may be fine,
1646–1653.
granular, or more coarse. Rupture of such cysts Berry, J. S., Trappey, A. F., Vreeland, T. J., Pattyn, A. R.,
with mucin extravasation into the stroma creates a Clifton, G. T., Berry, E. A., et al. (2016). Analysis of
differential diagnosis with mucocele-like lesions clinical and pathologic factors of pure, flat epithelial
atypia on core needle biopsy to aid in the decision of
(▶ Mucocele-like Lesion). The distinction may be
excision or observation. Journal of Cancer, 7, 1–6.
difficult to make on a core biopsy. Bjorner, S., Fitzpatrick, P. A., Li, Y., Allred, C., Howell, A.,
Usual ductal hyperplasia (▶ Usual Ductal Ringberg, A., et al. (2014). Epithelial and stromal
Hyperplasia (UDH)) may be a consideration microRNA signatures of columnar cell hyperplasia
linking Let-7c to precancerous and cancerous breast
when a columnar cell lesion becomes more pro-
cancer cell proliferation. PLoS One, 9, e105099.
liferative, but this is not commonly a difficulty Boulos, F. I., Dupont, W. D., Simpson, J. F.,
because of the characteristic columnar shape of Schuyler, P. A., Sanders, M. E., Freudenthal, M. E.,
the cells on the one hand and the more heteroge- et al. (2008). Histologic associations and long-term
cancer risk in columnar cell lesions of the breast:
neous architectural features associated with usual
A retrospective cohort and a nested case-control
ductal hyperplasia on the other. As they are both study. Cancer, 113, 2415–2421.
benign lesions, differentiating the two does not Desouki, M. M., Li, Z., Hameed, O., Fadare, O., &
have practical consequences. Zhao, C. (2013). Incidental atypical proliferative
lesions in reduction mammoplasty specimens: Analysis
Distinguishing columnar cell change and
of 2498 cases from 2 tertiary women’s health centers.
columnar cell hyperplasia from FEA is the key Human Pathology, 44, 1877–1881.
consideration. Columnar cell hyperplasia shows a Moinfar, F. (2009). Flat ductal intraepithelial neoplasia of
relatively orderly multilayered stratification of the breast: A review of diagnostic criteria, differential
diagnoses, molecular-genetic findings, and clinical
cells; the lining cells in FEA tend to have fewer
relevance – it is time to appreciate the Azzopardi con-
layers and show a loss of polarization, including a cept! Archives of Pathology & Laboratory Medicine,
loss of the perpendicular orientation that charac- 133, 879–892.
terizes both columnar cell change and columnar Rosen, P. P. (1999). Columnar cell hyperplasia is associ-
ated with lobular carcinoma in situ and tubular carci-
cell hyperplasia. The affected gland spaces of
noma. American Journal of Surgical Pathology, 23,
FEA appear more rounded and rigidly distended, 1561.
and with a more basophilic appearance overall. Said, S. M., Visscher, D. W., Nassar, A., Frank, R. D.,
Monomorphic cytological atypia, with rounder Vierkant R. A., Frost, M. H. et al (2015). Flat epithelial
atypia and risk of breast cancer: A Mayo cohort study.
nuclei and perceptible nucleoli, is seen. Architec-
Cancer, 121, 1548–1555.
tural atypia, however, in the form of cellular brid- Schnitt, S., & Collins, L. (2009). Biopsy interpretation of
ges, arcades, punched out cribriform spaces, or the breast (1st ed., pp. 96–122). Philadelphia:
more structured micropapillae, together with Lippincott Williams and Wilkins.
Simpson, P. T., Gale, T., Reis-Filho, J. S., Jones, C.,
polarization of cells around these various forma-
Parry, S., Sloane, J. P., et al. (2005). Columnar cell
tions, indicates either atypical ductal hyperplasia lesions of the breast: The missing link in breast cancer
or low-grade ductal carcinoma in situ. Though, of progression? A morphological and molecular analysis.
course, both atypical ductal hyperplasia and FEA The American Journal of Surgical Pathology, 29,
734–746.
may coexist.
Complex Sclerosing Lesion 79
Troxell, M. L., Brunner, A. L., Neff, T., Warrick, A., variety of epithelial structures with a complex
Beadling, C., Montgomery, K., et al. (2012). pattern of growth, which can include intraductal
Phosphatidylinositol-3-kinase pathway mutations are
common in breast columnar cell lesions. Modern papillomas (▶ Intraductal Papilloma), sclerosing
Pathology, 25, 930–937. adenosis (▶ Sclerosing Adenosis), and usual-type
Verschuur-Maes, A. H., de Bruin, P. C., & van Diest, P. J. ductal hyperplasia (▶ Usual Ductal Hyperplasia
(2012a). Epigenetic progression of columnar cell (UDH)) (Racz et al. 2017; Ellis and Simpson
lesions of the breast to invasive breast cancer. Breast
Cancer Research and Treatment, 136, 705–715. 2012; Eusebi and Millis 2010; Kennedy C
Verschuur-Maes, A. H., van Deurzen, C. H., et al. 2003).
Monninkhof, E. M., & van Diest, P. J. (2012b). Colum-
nar cell lesions on breast needle biopsies: Is surgical
excision necessary? A systematic review. Annals of
Surgery, 255, 259–265. Clinical Features
Verschuur-Maes, A. H., Moelans, C. B., de Bruin, P. C., &
van Diest, P. J. (2014). Analysis of gene copy number Occasionally, CSLs may be palpable firm irregu-
alterations by multiplex ligation-dependent probe lar masses (Hicks and Lester 2017) or a radiolog-
amplification in columnar cell lesions of the breast.
Cellular Oncology (Dordrecht), 37, 147–154. ical finding of a mass with spiculated margins,
Yu, C. C., Ueng, S. H., Cheung, Y. C., Shen, S. C., but more commonly CSLs cause architectural dis-
Kuo, W. L., Tsai, H. P., et al. (2015). Predictors of tortion on imaging, frequently containing micro-
underestimation of malignancy after image-guided calcifications. These radiological patterns may be
core needle biopsy diagnosis of flat epithelial atypia
or atypical ductal hyperplasia. The Breast Journal, 21, indistinguishable from invasive carcinoma. On
224–232. ultrasound, CSL is seen as hypoechoic area or
mass and at Magnetic Resonance Imaging (MRI)
as an irregular enhancing lesion, usually with
lower enhancement than invasive carcinoma
Complex Sclerosing Lesion (Hicks and Lester 2017).
Anna Sapino1,2 and Davide Balmativola1 • Incidence

1
Unit of Pathology, Candiolo Cancer Institute Some authors suggest CSLs are not uncommon,
FPO-IRCCS, Candiolo, Italy being present in 14–28% of autopsy studies.
2
Department of Medical Sciences, However, the literature reports that only
University of Turin, Turin, Italy 0.03–0.09% of all diagnosis performed on core
needle biopsies are CSLs. The majority of
patients have multiple lesions and almost 50%
Synonyms have bilateral CSLs (Hicks and Lester 2017).
• Age
Complex papillary sclerosing lesion; Non- In analogy to radial scar, CSLs are lesions
encapsulated sclerosing lesion; Radial sclerosing mainly detected during screening (mean age
lesion; Scleroelastotic scar 50 years).
• Sex
CSLs are found in female breasts, but very
Definition occasionally CSL occurs in male breasts.
• Site
Complex Sclerosing Lesion (CSL) is a benign No specific site had been described as concerns
proliferation of the breast. While the term “radial laterality or quadrant of the breast.
scar” (RS) (▶ Radial Scar) is typically reserved • Treatment
for small lesions (<1 cm), the term “complex The management of radiologically detected
sclerosing lesion” refers to a larger scar lesion CSL is still controversial because the reported
(1 cm) characterized by fibroelastosis, sclerosis, incidence of malignancy on excisional speci-
and sclero-hyalinosis with entrapped ducts and a mens following a diagnosis of CSL/RS on core
80 Complex Sclerosing Lesion
needle biopsy (CNB) varies widely, between epitheliosis/usual type hyperplasia, apocrine
0% and 23% (Nakhlis et al. 2018). However, metaplasia, and sclerosing adenosis (Racz et al.
the majority of cancers associated with CSL 2017; Ellis and Simpson 2012). All these lesions
are small, well-differentiated invasive carci- may be associated with cytological atypia.
noma and low grade DCIS. On the other At low magnification, two different regions
hand, some authors suggest that CSLs are asso- can be identified, although not pathognomonic
ciated with considerable risk of finding breast of CSL:
carcinoma in adjacent tissue, prompting rec-
ommendation for excision (Kennedy et al. • Central nidus: It is formed by hyalinized col-
2003). In conclusion, if epithelial atypia is lagen stroma with elastosis entrapping and
present on CNB, excision is recommended distorting tubules (two cell layers are retained)
due to the risk of having malignancy associated (Fig. 1, H&E).
to the CSL. It is possible to proceed with • Corona: Sclero-hyalinized bands of connec-
observation when radiological and pathologi- tive tissue radiating from central nidus and
cal features agree on CSL diagnosed on containing distorted tubular structures, fre-
vacuum-assisted CNBs in the absence of quently pointed and of different size. These
other associated high risk lesions (Racz et al. bands dissect normal parenchyma and/or cystic
2017). CSLs diagnosed on excisional surgery lobules and/or lobular structures with various
specimens do not require additional treatment degrees of proliferation and atypia (Fig. 2,
(Patterson et al. 2004). H&E).
• Outcome
As above reported CSL itself is considered
a proliferative benign lesion which exhibits CSL frequently involves papillomas leading
various secondary alterations in the epithelium to the diagnosis of “complex papillary
and carries an approximately twofold sclerosing lesions” (CPSL). The sclero-
increased risk of breast cancer (Racz et al. hyalinazed tissue is predominant in such cases
2017). For this reason, CSLs are diagnosed as and areas of infiltrating epitheliosis (▶ Usual
“lesion of undetermined risk” on core biopsies. Ductal Hyperplasia (UDH)) may be frequently
seen. In some cases of CSL, multiple foci of
“adenosquamous proliferation” (ASP), often
Macroscopy
regarded as representing benign squamous meta-
plasia, are situated within the nidus and
At difference with radial scar, CSLs are generally
permeated between ducts beyond the corona
of sufficient size to produce an irregular firm
mass, of yellow-white color, indurated, some-
times with central retraction. The central core is
usually firmer than the area of radiating arms;
most lesions are <2 cm. The gross appearance
may be indistinguishable from that of an invasive
carcinoma (Ellis and Simpson 2012); neverthe-
less, CSLs are usually firm but not as hard as
invasive carcinomas.
Microscopy
CSLs are heterogeneous lesions, characterized

Complex Sclerosing Lesion, Fig. 1 Small tubules
by lobulocentric proliferations and varying are entrapped in sclero-elastotic stroma in the central
degrees of proliferative epithelial changes: cysts, nidus of a complex sclerosing lesion (H&E)
Complex Sclerosing Lesion 81
Complex Sclerosing Lesion, Fig. 4 Immunostaining for

Complex Sclerosing Lesion, Fig. 2 At the periphery of
Cytokeratins 5/6 shows positivity of luminal epithelial
the nidus are radial structures formed by sclero-hyalinized
cells in a focus of adenosquamous proliferation in a com-
stroma entrapping distorted tubular structures (H&E)
plex sclerosing lesion
low grade adenosquamous carcinoma (▶ Low-

Grade Adenosquamous Carcinoma), which are
not a rare event in CSL (Tan et al. 2015).
Immunophenotype
Immunostains for myoepithelial markers (e.g.,

p63 or p40, calponin, smooth muscle myosin
heavy chain, cytokeratin 5/6) may be helpful
to distinguish entrapped benign tubules from
a tubular carcinoma (▶ Tubular Carcinoma);
however, in areas of sclero-hyalinosis, the
myoepithelium may be very attenuated or even
undetectable (Fig. 3, Immunostaining for p63). In
analogy, basal cytokeratins (CK5/6, CK14) may
not be just expressed at the periphery by basal/
myoepithelial cells but also by luminal epithelial
cells, particularly in cases associated with ASP
(Fig. 4, Immunostaining for Cytokeratins 5/6).
Complex Sclerosing Lesion, Fig. 3 Immunostaining

for p63 stains nuclei of myoepithelial cells. In some tubules Molecular Features
only rare nuclei are evident
No specific molecular genetics of CSL have been
of the CSL, with reactive hypercellular stroma. described (Ellis and Simpson 2012).
ASP may be related to infarction in the instance PIK3CA mutations are present in 50–75% of
of papilloma or following previous fine needle- sclerosing lesions (Wilsher et al. 2017). The muta-
or CNBs (Wilsher et al. 2017). These ASPs tion is a hallmark of ASP in CSL (Wilsher et al.
have been considered as precursors of 2017). Evidence suggests that radial scar/complex
metaplastic carcinoma (▶ Invasive Metaplastic sclerosing lesions, sclerosing papilloma or similar
Carcinoma) (Denley et al. 2000), in particular lesions, are phenotypically similar to low-grade
82 Complex Sclerosing Lesion
adenosquamous carcinoma (▶ Low-Grade (2000). Metaplastic carcinoma of the breast arising

Adenosquamous Carcinoma); their distinction is within complex sclerosing lesion: A report of fivecases.
Histopathology, 36, 203–209.
often subjective and is poorly defined in Ellis, I. O., & Simpson, J. F. (2012). Radial scar and
the literature. complex sclerosing lesion. In S. R. Lakhani (Ed.),
WHO classification of tumors of the breast
(pp. 114–115). Lyon: IARC Press.
Eusebi, V., & Millis, R. R. (2010). Epitheliosis, infiltrating
Differential Diagnosis epitheliosis, and radial scar. Seminar in Diagnostic
Pathology, 27, 5–12.
On core biopsy, it may be difficult to distinguish Gobbi, H., Simpson, J. F., Jensen, R. A., Olson, S. J., & Page,
the distorted glandular structures of CSL from D. L. (2003). Metaplastic spindle cell breast tumors aris-
ing within papillomas, complex sclerosing lesions, and
invasive carcinoma. Therefore, biopsies should nipple adenomas. Modern Pathology, 16, 893–901.
be reported with caution, using phrasing as “con- Hicks, D. G., & Lester, S. C. (2017). Diagnostic pathology:
sistent with radial scar/complex sclerosing Breast (2nd ed.). Philadelphia: Elsevier.
lesion,” also considering the frequency of addi- Ho, B. C., Tan, H. W., Lee, V. K., & Tan, P. H. (2006).
Preoperative and intraoperative diagnosis of low-grade
tional pathology on excision. The differential adenosquamous carcinoma of the breast: Potential
diagnosis with tubular carcinoma (▶ Tubular diagnostic pitfalls. Histopathology, 49, 603–611.
Carcinoma) has already been considered in the Kennedy, M., Masterson, A. V., Kerin, M., & Flanagan, F.
chapter “radial scar” (▶ Radial Scar) demonstra- (2003). Pathology and clinical relevance of radial scars:
A review. Journal of Clinical Pathology, 56, 721–724.
tion of myoepithelial cells by immunohistochem- Nakhlis, F., Lester, S., Denison, C., Wong, S. M.,
istry is useful. Mongiu, A., & Golshan, M. (2018). Complex scleros-
Gobbi et al. (2003) showed that distinction ing lesions and radial sclerosing lesions on core needle
from metaplastic carcinomas (▶ Invasive Meta- biopsy: Low risk of carcinoma on excision in cases
with clinical and imaging concordance. Breast Journal,
plastic Carcinoma) arising in radial sclerosing 24, 133–138.
lesions (RS, CSL, CPSL) and “pseudoinfiltrative Patterson, J. A., Scott, M., Anderson, N., & Kirk, S. J.
glands” is often difficult and stressed that “to (2004). Radial scar, complex sclerosing lesion and risk
avoid overdiagnosis of malignancy in the reac- of breast cancer. Analysis of 175 cases in Northern
Ireland. European Journal of Surgical Oncology, 30,
tive process, the lesion should present increased 1065–1068.
cellularity and clumps of cytokeratin Racz, J. M., Carter, J. M., & Degnim, A. C. (2017).
positive plump spindle cells, besides the ‘reac- Challenging atypical breast lesions including flat epi-
tive’ spindle cells and squamous elements”. It thelial atypia, radial scar, and Intraductal papilloma.
Annals of Surgical Oncology, 24, 2842–2847.
has also been stated that ductules of radial scars Tan, Q. T., Chuwa, E. W., Chew, S. H., Lim-Tan, S. K., &
do not display a syringoid appearance Lim, S. H. (2015). Low-grade adenosquamous carci-
(Ho et al. 2006). noma of the breast: A diagnostic and clinical challenge.
International Journal of Surgery, 19, 22–26.
Wilsher, M. J., Owens, T. W., & Allcock, R. J. (2017).
Next generation sequencing of the nidus of early
References and Further Reading (adenosquamous proliferation rich) radial sclerosing
lesions of the breast reveals evidence for a neoplastic
Denley, H., Pinder, S. E., Tan, P. H., Sim, C. S., Brown, R., precursor lesion. Journal of Pathology: Clinical
Barker, T., Gearty, J., Elston, C. W., & Ellis, I. O. Research, 3, 115–122.
D
Diabetic Mastopathy reported tumor-like lumps in the breast, which

clinically mimicked carcinoma, but on histology,
Savelina Popovska1,2, Ivan Ivanov2 and the lesion proved benign (Soler and Khardori
Vincenzo Eusebi3 1984).
1
University of Pleven, Pleven, Bulgaria The term “diabetic mastopathy” was intro-
2
Department of Pathology, Medical University, duced by Byrd et al., who described the presence
Pleven, Bulgaria of stromal fibrosis and perivascular lymphocytic
3
Department of Pathology, University of infiltrates (Byrd et al. 1987). The histology of the
Bologna, Bologna, Italy lesion was illustrated in 1990 (Foschini et al.
1990) and the presence of a lymphocytic lobulitis
was emphasized.
Synonyms The changes are nonspecific, and mammary
lesions with similar features had been reported in
Diabetic mastopathy; Lymphocytic mastitis; Scle- nondiabetic patients. A large number of patients,
rosing lymphocytic lobulitis who present with DMP, however, suffer from
autoimmune diseases. Thus, this same lesion
was also designated as sclerosing lymphocytic
Definition lobulitis (Weidner and Dabbs 2012).
The pathogenesis of DMP is not fully under-
Diabetic Mastopathy (DMP), also known as lym- stood. According to one of the most widely
phocytic mastitis or sclerosing lymphocytic accepted theories, DMP is an autoimmune pro-
lobulitis, is a relatively rare, fibro-inflammatory cess, comparable to those seen in other organs.
complication of diabetes mellitus (DM) (insulin- Other theories suggest that DMP is consequent
dependent diabetes of early onset and long dura- to insulin supplementation. Still others claim
tion), Hashimoto thyroiditis, Sjogren’s disease, that it may occur as a result of the alteration
and other autoimmune disorders (Weidner and of collagen metabolism and change in its
Dabbs 2012). Soler and Khardori were the first structural and antigenic properties in the context
to describe the entity in 1984. They reported of hyperglycemia (Soler and Khardori 1984;
12 cases of DMP in a group of female patients, Tomaszewski et al. 1992). The most widely
aged 25–40 years, with type I DM of 8–30 years accepted pathogenesis is related to autoimmu-
from onset. The complications registered included nity because DMP is often combined with auto-
limited mobility of the small joints of the hand, immune disorders of the thyroid gland (Weidner
and neuro-, retino-, and nephropathy. The authors and Dabbs 2012).
https://doi.org/10.1007/978-3-319-62539-3
84 Diabetic Mastopathy
It is assumed that key factors for the develop- • Site

ment of DMP are the nonenzymatic glycation of No specific sites are described.
proteins, caused by long persisting hyperglyce- • Treatment
mia (nonenzymatically glycosylated proteins) DMP is a lesion, which may cause diagnostic
and the formation of advanced glycosylation difficulties in clinical practice, because of its
end products in cases of long-term diabetes. clinical presentation and imaging, which
The glycated proteins form intermolecular sometimes resemble malignant conditions
cross-linking products that are not easily degrad- (Foschini et al. 1990; Weidner and
able and are deposited in the breast stroma. Dabbs 2012). After the histological diagnosis
Changes in the end products and the deposits of DMP, regular ultrasound and mammogra-
of modified matrix in the breast stroma are phy follow-up examination is the wisest
immunogenic and are identified as neoantigens. approach.
These cause a secondary humoral response by • Outcome
activation of antibody-producing B lympho- DMP is usually associated with a favorable
cytes. This local immune response, including prognosis, and spontaneous regression of the
the activation of macrophages, leads to lympho- lesion is possible. Recurrences after surgical
kine secretion and subsequent impairment of treatment may occur in some of the cases
the lobular and ductal epithelium. Lymphokines, (Weidner and Dabbs 2012).
in turn, act as a growth factor in activation of Due to the high incidence of relapses, sur-
fibroblasts and increased collagen production gery is not considered effective in the treatment
(Camuto et al. 2000). of DMP. In clinically and morphologically ver-
ified cases of DMP, any conservative treatment
is advisable.
Clinical Features
• Incidence Macroscopy
DMP accounts for approximately 1% of
benign lesions of the breast (Foschini et al. Diagnosis of DMP is a challenge for both
1990). It is usually associated with type clinicians and radiographers. On mammography,
I DM but it can also be seen, though rarely, the lesion is not well-delineated, with heter-
in type II DM patients (Weidner and Dabbs ogeneous density and no calcifications. It may
2012). be a focally asymmetric mass or a well-
• Age circumscribed nodule resembling a
The average age of female patients with DM, fibroadenoma. Some cases can be interpreted as
suffering from DMP varies between 34 and a carcinoma. All these characteristics make the
47 years. In most of the DM-associated cases, findings rather unspecific (Rosen 2009; Weidner
the interval between DM onset and its clinical and Dabbs 2012).
presentation of DMP is approximately 20 years Ultrasound examination may be a helpful diag-
(Rosen 2009). Long-term insulin-dependent nostic method in DMP cases. It is also useful in
DM and premenopause are considered to be core-needle biopsy diagnosis and follow-up of
among the main predisposing factors for the patients (Rosen 2009).
development of DMP in females (Weidner and The hyperdensity seen in DMP can also cause
Dabbs 2012). difficulties in distinguishing DPM from breast
• Sex carcinoma. In such cases, MRI is a reliable tech-
The changes manifest mostly in female nique for diagnosing malignant neoplastic lesions
patients. Single cases have been reported in (Rosen 2009).
male patients with insulin-dependent DM At macroscopy, DMP usually presents as pal-
(Lee et al. 1996; Rosen 2009). pable, mobile lump, firm on palpation, with gray-
Diabetic Mastopathy 85
white surface. Lumps are irregular in shape, with stroma (Fig. 4a, b). These same cells were
no distinct borders between the lesion and the interpreted as epithelioid fibroblasts and first
surrounding healthy tissue. Occasionally, DMP reported by Tomaszewski et al. (1992) and are
may present as a tumor-like lesion (Foschini seen in about 75% of the cases.
et al. 1990; Weidner and Dabbs 2012). Though rare, there are cases of DMP showing
necrosis and granuloma formation (Weidner and
Dabbs 2012). The histological findings in DMP
Microscopy in male patients share many similarities with the
findings seen in women. Morphologically, DMP D
Histologically, DMP is characterized by presence in the male breast is characterized by lympho-
of spindle to epithelioid myofibroblasts within a cytic periductitis, perivasculitis, dense fibrotic
collagenized frequently dense stroma. In addition, stroma, and epithelioid myofibroblasts (Lee
the main features of the lesion include circumfer- et al. 1996).
ential intralobular, periductal, and perivascular
B type lymphocyte infiltration. The intralobular
lymphocytic reaction is frequently very intense
and shows neat borders, as seen at low power, a
feature often very indicative of the disease. Duct-
ules are consistently atrophic and show thick basal
lamina. (Foschini et al. 1990; Tomaszewski et al.
1992) (Figs. 1, 2, and 3). The stroma varies from
loose to dense. It lacks inflammatory cells. Never-
theless, in the stroma, cells with round to elon-
gated nuclei, evident nucleoli, and abundant
amphophilic cytoplasm are present. These cells
are sparse or can be clumped in nests within the
Diabetic Mastopathy, Fig. 2 Dense lymphoid infiltrate

is located within the lobular stroma. Some ductules are
atrophic (H&E)
Diabetic Mastopathy, Fig. 1 A lobule is typically filled

by a dense lymphoid infiltrate. Ductules are mostly atro- Diabetic Mastopathy, Fig. 3 The cells present in the
phic and difficult to see at low magnification. The inflam- lobular stroma are constituted by lymphocytes and plasma
matory reaction shows neat peripheral borders (H&E) cells. Ductules show thick basal lamina (H&E)
86 Diabetic Mastopathy
Diabetic Mastopathy, Fig. 4 (H&E) (a) Sclerohyaline (b) Hyaline fibrous tissue with sparse fibroblasts showing
acellular fibrous tissue centered by a clump of epithelioid abundant cytoplasm. The nuclei are irregular and may
fibroblasts showing ovoid nuclei and well visible nucleoli. simulate neoplastic cells
Diabetic Mastopathy, Table 1 Histopathological char- Diabetic Mastopathy, Table 2 Immunohistochemical

acteristics of DMP findings in DMP
Inflammation The inflammatory infiltrate is constituted predominantly
Lymphocytic infiltrates are composed of mature by mature B lymphocytes (CD20 – positive), that are
lymphocytes, do not form follicles, and do not infiltrate polyclonal and express light chain immunoglobulin
the epithelium HLA-DR antigen is expressed in the lobular epithelium
Lobulo-centric inflammation together with periductitis Epithelioid fibroblasts are positive for CD 34 and actin
and perilobulitis and are negative for keratins
Lymphocytic vasculitis
Fibrosis
Involutional changes in lobules with thick basal lamina
(sclerotic lobulitis) cytometry have demonstrated that the proliferation
Loose to dense, collagenized stroma of mature B lymphocytes is not clonal and is not
Epitheloid fibroblasts related to increased risk for the development of lym-
Proliferation of epithelioid fibroblasts with irregular phoma. The expression of HLA-DR3, 4, or 5 in the
often pleomorphic nuclei epithelial cells of the affected lobular units may also
be observed. The presence of HLA-DR phenotype,
related to increased risk of autoimmune diseases and
Immunophenotype the findings of circulating autoantibodies in DMP
patients is probative for the autoimmune pathogene-
IHC staining is recommended in all cases of DMP. sis of the condition (Lammie et al. 1991).
Usually, the epithelioid fibroblasts express CD
34, actin (and occasionally CD68) and are negative
for all keratins, S100, desmin, factor VIII, CD45, Molecular Features
and CD20 (Weidner and Dabbs 2012). Immunophe-
notyping of the inflammatory infiltrates demon- So far, specific molecular studies are not available.
strates that these are predominantly composed of
polyclonal B lymphocytes. The inflammatory infil-
trates consist of small B lymphocytes with no signs Differential Diagnosis
of atypia, expressing light chain immunoglobulins
(Weidner and Dabbs 2012). Immunophenotyping DMP requires exclusion of several pathological
based on immunohistochemistry (IHC) and flow conditions, affecting the breast. Among these are
Duct Ectasia and Periductal Mastitis 87
granulomatous mastitis (▶ Granulomatous Mas-

titis), sclerotic lipogranuloma, vasculitis, lupus Duct Ectasia and Periductal
panniculitis, rheumatoid nodules, and infarction Mastitis
(▶ Infarct of Breast Tissue). The abundance of
inflammatory cell infiltrates and epithelioid Isabel Amendoeira1,2 and Margarida Sá Fernandes1
1
(myo)fibroblasts with pleomorphic nuclei often Centro Hospitalar de São João (CHSJ), Porto,
requires the lesion to be differentiated from an Portugal
2
invasive carcinoma (Weidner and Dabbs 2012). IPATIMUP - Instituto de Patologia e Imunologia
Because of the wide spectrum of differential Molecular da Universidade do Porto, Porto, D
diagnoses and different etiology of DMP, a thor- Portugal
ough examination of every single case is
required in terms of its morphological and
immunohistochemical characteristics and their Synonyms
correspondence to the established diagnostic
criteria. Mastitis obliterans; Periductal mastitis (PDM);
The histopathological and IHC character- Plasmacell mastitis
istics of DMP are presented on Tables 1 and 2.
Definition
References and Further Reading Periductal mastitis (PDM)/Duct ectasia (DE) is a

common benign breast condition mostly seen in
Byrd, B. F., Hartman, W. H., Graham, L. S., & Hogle, H. H. women. It is still debatable whether they are two
(1987). Mastopathy in insulin-dependent diabetics. clinical and pathological entities, which affect
Annals of Surgery, 205, 529–532.
Camuto, P. M., Zetrenne, E., & Ponn, T. (2000). Diabetic different age groups and have different etiologies
mastopathy. A report of 5 cases and a review of the or if PDM and DE are part of the same disease
literature. Archives of Surgery, 135, 1190–1193. process, PDM preceding DE.
Foschini, M. P., Cavazza, A., Macedo Pinto, I. M., & PDM/DE affects larger ducts and is character-
Eusebi, V. (1990). Diabetic fibrous mastopathy. Report
of two cases. Virchows Archiv. A, Pathological ized by duct dilatation, periductal inflammation,
Anatomy and Histopathology, 417(6), 529–532. and fibrosis.
Lammie, G. A., Bobrow, L. G., Staunton, M. D.,
Levison, D. A., Page, G., & Millis, R. R. (1991).
Sclerosing lymphocytic lobulitis of the breast – Clinical Features
Evidence for an autoimmune pathogenesis.
Histopathology, 19(1), 13–20. • Incidence
Lee, A. H. S., Zafrani, B., Kafiri, G., Rozan, S., & Millis, R. R.
(1996). Sclerosing lymphocytic lobulitis in the male DE represents an incidental finding in about
breast. Journal of Clinical Pathology, 49, 609–611. 8% of patients undergoing breast surgery.
Rosen, P. P. (2009). Inflammatory and reactive tumors. In • Age
P. P. Rosen (Ed.), Rosen’s breast pathology (3rd ed., PDM/DE occurs most frequently in women
pp. 33–70). Philadelphia: Lippincott Williams &
Wilkins. between the age 30 and 70 years. In infancy
Soler, N. G., & Khardori, R. (1984). Fibrous disease of the (average age is 38 months) and childhood, bleed-
breast, thyroiditis, and cheiroarthropathy in type ing is the most common presenting symptom and
I diabetes mellitus. Lancet, 1(8370), 193–195. the male:female ratio is 10:4, in contrast to adult
Tomaszewski, J. E., Brooks, J. S., Hicks, D., &
Livolsi, V. A. (1992). Diabetic mastopathy: population, probably representing a developmen-
A distinctive clinicopathologic entity. Human tal abnormality (McHoney et al. 2011).
Pathology, 23, 780–786. • Sex
Weidner, N., & Dabbs, D. J. (2012). Reactive and More frequent in women. It is very rare in men
inflammatory conditions of the breast. In D. J.
Dabbs (Ed.), Breast pathology (pp. 22–33). Philadel- as well as in infancy and childhood (O’Malley
phia: Saunders. and Pinder 2011).
88 Duct Ectasia and Periductal Mastitis
• Site
Major ducts. May be bilateral.
• Treatment
PDM/DE is a benign lesion with no increased
risk of malignancy. Excision biopsy should be
curative, although not always recommended.
Recurrence is not common (Dabbs 2016).
• Outcome
Although it may be asymptomatic, spontane-
ous and intermittent nipple discharge (clear,
yellow, green, or brown), pain, mass, and Duct Ectasia and Periductal Mastitis, Fig. 1 Gross.
edematous skin changes are described as the
first symptoms and are seen in younger
patients. In a later stage, duct dilatation, nipple 2017). The ductal epithelium is often thin and
retraction, and periductal fibrosis are seen more may be disrupted by inflammatory cells and mac-
preferentially in older patients (Dixon et al. rophages (Fig. 2) (O’Malley and Pinder 2011).
1983, 1996). Periductal inflammatory infiltrate, predominantly
Ulceration of the skin, abscess, and fistulas lymphocytes, and fibrosis are also
may occur and are often described at a later characteristic. Granulomatous inflammation with
stage and can mimic a carcinoma (Moinfar giant cells can occur (O’Malley and Pinder 2011).
2007). Although the inflammatory process is centered in
Mammography abnormalities include large major ducts, it can extend to the peripheral lob-
rod-like branching calcifications, usually ules. Lymphocytic infiltrate in lobules without
>1 mm, with lucent centers. Calcifications granulomas can be seen (Rosen et al. 2014). Stasis
are usually widespread, bilateral, and radially material can be discharged in stroma by disruption
oriented to the nipple-areolar complex of the ducts and cause inflammation and abscess
(Kamal et al. 2009). Lobulated smooth nod- formation (Rosen et al. 2014).
ules or spiculated masses suggesting carci- Duct content is often varied: granular amor-
noma have been described as well (Rosen phous, proteinaceous material admixed with
et al. 2014). foam-cells and desquamated duct epithelial cells.
Histiocytic reaction around cholesterol crystals
can be identified (Rosen et al. 2014).
Macroscopy
The thick layer of hyaline and elastic tissue in a
later stage can encase ducts and in some cases the
The most characteristic alteration in the mammary
lumen becomes totally obliterated by granulation
specimen is the presence of dilated subareolar
tissue – the so called “mastitis obliterans.” Within
ducts; depending on duct contents, cream-
the sclerotic duct, the persisting epithelium may
colored, soft or brown, different kinds of secretion
proliferate forming secondary glands, a pattern
can be observed (Fig. 1 gross appearance:
that resembles a recanalized thrombus in a blood
enlarged ducts are converging toward nipple).
vessel (Rosen et al. 2014).
Microscopy Immunophenotype
The hallmark of PDM/DE is the presence of three No specific variation of immunophenotypes

or more dilated ducts with luminal material and is described. The origin of foamy cells is contro-
foamy macrophages, periductal inflammation, versial and three types have been described:
fibrosis, and hyperelastosis (Ramalingam et al. epithelial derived (expressing cytokeratins and
Duct Ectasia and Periductal Mastitis 89
Duct Ectasia and Periductal Mastitis, Fig. 2 (H&E) Histiocytes and lymphocytes disrupt the duct epithelium
(Left (400x)); The lumen of the dilated duct is filled with granular, amorphous, eosinophilic material (right (100x))
epithelial membrane antigen); histiocytic-like References and Further Reading

(expressing CD68 and MAC387); cells with inter-
mediate features with immunoreactivity for CD68 Dabbs, D. (2016). Breast pathology (2nd ed.). Philadel-
phia, PA: Elsevier [2017].
and GCDFP-15 (Damiani et al. 1998).
Damiani, S., Cattani, M., Buonamici, L., & Eusebi, V. (1998).
Mammary foam cells. Virchows Archiv, 432, 433–440.
Dixon, J., Anderson, T., Lumsden, A., Elton, R., Roberts,
Molecular Features M., & Forrest, A. (1983). Mammary duct ectasia. Brit-
ish Journal of Surgery, 70, 601–603.
Dixon, J., Ravisekar, O., Chetty, U., & Anderson,
No important studies are available. T. (1996). Periductal mastitis and duct ectasia: Differ-
ent conditions with different aetiologies. British Jour-
nal of Surgery, 83, 820–822.
Kamal, R., Hamed, S., & Salem, D. (2009). Classification
Differential Diagnosis of inflammatory breast disorders and step by step diag-
nosis. The Breast Journal, 15, 367–380.
Although clinical features and mammography can Liu, L., Zhou, F., Wang, P., Yu, L., Ma, Z., Li, Y., Gao, D.,
raise problems of differential diagnosis with car- Zhang, Q., Li, L., & Yu, Z. (2017). Periductal mastitis:
An inflammatory disease related to bacterial infection
cinoma, pathologic diagnosis is usually
and consequent immune responses? Mediators of
straightforward. Inflammation, 2017, 5309081.
Differential diagnosis should include cysts, McHoney, M., Munro, F., & MacKinlay, G. (2011). Mammary
fibrocystic changes (▶ Fibrocystic Breast duct ectasia in children: Report of a short series and review
of the literature. Early Human Development, 87, 527–530.
Changes), and diabetic sclerosing lymphocytic
Moinfar, F. (2007). Essentials of diagnostic breast pathol-
lobulitis (▶ Diabetic Mastopathy). Lobular cysts ogy. Berlin: Springer.
are round with no inflammation, no fibrosis, and O’Malley, F., & Pinder, S. (2011). Breast pathology
no elastic tissue around the wall (O’Malley and (2nd ed.). Edinburgh: Churchill Livingstone/Elsevier.
Ramalingam, K., Vuthaluru, S., Srivastava, A., Dinda, A.,
Pinder 2011); fibrocystic changes are character-
& Dhar, A. (2017). Ultra structural changes occurring
ized by cysts frequently with apocrine metapla- in duct ectasia and periductal mastitis and their signif-
sia and apocrine hyperplasia, usual epithelial icance in etiopathogenesis. PLoS One, 12, e0173216.
hyperplasia and stromal fibrosis; diabetic scle- Rosen, P., Hoda, S., Brogi, E., & Koerner, F. (2014).
Rosen’s breast pathology (4th ed.). Philadelphia:
rosing lymphocytic lobulitis is thought to be an
Wolters Kluwer Health/Lippincott Williams & Wilkins.
autoimmune disease, perilobular and peri- Sweeney, D., & Wylie, E. (1995). Mammographic appear-
vascular lymphocytic infiltrate, lobular atrophy, ances of mammary duct ectasia that mimic carcinoma
and fibrosis being the main features (Dabbs in a screening programme. Australasian Radiology, 39,
18–23.
2016).
90 Ductal Adenoma
• Site
Ductal Adenoma Mostly unilateral, in the form of single or mul-
tiple nodules. Bilaterality has been reported in
Handan Kaya patients with Carney Syndrome (Carney and
Pathology Department, Marmara University, Stratakis 1996; Carney and Toorkey 1991)
Istanbul, Turkey • Symptoms and Treatment
Ductal adenoma may present as a palpable
mass or sometimes with nipple discharge.
Synonyms On mammography, it is a well-delineated
nodule, with smooth margins with or
Sclerosing Papilloma is used as a synonym in without coarse calcifications; ultrasonography
WHO 2012 (Foschini et al. 2012). may exhibit hypoechoic structure, sometimes
located within a cyst and MR imaging shows
smooth and clear margins (Matsubayashi et al.
Definition 2016). Excision is curative.
• Outcome
Solid benign tumor of the breast ducts, involving Benign lesion with no reported tendency to
small or medium size ducts described by recurrence.
Azzopardi and Salm (Azzopardi and Salm
1984). These lesions may rarely arise from large-
Macroscopy
sized ducts (Lammie and Millis 1989).
The typical gross appearance is well-
circumscribed, round nodule(s). Macroscopically,
Clinical Features
the lesions’ size varies from 0.5 cm to 4.0 cm. The
cut surface is greyish-white and may be gritty.
• Incidence
It is an uncommon disease.
• Age Microscopy
It is most frequently seen in women over
50 years. Microscopically these lesions are typically
• Sex located in the lumen of a duct demonstrating
Female single or multiple adenomatous nodules
Ductal Adenoma,
Fig. 1 Dilated duct
showing in intraductal
adenomatous growth with
areas of poorly cellular
connective tissue (H&E)
Ductal Carcinoma In Situ 91
composed of ductal epithelial and myoepithelial and complex sclerosing lesions (▶ Complex Scle-
cells surrounding a central scar (Fig. 1). Charac- rosing Lesion). Although sometimes it is not pos-
teristically, they are circumscribed by a thick layer sible to make a differential diagnosis,
of hyalinized fibrosis which often contains demonstrating only small foci of papillary growth
elastic fibers derived from the original ducts. pattern by examining multiple section levels
Hyalinized fibrosis with entrapped tubules, favors ductal adenoma diagnosis.
epithelial atypia, and pseudoinvasion pattern
may mimic malignancy. Demonstration of base-
ment membrane, dual cell population with epithe-
References and Further Reading D
lial and myoepithelial cells forming the tubules Azzopardi, J. G., & Salm, R. (1984). Ductal adenoma of
can be helpful in differential diagnosis. Myxoid the breast: A lesion which can mimic carcinoma.
change, calcifications, and infarction can be Journal of Pathology, 144, 15–23. https://doi.org/
10.1002/path.1711440103.
encountered. More than half of the reported
Carney, J. A., & Stratakis, C. A. (1996). Ductal adenoma
cases showed apocrine differentiation; squamous of the breast and the Carney complex. American Jour-
metaplasia has also been described. nal of Surgical Pathology, 20, 1154–1155.
Carney, J. A., & Toorkey, B. C. (1991). Ductal adenoma
of the breast with tubular features. A probable compo-
nent of the complex of myxomas, spotty pigmentation,
Immunophenotype endocrine overactivity, and schwannomas. American
Journal of Surgical Pathology, 15, 722–731.
Epithelial, myoepithelial, and basal membrane Foschini, M., Simpson, J., & O’Malley, F. (2012). Ductal
markers are expressed as in normal structures. adenoma. In S. Lakhani, I. Ellis, S. Schnitt, P. Tan, &
M. Van de Vijyer (Eds.), WHO classification of tumors
of the breast (pp. 117–118). Lyon: IARC.
Lammie, G. A., & Millis, R. R. (1989). Ductal adenoma
Molecular Features of the breast – A review of fifteen cases. Human Pathol-
ogy, 20, 903–908.
Matsubayashi, R. N., Momosaki, S., & Muranaka, T.
Molecular basis of these tumors is unknown. Next (2016). Ductal adenoma of breast: imaging characteris-
generation sequencing of 50 cancer-related genes tics and radiologic-pathologic correlation of unique find-
and Sanger sequencing analysis of nine ductal ings which reflect “pseudoinvasion”. Breast Cancer, 23,
597–606. https://doi.org/10.1007/s12282-015-0608-9.
adenomas showed 56% (5/9) harboring mutated
Troxell, M. L., Levine, J., Beadling, C., Warrick, A., Dunlap,
genes and from those 30% demonstrated mutant J., Presnell, A., Patterson, J., Shukla, A., Olson, N. R.,
AKT1 and 22% (3/9) an additional GNAS muta- Heinrich, M. C., & Corless, C. L. (2010). High preva-
tion, 11% (1/9) had mutant PIK3CA. AKT lence of PIK3CA/AKT pathway mutations in papillary
neoplasms of the breast. Modern Pathology, 23, 27.
1 E17 K mutations demonstrated in breast papil-
lomas without atypia supports the relation
between sclerosing intraductal papillomas and
ductal adenomas (Troxell et al. 2010). Ductal Carcinoma In Situ
Isabella Castellano1 and Jasna Metovic2

1
Differential Diagnosis Department of Medical Sciences, University of
Turin, Turin, Italy
2
Duct ectasia, cyst, and epithelial hyperplasia Department of Oncology, University of Turin,
can be seen and dominant myoepithelial cell Turin, Italy
proliferation may lead to misdiagnosis of
adenomyoepithelioma (▶ Adenomyoepitheli-
oma) (Azzopardi and Salm 1984; Carney and Synonyms
Toorkey 1991). Ductal adenomas presenting stro-
mal proliferation and fibrosis associated with the Ductal intraepithelial neoplasia; Intraductal carci-
distortion of tubular structures show an overlap noma; Noninvasive ductal breast cancer; Pre-
with sclerosing adenosis (▶ Sclerosing Adenosis) invasive breast cancer
92 Ductal Carcinoma In Situ
Definition • Site
The anatomic location of DCIS is similar to
Ductal carcinoma in situ (DCIS) is a neoplastic invasive carcinoma location. The majority
proliferation confined to the mammary ductal- of tumors are found in the upper outer quad-
lobular system, which is surrounded by a rant (43.9%), followed by the upper inner
myoepithelial layer and a basal membrane. DCIS quadrant (9.0%), the central quadrant
covers a heterogeneous group of diseases charac- (8.5%), the lower outer quadrant (8.1%), and
terized by subtle to marked cytological atypia, finally the lower inner quadrant (6.9%)
without any invasion of the stromal tissue (Ernster et al. 2000).
(Lakhani et al. 2012). In a study by Verkooijen et al. (2002), 35%
of DCIS were present in two different quad-
rants. Multi-quadrant presentation is often
Clinical Features observed, especially in micropapillary DCIS
(Bellamy et al. 1993).
• Incidence • Treatment
DCIS incidence gradually and constantly Surgery: over the past 20 years, the surgical
increased over the past decades (from 5.8 approach of DCIS changed from radical mastec-
per 100,000 women in 1975 to 34.4 per tomy with sentinel node (▶ Sentinel Node) to
100,000 women in 2014), according to data conservative surgery, without any intervention
of the National Cancer Institute’s Surveil- on axilla, as recommended by ASCO (Lyman
lance, Epidemiology, and End Results Pro- et al. 2014) and NCCN guidelines (2015)).
gram (SEER 2014). DCIS consequently Some studies suggest that low-grade lesions can
constitutes around 20% of all breast cancer be treated only with surgical excision excluding
diagnoses. radiotherapy (EORTC Breast Cancer Coopera-
The widespread use of mammography, as tive Group et al. 2006), while others reported
well as implementation of national breast that being often multicentric, low-grade DCIS
screening programs (Ernster and Barclay may recur and it may remain radiologically
1997), contributed to the diagnosis of breast silent, even if extensive (Tot and Gere 2008).
cancer in early stage. According to different Mastectomy with immediate breast recon-
studies, approximately 1 in every 1300 screen- struction is used for large/diffuse DCIS, in case
ing mammography leads to a diagnosis of of contralateral prophylactic mastectomy
DCIS (Ernster et al. 2002). (Rutter et al. 2015), especially in younger
• Age women, as well as in patients with BRCA
DCIS rarely occurs in women younger than mutations or with positive family history for
40 years, and its incidence rises between ovarian cancer (Elsayegh et al. 2014). The
40 and 70 years, with a plateau after the age main feature that guides surgical approach is
of 70. the lesion size, measured with mammography
• Sex and magnetic resonance (MR). In case of con-
DCIS is common in women. However, servative approach, the margins should be free
according to SEER database, DCIS represents of disease with a minimum recommended dis-
9.4% of all male breast carcinomas (Anderson tance of 2 mm (Pilewskie and Morrow 2018).
and Devesa 2005) with an average age of Very recently three multi-institutional, random-
62 years. Although all DCIS subtypes could ized phase III trials are addressed to avoid sur-
be present in both genders, in general, papillary gery in case of low-grade DCIS, in favor of an
in situ (▶ Intraductal Papillary Carcinoma) active surveillance strategy (Elshof et al. 2015;
lesions are more common in men (Staerkle COMET trial- https://clinicaltrials.gov/ct2/show/
et al. 2006). NCT02926911; Francis et al. 2015).
Radiotherapy: conservative surgery is gen- radiation were 73% and 78%, respectively
erally associated with postsurgical radiother- (Kong et al. 2014). The presence of comedo-
apy, regardless of DCIS histology. necrosis is closely related to the risk of ipsilat-
Randomized trials have proven that RT reduces eral recurrences following lumpectomy, and a
local recurrence rates by 50% (McCormick meta-analysis demonstrated that this risk
et al. 2015; EORTC Breast Cancer Cooperative ranges from 1.3 to 5.0 (Wapnir et al. 2011;
Group et al. 2006); however, many studies are Wai et al. 2011).
now addressed to avoid radiation in low-risk Observational studies reported that about
DCIS. Several trials have been performed 14–50% of DCIS may progress to invasive D
using the multigene assay, Oncotype DX ® carcinomas (King et al. 2017; Erbas et al.
(Genentech, Houston, TX), able to quantify 2006; Pluchinotta 2018). Many evidences
the 10-year risk of local recurrences, both for suggested that the majority of invasive carci-
in situ and invasive breast cancer. The results noma may derive from DCIS disease. Actually,
are reported as a numerical score called “DCIS invasive cancers are generally accompanied by
Score,” which classifies patients into low-, DCIS, which share similar molecular features.
intermediate-, and high-risk group. It has However, a high number of DCIS was found in
been proposed to avoid radiotherapy in low- autopsy studies, to emphasize that not all DCIS
risk categories (Solin et al. 2013). will progress to invasive cancer (Pluchinotta
Hormonal treatment: 75–80% of DCIS 2018).
express estrogen receptor (ER). Hormonal treat-
ment (HT) is debated; nevertheless, HT for
patients with ER-positive DCIS has been dem-
onstrated to reduce recurrent events of about Macroscopic Features
37% in patients with conservative surgery
(Wapnir et al. 2011). The NSABP B-35 trial The majority of DCIS are detected by mammog-
demonstrated similar rates of disease-free sur- raphy due to microcalcifications; thus, the macro-
vival comparing tamoxifen and aromatase scopic appearance may be completely negative.
inhibitors in postmenopausal patients with Sometimes these lesions may form a nodular
DCIS (Margolese et al. 2016). thickening or spot gray-yellow lesions with strand
Anti-HER2 therapy: Although trastuzumab of dense material that may exude from the cut
treatment (Kuerer et al. 2011) or lapatinib surface, especially in case of comedo-necrosis.
(Decensi et al. 2011) in HER2-positive DCIS To better define extension of the lesion, margin
is proposed, so far, the clinical effect of anti- status, and the correlation with radiological fea-
HER2 blockade is unclear. A prospective, ran- tures (calcifications on mammography and on
domized phase III multi-institutional clinical intraoperative radiogram), the use of large histo-
trial – National Surgical Adjuvant Breast Pro- logical sections in routine clinical practice is
ject (NSABP) – treating HER2-positive DCIS encouraged. However, not every case of DCIS
patients with trastuzumab associated with calcifies, or calcifications may be partially pre-
radiotherapy (Siziopikou et al. 2013) is cur- sent, and, when measured by mammography, the
rently in progress. real size of the lesion may be underestimated. In
• Outcome 10% of cases, DCIS grows in form of nodular
The age at diagnosis has been identified as the mass or architectural distortion (Giuseppetti
strongest predictor of invasive and in situ local et al. 2018). At ultrasound, DCIS calcifications
recurrences. For women under 45 years of age manifest as echogenic foci within the breast tis-
at diagnosis, the 10-year local recurrence-free sue, unlike non-calcified DCIS, which may appear
survival and invasive local recurrence-free sur- as hypoechoic mass with microlobulated margins.
vival after breast-conserving surgery and MR is the most sensitive examination to evaluate
the correct size of DCIS, mainly in high-grade The lumens may contain amorphous material with
lesions (Greenwood et al. 2013). The most apoptotic cells, calcifications (generally with
common morphologic feature of DCIS at MR is powdered/granular pattern), and necrosis. Micro-
“nonmass” enhancement (60–81% of cases) papillary DCIS is composed of numerous epithe-
(Greenwood et al. 2013). Although many lial projections lacking fibrovascular cores
studies have demonstrated overestimations of the (Fig. 2c. H&E); these cell clusters may detach in
disease extent by MR (Rominger et al. 2016), this the lumen and flow to the nipple (Castellano et al.
method principally guides the surgical treatment 2010). Papillary DCIS (▶ Intraductal Papillary
approach. Carcinoma) is characterized by fibrovascular pap-
illary fronds. In some cases, the papillary over-
growth fills the lumen completely, simulating
Microscopy solid DCIS, but fibrovascular cores are still iden-
tifiable. WHO classification system categorized
Nuclear Grade papillary lesions as a separate group, composed
Classification of DCIS should be based primarily of intraductal (▶ Intraductal Papillary Carci-
on nuclear grade, as it represents the most noma), encapsulated (▶ Encapsulated Papillary
significant predictor of local recurrence at both Carcinoma), and solid papillary carcinoma
univariate and multivariate analyses (Wapnir (▶ Solid Papillary Carcinoma) (Lakhani et al.
et al. 2011). 2012). While the intraductal papillary carcinoma
Depending on the degree of nuclear atypia, is characterized by the presence of myoepithelial
DCIS is generally classified in low-, intermedi- layer, the other two entities may lack it at the
ate-, and high-grade DCIS. In particular, low periphery of the lesion. For this reason, there is
grade is characterized by small, monomorphic, no universal agreement on how to stage papillary
well-polarized cells, with uniform size and carcinomas; however, it is suggested that both
regular chromatin pattern and rare mitotic encapsulated and solid type should be managed
figures (Fig. 1a. H&E). Microcalcifications as DCIS form. Comedo DCIS is characterized by
are often of psammomatous/granular/powdery a strongly atypical cell proliferation distending
type. DCIS of intermediate nuclear grade and enlarging ducts with central necrotic debris
consists of cells similar to those of low grade and amorphous calcifications (Fig. 2d. H&E).
but with variability in size, shape and placement, These generally appear as crushed-stone-like/
occasional nucleoli, mitotic figures, and casting-type calcifications, distributed with a lin-
coarse chromatin (Fig. 1b. H&E). Finally, high- ear or segmental pattern at mammography exam-
nuclear-grade DCIS is composed of highly ination. The periductal stroma may be dense and
atypical cells, large in size, with pleomorphic thick and frequently shows a mild inflammatory
and poorly polarized irregular nuclei, prominent reaction. Comedo DCIS usually belongs to high
nucleoli, numerous mitotic figures, and presence or intermediate histopathology nuclear grade.
of necrosis (Fig. 1c. H&E) (Tavassoli and
Devilee 2003). The “DIN” Classification
In 2003 Tavassoli et al. proposed a novel classi-
Histological Growth Patterns fication system (Tavassoli and Devilee 2003),
The histological variants are solid, cribriform, suggesting to replace the term DCIS in favor of
micropapillary, papillary, comedo (Fig. 2. H&E), “ductal intraepithelial neoplasia” (DIN), reserv-
apocrine, and mixed (Bellamy et al. 1993). Solid ing the term “carcinoma” only for invasive
DCIS is characterized by an orderly proliferation tumors.
of crowded neoplastic cells that expand the ducts The subgroup of lesions classified as “DIN 1”
(Fig. 2a. H&E). Cribriform DCIS is formed by encompasses a series of low-grade intraductal
well-defined roundish lumens regularly spaced, proliferations, such as flat epithelial atypia
lined by uniform polarized cells (Fig. 2b. H&E). (▶ Columnar Cell Lesions) (DIN1a), atypical
Ductal Carcinoma In Situ, Fig. 1 (a) Low-grade DCIS presents occasional mitotic figures and coarse chromatin.
is characterized by small, monomorphic, well-polarized (c) High-grade DCIS is composed of highly atypical cells,
cells, with uniform size. (b) Intermediate-grade DCIS con- large in size, with pleomorphic and poorly polarized irreg-
sists of cells variable in size, shape, and placement and ular nuclei and presence of necrosis (H&E, 20x)
ductal hyperplasia (▶ Atypical Ductal Hyperpla- and pleomorphic cells and shows genetic alter-
sia) (ADH) (DIN 1b), and low-grade DCIS ations of high-grade neoplasia (Reis-Filho
(DIN1c). Molecular studies demonstrated that et al. 2005).
these lesions share similar genetic alterations, typ- DIN terminology did not reach widespread
ical of low-grade neoplasia (Reis-Filho consensus. Thus, the WHO in 2012 (Lakhani
et al. 2005). et al. 2012) abandoned the term DIN in favor of
DIN 2 represents intermediate-nuclear-grade DCIS classifications based on the nuclear grade.
DCIS, with intermediate level of differentiation Some authors still support the use of “DIN”
between low- and high-grade lesions. This nomenclature, in order to reduce negative psycho-
latter called DIN 3 is characterized by atypical logical impact on patients and confusion in
Ductal Carcinoma In Situ, Fig. 2 Different histologic composed of numerous epithelial projections into the
subtypes of DCIS. (a) Solid DCIS is characterized by a lumen. Clusters of neoplastic cells without fibrovascular
proliferation of crowded neoplastic cells, which fills the cores are floating in the lumen. (d) Comedo DCIS is
lumen. (b) Cribriform DCIS is represented by neoplastic characterized by enlarged ducts containing necrotic debris.
lumens regularly spaced. The lumens contain amorphous The periductal stroma shows mild inflammatory reaction
material with calcifications. (c) Micropapillary DCIS is (H&E, 10x)
medical management of in situ lesions CD10, cytokeratin 5/6) or their nucleus (p63 and
(Galimberti et al. 2013). p40) (Fig. 3. p63 immunostaining). In routine
practice, the use of both nuclear and cytoplasmic
antibodies is recommended. ERs and progester-
Immunophenotype one receptors (PR) are included as part of the
workup of DCIS by the National Comprehensive
Myoepithelial cells around DCIS may be Cancer Network guidelines. ER is found positive
highlighted by antibodies which stain either in 75–80% of DCIS lesions. Its expression is
their cytoplasm (smooth muscle actin, calponin, generally related to low-intermediate-nuclear-
grade DCIS cases (Fig. 4. ER immunostaining in Molecular Features

low-grade DCIS). Routine testing of PR is still
debated (Lakhani et al. 2012). HER2 is over- Several studies have demonstrated that nuclear
expressed in 50 to 60% of DCIS with high grade is related not only to prognosis but also to
nuclear grade, comedo-necrosis, and presence distinct genetic alterations and different evolu-
of stromal microinvasion (Fig. 5. HER2 tionary pathways (Bombonati and Sgroi 2011).
immunostaining). HER2 may play a pivotal Low-grade DCIS is generally ER/PR positive
role in the progression to invasive carcinoma and HER2 negative, and it is commonly associ-
(Curigliano et al. 2015), and its expression is ated with concomitant chromosomal alterations, D
frequently related to recurrence after surgical such as deletion of 16q and gains of 1q and 16p.
excision, mainly in patients without radiation On the other hand, high-grade DCIS, frequently
therapy (Holmes et al. 2011). ER/PR negative and HER2 positive, is
Similar to invasive breast cancer, the expres-
sion of ER, PR, HER2, and Ki67 may classify
DCIS in “surrogate molecular subtypes,” Luminal
A and B, HER2, and triple negative. Nevertheless,
the prognostic impact of this classification is to
be clarified.
Additional markers such as TP53, Bcl2, and
androgen receptor (AR) have been studied as
promising prognostic markers. Specifically, it
has been demonstrated that TP53 commonly
occurs in high-grade, HER 2-positive DCIS rather
than in ER-/PR-positive low-grade lesions
(Vincent-Salomon et al. 2008). On the other
hand, Bcl2 is highly expressed in low-grade
DCIS (Mustonen et al. 1997).
Limited information is available on AR role
Ductal Carcinoma In Situ, Fig. 4 ER uniform immuno-
in DCIS. Some studies proposed its use in associ- reactivity in 100% of neoplastic cell nuclei in low-grade
ation with ER (AR/ER ratio) as significant prog- micropapillary DCIS (10x)
nostic marker of recurrent disease (Ravaioli
et al. 2017).
Ductal Carcinoma In Situ, Fig. 3 A discontinuous

myoepithelial layer is shown by p63 nuclear Ductal Carcinoma In Situ, Fig. 5 HER2 overexpression
immunostaining around DCIS (20x) in high-grade comedo-DCIS (20x)
characterized by complex karyotypes (Reis- composed of collagen type IV, laminin 1, and
Filho et al. 2005; Lopez-Garcia et al. 2010), some proteoglycans. The overexpression of
including gain in 1q+, 5p+, 8q+, and 17q+; loss some markers, such as matrix metalloproteinase
in 8p , 11q , 13 , and 14q ; and focal ampli- 2 (MMP2), involved in extracellular matrix
fications on 6q22, 8q22, 11q13, 17q12, remodeling, may provoke basal membrane degra-
17q22–24, and 20q13 (Reis-Filho and Lakhani dation (Abba et al. 2004), allowing cancer stromal
2003; Shackney and Silverman 2003). As a result invasion.
of such molecular profile, it is hypothesized that Recently, a number of studies have focused
DCIS may progress along two distinct pathways on analysis of microRNA (miRNA), a class of
of low or high grade. The low-grade arm is char- small RNA molecules that control mRNA expres-
acterized by pathways related to ER activation sion and regulate stem cell division, cell
and well-differentiated invasive carcinoma (such growth, apoptosis, and carcinogenesis. In com-
as tubular carcinoma (▶ Tubular Carcinoma)). parison to normal breast tissue, in DCIS,
The majority of high-grade DCIS lesions show some miRNAs are under- or overexpressed
identical genomic profile of invasive cancers (Hannafon et al. 2011). miRNA deregulations
(Abba et al. 2015). It has been shown that TP53 seem to occur during the transition from
(Kim et al. 2015), PTEN (Yates et al. 2015) normal to DCIS epithelium, such as the loss of
mutations, as well as amplifications of chromo- miR-125b and miR-132 and the gain of miR-182
some 20, 11, and 17 (Aubele et al. 2000) may and miR-183 (Hannafon et al. 2011). A specific
occur in the transition from normal epithelium to miRNA signature was described as differently
in situ carcinoma cells (Casasent et al. 2017). expressed in invasive and DCIS lesions (Volinia
Concomitant factors such as stromal environ- et al. 2012).
ment, cell-mediated immune mechanisms, vas- Finally, DNA methylation seems to play a piv-
cular spaces, and myoepithelial cells contribute otal role in early breast carcinogenesis with an
to progression of DCIS to invasive breast cancer increase of methylated genes from normal breast
(Mardekian et al. 2016; Adriance et al. 2005). In to DCIS (Mardekian et al. 2016).
particular, tumor suppressor functions of
myoepithelial layer are well established, with
the maintenance of integrity of basal membrane Differential Diagnosis
and epithelial cell polarity (Polyak and Hu 2005).
A study conducted by Allinen et al. (2004), com- The differential diagnosis of DCIS may include
paring the microenvironment of normal and can- (i) epitheliosis/usual ductal hyperplasia (UDH),
cerous breast tissue, discovered that the DCIS (ii) atypical ductal hyperplasia (ADH), (iii) lobu-
myoepithelial layer displayed the most abundant lar carcinoma in situ (LCIS), and (iv) minimally
gene expression changes of all the microenviron- invasive carcinoma:
mental cell types. Actually, myoepithelium sur-
rounding DCIS shows some morphological 1. The solid growth pattern of DCIS can be
differences compared to normal breast tissue, misinterpreted as florid epitheliosis/UDH
losing the power to polarize luminal epithelial lesions (▶ Usual Ductal Hyperplasia (UDH)).
cells and showing a discontinuity in the expres- Cell proliferation of epitheliosis is heteroge-
sion of myoepithelial markers (Rakha et al. neous; cells show different shapes, sizes, and
2017). Moreover, it has been shown that genes streaming arrangements and irregular periph-
that are specific for normal myoepithelial cells, eral fenestrations. Cells forming the bridges in
such as CTK14, CTK17, and EGFR, are absent low grade DCIS are more clonal and arranged
or downregulated in DCIS myoepithelial cells haphazardly or transversely to the long axis
(Polyak and Hu 2005). and do not manifest streaming pattern. More-
Besides myoepithelium, basal membrane rep- over, an immunohistochemical mosaicism of
resents a constitutive barrier to invasion, CK5/14+ and CK5/14- cells is characteristic
observed. Poor cellular cohesion and the pres-

ence of intracytoplasmic lumina favor LCIS,
whereas cohesive growth, lack of cytoplasmic
lumina, polarization of cells at the periphery of
the involved spaces, and microacinar forma-
tions favor diagnosis of low-grade DCIS
(Böcker 2006). E-cadherin is typically absent
in ALH/LCIS and expressed in DCIS. In addi-
tion, the expression of high-molecular-weight D
cytokeratin (CK34bE12) is usually seen in
LCIS but not in DCIS (Bratthauer et al. 2002).
4. Microinvasive carcinoma (▶ Microinvasive
Carcinoma of the Breast). Foci of invasive
carcinomas 1 mm or less can be present around
Ductal Carcinoma In Situ, Fig. 6 Microinvasive carci-
DCIS, mainly in inflamed periductal stroma.
noma. Cytokeratin AE1-AE3 immunoreaction highlights
single cells or clusters infiltrating the mildly inflamed Cytokeratins may stain single neoplastic cells
stroma around high-grade DCIS (20x) or small cell clusters invading the periductal
stroma (Fig. 6. Microinvasive carcinoma.
for epitheliosis/UDH, while low grade DCIS is AE1-AE3 immunostaining). Additionally, a
composed of clonal cells, uniformly negative careful study of myoepithelial layer is useful
for basal CK5/14 and positive for ER (Böcker in the diagnosis of microinvasion. An
2006). uncommon invasive cribriform carcinoma
2. The differential diagnosis between ADH (▶ Invasive Cribriform Carcinoma) can be
(▶ Atypical Ductal Hyperplasia) and DCIS mistaken for cribriform DCIS (Lakhani
can be difficult, especially with well- et al. 2012).
differentiated, non-comedo DCIS. Intraductal
proliferation of monomorphic epithelial
cells with histologic and cytologic features of
ADH is identical to those seen in low-grade
DCIS (Page and Rogers 1992). Actually, ADH Abba, M. C., Drake, J. A., Hawkins, K. A., et al. (2004).
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markers for patients with ductal carcinoma in situ treated (2011). Predictors of local recurrence in a population-
with surgery and radiotherapy. International Journal of based cohort of women with ductal carcinoma in situ
Experimental Pathology, 98, 289–295. treated with breast conserving surgery alone. Annals of
Reis-Filho, J. S., & Lakhani, S. R. (2003). The diagnosis Surgical Oncology, 18, 119–124.
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Genetic alterations in pre-invasive lesions. Breast term outcomes of invasive ipsilateral breast tumor
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E
Encapsulated Papillary Clinical Features

Carcinoma
• Incidence
Eliano Cascardi1,2 and Anna Sapino2,3 EPC is an extremely uncommon type of carci-
1
Department of Emergency and Organ noma and it accounts for less than 2% of all
Transplantation, Unit of Pathology, University of breast cancers (Li et al. 2018).
Bari, Bari, Italy • Age
2
Unit of Pathology, Candiolo Cancer Institute It generally affects postmenopausal women;
FPO-IRCCS, Candiolo, Italy the mean age at diagnosis is around
3
Department of Medical Sciences, University of 65–70 years (Mogal et al. 2016).
Turin, Turin, Italy • Sex
This malignancy is frequently diagnosed in
female patients, but EPCs have also been
Synonyms described in men.
• Site
Encysted papillary carcinoma; Intracystic EPC is usually unifocal. It may arise in the
papillary carcinoma larger and more centrally placed ducts, often
located in the subareolar area and rarely in
external quadrants of the breast (Solorzano
Definition et al. 2002).
• Clinical Presentation
Encapsulated papillary carcinoma (EPC) was It can be asymptomatic or manifests as a pal-
described for the first time in 1969 as a papillary pable and mobile breast mass or with a bloody
entity arising from the ductal–lobular system, nipple discharge. Radiologic manifestations of
developing in a cyst, and surrounded by a fibrous EPC are not specific, being suggestive of either
capsule. benign tumors (▶ Fibroadenoma) or medullary
The WHO Working Group, in the fourth edi- carcinoma (▶ Invasive Carcinoma with Med-
tion, considered EPC as a malignant non-invasive ullary Features) or ▶ Invasive Mucinous Car-
neoplastic ductal proliferation with a papillary cinoma (Costa et al. 1998). Ultrasound is more
architecture circumscribed by a fibrous capsule specific, depicting the presence of the
(Lakhani et al. 2012). However, cases of EPC intracystic growth with a heterogeneous
may show invasion. echostructure.

https://doi.org/10.1007/978-3-319-62539-3
104 Encapsulated Papillary Carcinoma
• Treatment
Because of its low incidence, no clearly
defined guidelines have been established for
EPC treatment. Breast conserving surgery is
the standard treatment for patients with the
pure form. In addition to surgical excision,
several studies report on the use of adjuvant
radiation, chemotherapy, or endocrine therapy
in the management of EPC; however, their role
remains undefined (Solorzano et al. 2002;
Fayanju et al. 2007).
Due to the low incidence of axillary lymph
node metastases, sentinel node (▶ Sentinel Encapsulated Papillary Carcinoma, Fig. 1 Low power
Node) evaluation is suggested only in EPC magnification of encapsulated papillary carcinoma shows a
associated to invasive component (Solorzano well-defined lesion surrounded by a fibrous capsule. The
proliferating epithelium has a papillary and cribriform pat-
et al. 2002). tern (H&E 4)
• Outcome
EPC presents a favorable prognosis, even
when associated with invasion (Rakha et al.
2011), showing low local recurrence, rare dis-
tant metastases, and an excellent survival (91%
disease-free survival rate at 10-year follow-up)
(Lefkowitz et al. 1994).
Macroscopy
On gross examination, EPC appears as a nodular

and friable lesion, usually well-delimited or
within a large cystic cavity containing bloody
material. The size may be variable, with a reported
Encapsulated Papillary Carcinoma, Fig. 2 Encapsu-
median tumor size of 2.25 cm (Zhang et al. 2018). lated papillary carcinoma with invasion. Foci of invading
cancer cells are beyond the fibrous capsule (H&E 4)
Microscopy eosinophilic cytoplasm, sometimes with apocrine

differentiation (Kővári et al. 2018) and usually
Histopathological examination of EPC shows a show hyperchromatic nuclei with low or interme-
well-defined lesion surrounded by a fibrous cap- diate nuclear grade (Costa et al. 1998). Rare cases
sule (Fig. 1). EPC presents papillary, cribriform, of high nuclear grade EPC have been described.
or solid pattern, with fibrovascular core covered EPC presenting high nuclear grade, spindle cells
by a single or multiple layers of cancer cells (Hill with malignant features and necrosis or associated
and Yeh 2005). Myoepithelial cells are not pre- with invasive growth seems to be more aggressive
sent, neither at the periphery of the lesion nor (Costa et al. 1998). True invasion in EPC is a rare
within the fibrovascular cores. event and corresponds to the presence of infiltrat-
Cancer cells are often monomorphic and ing cancer nests outside the fibrous capsule
monotonous and show minimal atypia (slight (Fig. 2). EPC may be accompanied by peripheral
nuclear pleomorphism and low mitotic index). foci of ductal carcinoma in situ (DCIS) (▶ Ductal
Commonly, the malignant cells are cuboidal with Carcinoma In Situ), usually with similar nuclear
Encapsulated Papillary Carcinoma 105
type breast carcinomas, it has been shown that all

EPCs had low recurrence score using the
Oncotype DX test (Turahvili et al. 2017).
To differentiate EPC from other papillary

breast lesions is difficult on preoperative core needle
biopsies and surgical excision is necessary for accu-
E
rate pathological diagnosis (Valdes et al. 2006).
Intraductal and sclerosing papillomas
Encapsulated Papillary Carcinoma, Fig. 3 Immuno- (▶ Intraductal Papilloma) at difference from
histochemical staining for basal keratins (CK14) shows EPC show a layer of myoepithelial cells along
absence of myoepithelial cells both at the periphery and the fibrovascular cores of the papillae. In general,
within the intracystic papillary structures (IHC 4)
papillary DCIS (▶ Intraductal Papillary Carci-
noma) affects multiple ducts and myoepithelial
grade and histological features (papillary or solid cells surround their periphery, while EPC presents
DCIS). negative staining for myoepithelial markers
(Collins et al. 2006).
True invasion has to be differentiated from
Immunophenotype displaced fragments of tumor tissue outside the
fibrous capsule that may follow preoperative fine
Due to the absence of the myoepithelial layer needle aspiration or core biopsy sampling. Reac-
within the papillae and around the tumor, tive changes in and around the fibrous capsule
calponin, p63, basal keratins (CK5 and CK14), together with hemosiderin laden macrophages
and CD10 immunostaining are negative (Fig. 3). favor pseudoinvasion.
However, a moderate or intense immunohisto-
chemical staining for type IV collagen is reported
(Esposito et al. 2009). The majority of EPC cases References and Further Reading
are classified as Luminal A and B types, being
positive for estrogen and progesterone receptors Collins, L. C., Carlo, V. P., Hwang, H., Barry, T. S., Gown,
and negative for HER2. Isolated triple-negative A. M., & Schnitt, S. J. (2006). Intracystic papillary
carcinomas of the breast: A reevaluation using a panel
EPC cases have been reported (Zhang et al. 2018). of myoepithelial cell markers. The American Journal of
EPC is a low-proliferating tumor: the Ki67 prolif- Surgical Pathology, 30, 1002–1007.
eration index is generally below 20%. GCDFP-15 Costa, I., Fonseca, D., Lopes, P., Bento, M. J., & Lopes,
may be expressed in EPC showing apocrine dif- C. (1998). Intracystic (encysted) papillary carcinoma of
the breast: A clinical, pathological, and immunohisto-
ferentiation (Kővári et al. 2018). chemical study. Human Pathology, 29, 1097–1104.
Duprez, R., Wilkerson, P. M., Lacroix-Triki, M., Lambros,
M. B., MacKay, A., Hern, R. A., Gauthier, A., Pawar,
Molecular Features V., Colombo, P. E., Daley, F., Natrajan, R., Ward, E.,
MacGrogan, G., Arbion, F., Michenet, P., Weigelt, B.,
Vincent-Salomon, A., & Reis-Filho, J. S. (2012).
The genomic profile of EPC shows low number of Immunophenotypic and genomic characterization of
genomic aberrations, loss of 16q, and PIK3CA papillary carcinomas of the breast. The Journal of
mutations. These genetic alterations have been Pathology, 226, 427–441.
Esposito, N. N., Dabbs, D. J., & Bhargava, R. (2009). Are
correlated with good clinical outcome of EPC in encapsulated papillary carcinomas of the breast in situ or
analogy to other ER-positive breast tumors invasive? A basement membrane study of 27 cases.
(Duprez et al. 2012). In a recent study of special American Journal of Clinical Pathology, 131, 228–242.
106 Encapsulated Papillary Carcinoma
Fayanju, O. M., Ritter, J., Gillanders, W. E., Eberlein, T. J., the breast: A SEER database analysis of implications
Dietz, J. R., Aft, R., & Margenthaler, J. A. (2007). for therapy. The Breast, 27, 87–92.
Therapeutic management of intracystic papillary carci- Rakha, E. A., Gandhi, N., Climent, F., van Deurzen, C. H.,
noma of the breast: The roles of radiation and endocrine Haider, S. A., Dunk, L., Lee, A. H., Macmillan, D., &
therapy. The American Journal of Surgery, 194, Ellis, I. O. (2011). Encapsulated papillary carcinoma of
497–500. the breast: An invasive tumor with excellent prognosis.
Hill, C. B., & Yeh, I. T. (2005). Myoepithelial cell staining The American Journal of Surgical Pathology, 35,
patterns of papillary breast lesions: From intraductal 1093–1103.
papillomas to invasive papillary carcinomas. American Solorzano, C. C., Middleton, L. P., Hunt, K. K., Mirza, N.,
Journal of Clinical Pathology, 123, 36–44. Meric, F., Kuerer, H. M., Ross, M. I., Ames, F. C., Feig,
Kővári, B., Ormándi, K., Simonka, Z., Vörös, A., & B. W., Pollock, R. E., Singletary, S. E., & Babiera,
Cserni, G. (2018). Apocrine encapsulated papillary G. (2002). Treatment and outcome of patients with
carcinoma of the breast: The first reported case with intracystic papillary carcinoma of the breast. The Amer-
an infiltrative component. Journal of Breast Cancer, ican Journal of Surgery, 184, 364–368.
21, 227–230. Turahvili, G., Brogi, E., Morrow, M., Hudis, C., Dickler,
Lakhani, S.R., Ellis, I.O., Schnitt, S.J., Tan, P.H., & van de M., Norton, L., & Wen, H. Y. (2017). The 21-gene
Vijver, M.J.. (2012). WHO classification of tumors of recurrence score in special histologic subtypes of breast
the breast (pp. 106–107). World Health Organization. cancer with favorable prognosis. Breast Cancer
ISBN-10: 9283224337. Lyon, IARC press. Research and Treatement, 165(1), 65–76.
Lefkowitz, M., Lefkowitz, W., & Wargotz, E. S. (1994). Valdes, E. K., Tartter, P. I., Genelus-Dominique, E.,
Intraductal (intracystic) papillary carcinoma of the Guilbaud, D. A., Rosenbaum-Smith, S., & Estabrook,
breast and its variants: A clinicopathological study of A. (2006). Significance of papillary lesions at percuta-
77 cases. Human Pathology, 25, 802–809. neous breast biopsy. Annals of Surgical Oncology, 13,
Li, X., Xu, Y., Ye, H., Qin, S., Hou, F., & Liu, W. (2018). 480–482.
Encapsulated papillary carcinoma of the breast: Zhang, J., Zhang, T., Wu, N., Zhao, X., Wang, Q., Jiang, Y.,
A clinicopathological study of 49 cases. Current Prob- Gao, M., & Gu, L. (2018). Intracystic papillary carci-
lems in Cancer, 42, 291–301. noma of the breast: Experience of a major Chinese
Mogal, H., Brown, D. R., Isom, S., Griffith, K., & Howard- cancer center. Pathology-Research and Practice, 214,
McNatt, M. (2016). Intracystic papillary carcinoma of 579–585.
F
Fibroadenoma • Imaging
Mammography can detect FA if a calcific com-
Elena Maldi1 and Anna Sapino1,2 ponent is present, otherwise it cannot distin-
1
Unit of Pathology, Candiolo Cancer Institute guish FAs and cysts. FA is a round or ovoid
FPO-IRCCS, Candiolo, Italy hypoechoic lesion at ultrasound evaluation.
2
Department of Medical Sciences, University of • Treatment & Outcome
Turin, Turin, Italy FAs are painless lesions with slow growth thus
they do not require any treatment, but imaging
follow up. About 10% to 40% of FAs resolve
Synonyms spontaneously or if completely excised they do
not recur (Song et al. 2014). Cases of juvenile FA
Benign fibroepithelial lesion (see below) can grow rapidly and occupy most of
the breast resulting in esthetic problems due to
breast asymmetry or hypertrophy. Complete
Definition lumpectomy is recommended because they may
recur in 33% at 5 years (Song et al. 2014).
Fibroadenoma (FA) is a common benign neo- Complex FAs (see below) are associated
plasm of the breast. It is classically defined as a with increased risk (1.89 times) of breast can-
biphasic lesion, meaning a proliferation of both cer compared to simple FAs if associated with
the epithelial and stromal component. proliferative diseases and when there is a rele-
vant family history of breast cancer (Dupont
et al. 1994). In general, FA-carcinoma associ-
Clinical Features ation varies between 0.1% and 0.3% in the
screened population (Dupont et al. 1994).
• Age & Sex
FA has been described at any age, but it
occurs mainly in young women of Macroscopy
reproductive age. Juvenile FA occurs at ages
between 10 and 18 years (Wechselberger FA is a firm, fibro-elastic, round–oval nodule with
et al. 2002). smooth or rarely nodular margins. The cut surface
• Site shows a relatively homogenous whitish tissue,
It may be multiple and bilateral, with no site with a delicate lobulated pattern, and in many
preference. cases, slits are also present.
https://doi.org/10.1007/978-3-319-62539-3
108 Fibroadenoma
Microscopy misinterpreted as mucinous carcinoma

(▶ Invasive Mucinous Carcinoma).
FA is a biphasic hyperplastic lesion that arises in – Cellular FA displays prominent cellularity of
the terminal duct lobular unit (TDLU) where spe- stromal component. Differential diagnosis of
cialized intralobular mammary stroma proliferates intracanalicular cellular FA with benign
causing distortion of the glandular component phyllodes tumor (▶ Phyllodes Tumor) is chal-
(Kuijper et al. 2001). lenging (Fig. 3 H&E).
Two different growth patterns (with no clinical – Complex FA shows at least one of the
significance) are reported: following features: cystic component
>3 mm, epithelial calcifications, sclerosing
– Pericanalicular: circumferential proliferation adenosis (▶ Sclerosing Adenosis), and
of stromal cells around ducts. Intralobular (papillary) apocrine hyperplasia (Page and
stroma may be part of the stromal growth Anderson 1987; Dupont et al. 1994).
(Fig. 1 H&E). – Juvenile FA or giant type FA is a rare variant
– Intracanalicular: proliferation of stromal cells characterized by rapid growth; they occur
causing compression of the ducts (Fig. 2
H&E).
Mitotic figures in either component are unusual

but may be present in young or pregnant women.
Stromal cellularity of FA may be prominent and
homogeneous. In elderly woman, FA may become
sclerotic and dystrophic calcifications may occur.
The epithelial component of FA may show hyper-
plastic features of varying degrees.
Variants:
– Myxoid FA shows prominent myxoid

changes in the stromal component and may Fibroadenoma, Fig. 2 Intracanalicular fibroadenoma:
be associated to Carney syndrome. On frozen myxoid stroma compresses and distorts the epithelial com-
sections or on FNA myxoid FA may be ponent. (H&E)
Fibroadenoma, Fig. 3 In this case of intracanalicular

Fibroadenoma, Fig. 1 Pericanalicular fibroadenoma: fibroadenoma the stroma is cellular, and occasional leaf-
the stroma is sclerotic and the epithelial structures are like protrusions are present, simulating a benign phyllodes
partly compressed. (H&E) tumor. (H&E)
Fibroadenoma 109
typically in adolescence. They show high development (Loke et al. 2018). A recent study
stromal cellularity and pericanalicular has shown that MED12 mutations are common
growth pattern with usual hyperplasia (Song particularly among intracanalicular FAs
et al. 2014; Calcaterra et al. 2009). Apical (Volckmar et al. 2017).
snouts and gynecomastia-like micropapillary
projections and rare mitoses are features
of the luminal epithelial layer (Fig. 4 H&E). Differential Diagnosis
The main differential diagnosis is between

Atypia or malignant proliferations, either duc- intracanalicular FA and phyllodes tumor
tal or lobular, are found as incidental finding after (PT) (▶ Phyllodes Tumor). PT may be suspected
FA excision. Atypia present only in the context of when rapid growth or skin ulceration are reported, F
the FA, sparing the surrounding normal tissue, is otherwise FA and PT are clinically indistinguish-
not considered at high risk of developing breast able. At ultrasound examination, large PT may be
cancer, if FA is removed. Invasive or in situ can- more heterogeneous because of secretion within
cers are very rare in FA. Invasive carcinoma may the lumen of ducts. The stroma in FA is typically
arise within the FA or more frequently invasion is uniform and less cellular than in PT, with no atypia
the result of an extrinsic infiltration (Hoda or overgrowth. The presence of areas, at 10x fields,
et al. 2014). composed only of stroma favor the diagnosis of PT
and accumulation of histiocytes within the lumen
Immunohistochemical Features of distorted epithelial structures is a feature mainly
Estrogen and progesterone receptors positivity is observed in PT. Mitotic count may help distinguish
confined to the epithelium. CD34 may be variably between FA and PT, being virtually absent in
positive in the stroma. FA. Differential diagnosis between FA and PT is
particularly difficult in core biopsies (Hoda et al.
2014; Yasir et al. 2014), in this case the lesion
Molecular Features should be better classified as “fibroepithelial
lesion” and surgery is suggested.
No specific molecular feature has been described
in FA. Cytogenetic aberrations, in particular in the
12q13–15 region have been reported, but no spe- References and Further Reading
cific mutations have been found to drive FA
Calcaterra, V., Coscia, D. R., Sgarell, A., Burroni, B.,
Podetta, M., Andorno, A., Ferrari, A., & Larizza, D.
(2009). Recurrence of giant juvenile breast
fibroadenoma in a girl with Turner’s syndrome.
Journal of Pediatric Endocrinology and Metabolism,
22, 281–283.
Dupont, W. D., Page, D. L., Parl, F. F., Vnencak-
Jones, C. L., Plummer, W. D., Jr., Rados, M. S., &
Schuyler, P. A. (1994). Long term risk of bresat cancer
in woman with fibroadenoma. New England Journal of
Medicine, 331, 10–15.
Hoda, S. A., Brogi, E., Koerner, F. C., & Rosen, P. P.
(2014). Rosen’s breast pathology (pp. 213–232).
Philadelphia: Lippincott Williams & Wilkins.
Kuijper, A., Mommers, E. C. M., van der Wall, E., &
van Diest, P. J. (2001). Histopathology of fibroadenoma
of the breast. American Journal of Clinical Pathology,
Fibroadenoma, Fig. 4 Juvenile fibroadenoma: an epi- 115, 736–742.
thelial structure within a juvenile FA shows signs of hyper- Loke, B. N., Nasir, N. D., Thike, A. A., Lee, J. Y. H.,
plasia and apical snouts. (H&E) Lee, C. S., Teh, B. T., & Tan, P. H. (2018).
110 Fibrocystic Breast Changes
Genetics and genomics of breast fibroadenomas. stated in a consensus meeting in New York in
Journal of Clinical Pathology, 71, 381–387. 1985 (Hutter et al. 1986). In addition, for some
Page, D. L., & Anderson, T. J. (1987). Diagnostic
histopathology of the breast (p. 362). Edinburgh: authors this entity may be simply an “aberration of
Churchill Livingstone. normal development and involution of breast tis-
Song, B. S., Kim, E. K., Seol, H., et al. (2014). Giant sue,” in which the diagnostic definition of FCs is
juvenile fibroadenoma of the breast: A case report and more quantitative than qualitative (Tot et al.
brief literature review. Annals of Pediatric
Endocrinology & Metabolism, 19, 45–48. 2014). However, it is necessary to underline that
Volckmar, A. L., Leichsenring, J., Flechtenmacher, C., et al. the term FCs is used occasionally in a redundant
(2017). Tubular, lactating, and ductal adenomas are way, including also other benign breast entities
devoid of MED12 Exon2 mutations, and ductal adenomas such as fibroadenoma (▶ Fibroadenoma), ductal
show recurrent mutations in GNAS and the PI3K–AKT
pathway. Genes, Chromosomes & Cancer, 56, 11–17. hyperplasia (▶ Usual Ductal Hyperplasia (UDH)),
Wechselberger, G., Schoeller, T., & Piza-Katzer, H. (2002). papilloma (▶ Intraductal Papilloma), and scleros-
Juvenile fibroadenoma of the breast. Surgery, ing adenosis (▶ Sclerosing Adenosis).
132, 106–107.
Yasir, S., Gamez, R., Jenkins, S., Visscher, D. W., &
Nassar, A. (2014). Significant histological features dif-
ferentiating cellular fibroadenoma from phyllodes Clinical Features
tumor on core needle biopsies. American Journal of
Clinical Pathology, 142, 362–369. • Incidence
FCs represent the most common breast modifica-
tion. Their incidence is so high that they are
considered as a paraphysiological condition by
Fibrocystic Breast Changes some authors (Tot et al. 2014). From 58% to 61%
of breast tissue examined at autopsy show micro-
Isabella Castellano1 and Jasna Metovic2 scopic evidence of FCs (Bartow et al. 1982).
1
Department of Medical Sciences, University of • Age
Turin, Turin, Italy FCs are rarely encountered in women younger
2
Department of Oncology, University of Turin, than 21 years. Their incidence rises during the
Turin, Italy second decade of life, with a peak in the fourth
and fifth decade during premenopause period.
Family cancer history is frequently reported
Synonyms positive (Kabat et al. 2010; Shaaban
et al. 2002).
Fibrocystic condition; Fibrocystic disease; Fibro- • Sex
cystic mastopathy; Mammary dysplasia FCs are typical of female breast, because they
classically arise in the terminal ductal lobular
unit (TDLU); thus they are only occasionally
Definition seen in male breast tissue.
• Site
The term “fibrocystic changes” (FCs) covers a FCs tend to be bilateral and symmetrical. They
wide variety of clinical and pathological condi- are mainly located at the upper outer quadrants,
tions from painful breast to solid lump, multiple where glandular tissue is more abundant.
cysts, or diffuse nodularity. These abnormalities Occasionally, they may produce a clinically
are noncancerous disorders and do not represent a palpable nodule.
specific disease but rather a sign of response of the • Treatment
breast tissue to hormone levels in different phases FCs mainly occur due to relative hormone
of women life. Since FCs are the most frequent imbalance, in particular, hyperestrogenism.
breast abnormalities, the previous definition This imbalance may cause gradual dilatation
referred as “fibrocystic breast disease” was aban- of the ducts with an overgrowth of stromal
doned in favor of “fibrocystic breast changes,” as tissue and blood vessel dilatation with fluid
Fibrocystic Breast Changes 111
retention, resulting in swelling, edema, and of 15 years, the relative risk to develop a
sometimes pain in the breast. Symptoms cancer was of 1.27 (Hartmann et al. 2005).
related to FCs are generally associated with On the other hand, this risk may increase to
menstrual cycles, and they may subside with 1.62 in women with a strong family history of
menopause. Although the relationship breast cancer (Hartmann et al. 2005). More
between hormones and development of FCs recently, a study on a screening population, in
is clear, hormonal treatment with progestins which predominated postmenopausal
and tamoxifen is prescribed only for patients women, demonstrated a higher (OR = 2.23)
with severe and prolonged pain (Faiz and relative risk to develop cancer from non-
Fentiman 2000). The synthetic steroid most proliferative benign breast disease (Castells
commonly prescribed is Danazol, which has et al. 2015). The current view is that FCs per
high affinity for androgen receptor (AR), se have no impact on cancer development. F
moderate affinity for progesterone receptor However, the risk of malignant differentiation
(PR), and poor affinity for estrogen receptor may vary depending on age, family history,
(ER) (Mousavi et al. 2010). Its efficacy may and/or the association with other lesions, such
be explained by the presence of AR in the as ductal atypical hyperplasia (▶ Atypical
apocrine epithelium that normally lines cysts Ductal Hyperplasia), papillomas
of FCs. A wide variety of non- (▶ Intraductal Papilloma), radial scars
pharmacological interventions has been pro- (▶ Radial Scar), etc.
posed, such as quitting smoking and dietary
changes. In particular, lowering the intake of
Macroscopy
tea, coffee, chocolate, and fat may cause
reduction of methylxanthines that are impli-
FCs may be palpable, generally in the form of a
cated in the development of cystic formation
nodule or plaque. Radiologically, FCs can mimic
(Smith et al. 2004). In more painful cases,
other pathological conditions forming nodular
therapeutic efficacy of vitamin E on
thickening, microcalcifications, or cystic lesions.
mastalgia, with minimal or absent side
Ultrasound examination is the most accurate
effects, has been described (Pruthi et al.
method to detect cystic lesions, which appear
2010). Surgical removal of the lesion is not
commonly as well-defined anechoic nodules.
recommended.
Low-level echoes may be seen in cysts
• Outcome
containing inflammatory reactive tissue, blood
Page et al. (1978) classified FCs into
clots, and dense protein. FCs at magnetic reso-
(i) non-proliferative FCs, (ii) proliferative
nance (MR) appear as non-mass enhancement,
FCs without atypia, and (iii) proliferative
mainly due to apocrine cysts, and share the same
FCs with atypia. In this chapter only the first
features with ductal carcinoma in situ (▶ Ductal
group will be described, because the second
Carcinoma In Situ) leading sometimes to unnec-
includes papilloma, radial scar, or sclerosing
essary biopsy (Milosevic et al. 2017).
adenosis, while the third encompasses atypi-
Dense white stromal tissue with a number of
cal ductal and lobular hyperplasia. Most of
blue-greenish cysts of different size characterizes
the studies report that women with FCs are
the cut surface of breast surgical specimens (Fig. 1).
not at greater risk for subsequent carcinoma
than women in the general population (Page
et al. 1978; Dupont and Page 1985) in the
absence of positive family history, while in Microscopy
other studies, the relative risk is 1.6 (Wang
et al. 2004) with an increase to 1.95 in women FCs are characterized by histological tetrad
50 years of age and older. In one of the largest consisting of fibrosis, cysts, adenosis, and epithe-
cohorts of 9087 women affected by non- lial hyperplasia: (i) Areas of fibrosis with
proliferative FCs, with a median follow-up hyalinized stroma are prominent and cause
Fibrocystic Breast
Changes, Fig. 1 FCs in a
breast nodule: white stromal
tissue with cystic structures
is visible on cut surface
Fibrocystic Breast
Changes, Fig. 2 (H&E)
(a) Vacuum-assisted biopsy
sampling of FCs.
(b) Cluster of variably
enlarged cystic acini
containing amorphous
material and bluish
calcifications
permanent atrophy of the glandular breast tissue. entire lobule and contain amorphous secretion
(ii) Cysts are the most frequent condition, proba- rich in proteins and microcalcifications (Fig. 2).
bly due to obstruction of the duct by the exuberant Microcalcifications are present in form of calcium
fibrosis that causes dilatation of terminal ducts phosphate, appearing as basophilic and non-
and acini. Cysts may vary in size from very large birefringent round deposits forming psammoma
to microscopic. Often multiple cysts occupy an bodies easily recognizable at routine staining or
Fibrocystic Breast
Changes, Fig. 3 Single
cyst containing many
psammoma bodies (H&E)
Fibrocystic Breast
Changes,
Fig. 4 Micropapillae of
apocrine cells protrude
within the cyst (H&E)
calcium oxalate, characterized by birefringent by an increase in the size and number of

crystals, sometimes missed at morphological lobules, frequently appears as sclerosing
evaluation. This type of crystals, radiologically adenosis (▶ Sclerosing Adenosis). (iv) Epithelial
recognized as calcifications, have been described hyperplasia of usual type (▶ Usual Ductal Hyper-
only in benign cysts and were never associated plasia (UDH)) is a proliferation of epithelial
with carcinoma or epithelial hyperplasia (Radi cells within TDLU characterized by hetero-
1989). Metaplastic apocrine epithelium usually geneity in term of shape and size of cells and it is
covers the surface of cysts as a single layer but not associated with risk of subsequent malignancy.
sometimes forms papillae and/or micropapillae. FCs may be associated to any type of epithelial and
Apocrine cells are cuboidal and monomorphic, stromal lesions (Figs. 3 and 4).
their cytoplasm is large and contains eosinophilic
granules, and the nucleus is roundish and contains a
single eosinophilic nucleolus. An outer layer of Immunophenotype
myoepithelial cells is usually present and detectable
around the cysts with classical immunohistochem- AR is usually detected in the apocrine epithelium
ical markers (such as p63, smooth muscle actin of cystic lesions, while ER and PR are absent.
(SMA), and calponin). However, in benign apo- Apocrine epithelium is rich in gross cystic disease
crine lesions, myoepithelial cells may be missing fluid protein (GCDFP)-15. GCDFP-15, 24 and
(Cserni 2012; Tramm et al. 2011). In some cases, 44 are present at high concentration in cystic
rupture of cysts induces pericystic inflammatory fluid. In vitro studies suggested that presence of
reaction with lymphocytes and granulocytes. (iii) GCDFP-15 may be stimulated by androgens
Adenosis (▶ Adenosis, Other Types), characterized (Simard et al. 1989) and inhibited by estrogens.
Fibrocystic Breast Changes, Fig. 5 (IHC) (a) Nuclei of apocrine cells in a cyst are positive for AR and negative for
(b) ER, (c) PR, (d) IHC of GCDFP-15
GCDFP-15 is usually not expressed in normal aggressive potential from those at risk to become
non-apocrine breast epithelium (Fig. 5). malignant (Gromov et al. 2015).
Molecular Features Differential Diagnosis
Molecular profile of FCs was rarely analyzed. Concomitant presence of fibrosis, cysts with
High levels of ER gene transcripts (Boyd et al. apocrine metaplasia, (sclerosing) adenosis, and
1996) and ER aberrant promoter methylation have ductal hyperplasia of usual type is patho-
been described (Parrella et al. 2004). The molec- gnomonic of FCs. However, each singular histo-
ular origin of apocrine epithelium remains contro- logic pattern is subjected per se to differential
versial. Washington et al. (2000) showed loss of diagnosis with other lesions. Validated criteria
heterozygozity (LOH) in the apocrine compo- used to differentiate benign from atypical or
nents of FCs, as well as in associated carcinoma, neoplastic non-apocrine lesions are not readily
indicating possible common clonal precursors. In applicable to apocrine lesions. For example,
line with these findings, IHC screening of a vari- sclerosing adenosis with apocrine epithelium
ety of apocrine lesions from benign to malignant may simulate an apocrine-invasive carcinoma
showed similar protein signature characterized by (▶ Apocrine Carcinoma) and may require the
positive or negative expression of the following use of myoepithelial markers (such as p63,
proteins: 15-PGDH, HMGCR, S110A7, S100A9, Calponin, SMA, CK5/6). Nevertheless, as men-
and p53 (Celis et al. 2006). Thus, so far, available tioned above, pathologists should be aware that
protein markers are not sufficiently specific to benign apocrine papillary lesions, which may be
differentiate benign apocrine lesions without placed nearby to foci of sclerosing adenosis, may
lack myoepithelial layer (Cserni 2012) and should expression signature specific for benign apocrine meta-
not be confused with invasive lesions. Apocrine plasia. FEBS Letters, 580, 2935–2944.
Cserni, G. (2012). Benign apocrine papillary lesions of the
epithelium should be differentiated from atypical breast lacking or virtually lacking myoepithelial cells-
apocrine adenosis, atypical apocrine hyperplasia, potential pitfalls in diagnosing malignancy. Acta
and/or apocrine ductal carcinoma in situ. The Pathologica, Microbiologica, et Immunologica
presence of nuclear atypia (threefold nuclear Scandinavica, 120, 249–252.
Dupont, W. D., & Page, D. L. (1985). Risk factors for
enlargement with presence of large nucleolus or breast cancer in women with proliferative breast dis-
with multiple small nucleoli) seems to be the ease. New England Journal of Medicine, 312, 146–151.
major diagnostic criteria. In addition to nuclear Faiz, O., & Fentiman, I. S. (2000). Management of breast
atypia, the extent of the apocrine proliferation, pain. International Journal of Clinical Practice, 54,
228–232.
architectural features, and presence of necrosis Gromov, P., Espinoza, J. A., & Gromova, I. (2015). Molec-
have been emphasized to differentiate non-atypical ular and diagnostic features of apocrine breast lesions. F
from atypical apocrine proliferations or in situ car- Expert Review of Molecular Diagnostics, 15,
cinomas (Tavassoli and Norris 1994; O’Malley and 1011–1022.
Hartmann, L. C., Sellers, T. A., Frost, M. H., Lingle, W. L.,
Bane 2008). Finally, foci of epithelial hyperplasia Degnim, A. C., Ghosh, K., Vierkant, R. A.,
of usual type (▶ Usual Ductal Hyperplasia (UDH)) Maloney, S. D., Pankratz, V. S., Hillman, D. W., Suman,
in FCs should be differentiated from atypical V. J., Johnson, J., Blake, C., Tlsty, T., Vachon, C. M.,
hyperplasia and low-grade ductal in situ carcinoma. Melton, L. J., 3rd, & Visscher, D. W. (2005). Benign
breast disease and the risk of breast cancer. The New
Briefly, epithelial hyperplasia of usual type is a England Journal of Medicine, 353, 229–237.
non-monoclonal proliferation of cells filling Hutter, R. V. P., Albores-Saavedra, J., & Anderson, E. et al.
lumens of ducts or acini with irregular fenestrations (1986). Is ‘fibrocystic disease’ of the breast precancer-
at the periphery and expresses both low and high ous? Consensus meeting, New York, October 1985.
Archives of Pathology & Laboratory Medicine, 110,
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CK8/18 and CK5/6 and 14. In addition at differ- Kabat, G. C., Jones, J. G., Olson, N., Negassa, A.,
ence with atypical hyperplasia (▶ Atypical Ductal Duggan, C., & Ginsberg, M. (2010). A multi-center
Hyperplasia) and low-grade ductal carcinoma in prospective cohort study of benign breast disease and
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G
Glycogen-Rich Clear Cell carcinoma cases when strict criteria are applied
Carcinoma (Eusebi et al. 2012). In everyday practice, the
frequency seems to be much lower.
Noëlle Weingertner and Jean-Pierre Bellocq • Age
Department of Pathology, Strasbourg University Patients are 37–78 years old (median age
Hospital, Strasbourg, France of 57).
• Treatment
Patients with GRCCC are treated according to
Definition routine guidelines for breast cancer in general.
• Outcome
Glycogen-rich clear cell carcinoma (GRCCC) Opinions differ concerning the prognosis of
occurs in many organs. GRCCC of the breast is GRCCC. Most reports suggest more aggres-
an exceptionally rare subtype of infiltrative carci- sive behavior than carcinoma NST, but Hayes
noma in which more than 90% of the neoplastic et al. contend that prognosis is not different
cells have abundant clear cytoplasm containing once tumors are matched by size, grade, and
glycogen (Eusebi et al. 2012). Extraction of the lymph node status (Hayes et al. 1995).
water-soluble glycogen during tissue processing
gives the cytoplasm an optically clear, vacuolated
appearance on tissue sections. It was first
Macroscopy
described by Hull in 1981 (Hull et al. 1981), and
The tumor size ranges from 1 to 15 cm.
since then, fewer than 200 cases have been
reported. According to Hull et al., the features of
GRCCC are very similar to the morphology of the
developing mammary gland in 13-week-old fetus. Microscopy
The clinical features of GRCCC are similar to
those of invasive carcinoma NST (▶ Invasive Histologically, GRCCC shows clusters of clear
Carcinoma NST). cells (Figs. 1 and 2 H&E) and must have more
than 90% of cells containing intracytoplasmic
Clinical Features glycogen, stained by periodic acid stain (PAS)
but not stained by diastase-periodic acid stain
• Incidence (Fig. 3 PAS staining). The tumor cells tend to
According to the 2012 WHO classification, the have sharply defined borders and polygonal con-
incidence is estimated to be 1–3% of breast tours. The cytoplasm is clear or finely granular.
https://doi.org/10.1007/978-3-319-62539-3
118 Glycogen-Rich Clear Cell Carcinoma
Glycogen-Rich Clear Cell Carcinoma, Fig. 3 GRCCC –

microscopic features of the same case (PAS x20). Glyco-
gen is stained magenta on the PAS stained slide and will be
Glycogen-Rich Clear Cell Carcinoma, Fig. 1 GRCCC – absent on the PAS/Diastase stained slide. (Courtesy of
microscopic features (H&E x0.5). Circumscribed invasive Gaëtan MacGrogan)
carcinoma. (Courtesy of Gaëtan MacGrogan)
Progesterone receptor (PR) is generally not expressed

but in rare instances has been reported positive (Kim
et al. 2012). Cases that are positive for HER2 and
negative for ER and PR have been described, as well
as triple-negative cases (Kim et al. 2012).
Molecular Features
This subject has not been discussed in the litera-

Glycogen-Rich Clear Cell Carcinoma, Fig. 2 GRCCC –
ture so far.
microscopic features of the same case (H&E x10). Broad
nests of polygonal cells with distinct cell borders and clear
cytoplasm. (Courtesy of Gaëtan MacGrogan)
The nuclei are hyperchromatic, sometimes with
GRCCC has to be differentiated first and foremost
clumped chromatin and prominent nucleoli
from metastases of clear cell carcinoma, particu-
(Fig. 2 H&E).
larly of renal or gynecologic origin. Other diag-
The lesions have the architectural features of
noses should also be considered: lipid-rich
carcinoma NST and rarely those of lobular
or histiocytoid breast carcinoma, adenomyoe-
(▶ Invasive Lobular Carcinoma), medullary
pithelioma (▶ Adenomyoepithelioma), clear cell
(▶ Invasive Carcinoma with Medullary Features),
hidradenoma, pecoma, and xanthogranulomatous
or tubular carcinoma (▶ Tubular Carcinoma). An
mastitis.
intraductal component may be present with the
Clear-cell appearance of carcinoma can be an
same cytological characteristics.
artifact of the extraction of intracytoplasmic sub-
stances during tissue processing, but in this case,
PAS staining will be negative.
Immunophenotype
The tumor cells are positive for cytokeratin 7,

GCDFP-15 and negative for cytokeratin 20. Positiv-
ity for chromogranin and synaptophysin has been
Eusebi, V., Ichihara, S., Vincent-Salomon, A., Sneige, N., &
reported (Markopoulos et al. 2008). Tumor cells Sapino, A. (2012). Exceptionally rare types and variants.
express estrogen receptor (ER) in 50% of the cases. In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H. Tan, &
Granular Cell Tumor 119
M. J. van de Vijver (Eds.), WHO classification of elderly ladies aged more than 70 years (Torous
tumours of the breast (pp. 74–75). Lyon: IARC. et al. 2017).
Hayes, M. M. M., Seidman, J. D., & Ashton, M. A. (1995).
Glycogen rich clear cell carcinoma of the breast. • Sex
A clinicopathologic study of 21 cases. American Breast GCT affects more frequently female
Journal of Surgical Pathology, 19, 904–911. patients, but rare cases have been reported in
Hull, M. T., Priest, J. B., Broadie, T. A., Ransburg, R. C., & males (Damiani et al. 1992). African-American
Mc Carthy, L. J. (1981). Glycogen-rich clear cell car-
cinoma of the breast: A light and electron microscopic women are more frequently affected than Cau-
study. Cancer, 48, 2003–2009. casian women (Torous et al. 2017).
Kim, Z. E., Koo, J. S., & Jung, W. H. (2012). • Site
Immunophenotypes of glycogen rich clear cell carci- GCT is usually located in the upper-internal
noma. Yonsei Medical Journal, 53(6), 1142–1146.
Markopoulos, C., Mantas, D., Philipidis, T., Kouskos, E., quadrant of the breast, even if all the breast
Antonopoulou, Z., Hatzinikolaou, M. L., & Gogas, H. quadrants can be affected, comprising the axil-
(2008). Glycogen-rich clear cell carcinoma of the lary tail (Damiani et al. 1992, Torous et al.
breast. World Journal of Surgical Oncology, 6, 44. 2017). GCT of the breast can be located both G
in the deep parenchyma and in the subcutane-
ous tissue. Cases deeply located and infiltrating
the pectoralis muscle are on record (Damiani
Granular Cell Tumor et al. 1992). Cases arising in the retro-areolar
region can cause nipple retraction. Subcutane-
Maria P. Foschini and Luca Morandi ous lesions can cause skin retraction.
Department of Biomedical and Neuromotor • Treatment
Sciences (DIBINEM), Unit of Anatomic GCT is more frequently benign; therefore it is
Pathology at Bellaria Hospital, University of usually treated with tumor resection, with clear
Bologna, Bologna, Italy margins. Sentinel lymph node dissection is not
needed. Correct treatment largely depends on
correct preoperative diagnosis. As GCT fre-
Synonyms quently mimics malignancy both on clinical
and histological grounds (Torous et al. 2017),
Abrikossoff’s tumor, Granular cell myoblastoma sometimes an erroneous aggressive treatment
is performed.
Aggressive treatment is needed in those rare
Definition cases showing malignant features.
• Outcome
Granular cell tumor (GCT) is a rare tumor, of Most of breast GCT follow a benign clinical
neurogenic derivation, composed of cells with course. Recurrences can appear when initial
pale and granular cytoplasm. surgical excision has not achieved free
margins.
Clinical Features
Macroscopy
• Incidence
GCT usually arises in the tongue, but all the On macroscopy GCT presents as a firm nodule,
organs can be affected. About 6% of GCT gray-whitish in color. Margins are more fre-
arises in the breast (Damiani et al. 1992; quently invasive, therefore simulating a breast
Sanguinetti et al. 2016; Rexeena et al. 2015). carcinoma. Rare cases with well-defined margins,
• Age simulating fibroadenoma have been described
Breast GCT most frequently presents in middle (Damiani et al. 1992). Size varies, but it is usually
aged women, but age can vary from puberty to smaller than 3 cm.
120 Granular Cell Tumor
Microscopy Immunophenotype
On histology breast GCT is similar to GCT of other GCT cells are typically strongly and diffusely immu-
body sites. It is characterized by a proliferation of noreactive with S-100 protein. In addition, CD68,
cells with wide, pale eosinophilic granular cyto- carcino-embryonic antigen (CEA), vimentin, and
plasm (Figs. 1 and 2). Nucleus is centrally located, calretinin have been described as positive
small, with delicate chromatin, and inconspicuous (Sanguinetti et al. 2016; Rexeena et al. 2015). Epithe-
nucleolus (Fig. 3a, b). Cytoplasmic granules are lial markers as low and high molecular weight
positive with PAS after diastase reaction. No in cytokeratins, epithelial membrane antigen, and apo-
situ carcinoma or lymph-vascular invasion is seen. crine marker GCDFP-15 are negative. Estrogen, Pro-
GCT has invasive margins, therefore infiltrat- gesterone and Androgen receptors are negative as
ing the surrounding breast and fat tissue. well as HER2 does not show features of amplification.
Mitoses, cellular atypia, and necrosis are usually Proliferative index, as evaluated with Ki67, is low.
absent, as most of the GCT are benign. These latter On electron microscopy the GCT cells show
features can be encountered in those rare cases of numerous membrane-bound vesicles, mostly
malignant GCT (Sanguinetti et al. 2016; Rexeena filled with flocculent and solid electron-dense
et al. 2015). material (Damiani et al. 1992).
Granular Cell Tumor,

Fig. 1 GCT of the breast
shows infiltrative margins
(H&E)

Fig. 2 GCT of the breast is
composed of granular cells;
there is no evidence of in
situ carcinoma (H&E)
Granular Cell Tumor 121

Fig. 3 (a) and (b) GCT is
composed of cells with
granular cytoplasm, bland
nuclei, and inconspicuous
nucleolus (H&E)
Molecular Features can be difficult. Difficulty may be enhanced during

frozen section examination or in preoperative
No molecular data have been reported on GCT of diagnosis.
the breast, to the best of our knowledge. One case On histological examination, GCT differs from
of multiple GCT has been described in association invasive carcinoma NST for the bland cytological
with LEOPARD Syndrome caused by mutation in features, absence of nuclear atypia and of mitotic
PTPN11 (Schrader et al. 2009). figures. In addition, invasive carcinoma is usually
associated with in situ carcinoma that is lacking in
GCT cases (Torous et al. 2017). When paraffin
Differential Diagnosis embedded sections are under examination, immu-
nohistochemistry can be of great help, evidencing
The breast can harbor a great variety of neoplastic the typical profile, with S-100 protein positivity
lesions, characterized by granular and eosinophilic and negativity for epithelial markers.
cells (Eusebi et al. 1995; Damiani et al. 1999). Benign stromal spindle cell tumors (BSST) of
The more frequent and most important differen- the breast (Tavassoli and Eusebi 2009), with pre-
tial diagnosis is invasive lobular carcinoma dominant myofibroblastic differentiation, can, on
(▶ Invasive Lobular Carcinoma), particularly the occasion, present granular cytoplasm. The typical
lobular histiocytoid variant. GCT simulates malig- immunophenotype, characterized by positivity for
nancy on clinical, radiological, and pathological CD34, BCL2, smooth muscle actin, desmin, is
features, and sometimes the differential diagnosis useful to differentiate the two lesions.
122 Granulomatous Mastitis
Once the diagnosis of GCT is achieved, it is Synonyms

important to differentiate benign from malignant
lesions. Granulomatous lobular mastitis; Idiopathic
Malignant GCT is diagnosed when nuclear granulomatous mastitis (IGM)
atypia (vesicular nuclei with evident nucleoli),
presence of mitotic figures (more than 2 per
10 high power fields), and necrosis are observed Definition
(Rexeena et al. 2015).
Granulomatous mastitis is a benign condition,
defined by a granulomatous inflammation in the
References breast, specifically an inflammatory infiltrate com-
posed of histiocytes, sometimes epithelioid, accom-
Damiani, S., Koerner, F. C., Dickersin, G. R., Cook, M. G., panied by multinucleated giant cells. Other types of
& Eusebi, V. (1992). Granular cell tumour of the breast.
inflammatory cells may be associated with it: lym-
Virchows Archiv. A, Pathological Anatomy and
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and granular cell tumors of the breast. Seminars in dition, and its etiology includes infectious and non-
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Eusebi, V., Foschini, M. P., Bussolati, G., & Rosen, P. P.
(1995). Myoblastomatoid (histiocytoid) carcinoma of The term idiopathic granulomatous mastitis
the breast. A type of apocrine carcinoma. The American (IGM) was first used by Kessler and Wolloch in
Journal of Surgical Pathology, 19(5), 553–562. 1972 (Kessler and Wolloch 1972). This is a diag-
Rexeena, B., Paul, A., Nitish, R. A., Kurian, C., &
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of Surgical Oncology, 6(4), 446–448. be no extra-mammary lesion and no biologic
Sanguinetti, A., Polistena, A., Lucchini, R., Monacelli, M., inflammatory syndrome, but association with ery-
Galasse, S., Avenia, S., Bugiantella, W., Triola, R.,
thema nodosum is possible. Current hypotheses on
Cirocchi, R., Rondelli, R., & Avenia, N. (2016).
Myoblastoma of the breast: Our experience and review the etiology of IGM include extravasation of lacta-
of literature. International Journal of Surgery Case tional secretions during breastfeeding, response to
Reports, 20S, 5–7. local trauma, metabolic or hormonal processes, and
Schrader, K. A., Nelson, T. N., De Luca, A.,
underlying autoimmune or infectious processes
Huntsman, D. G., & McGillivray, B. C. (2009). Multi-
ple granular cell tumors are an associated feature of (principally Corynebacteria infection) that cannot
LEOPARD syndrome caused by mutation in PTPN11. be detected by usual techniques (Bani-Hani et al.
Clinical Genetics, 75(2), 185–189. 2004). Idiopathic granulomatous mastitis can
Tavassoli, F. A., & Eusebi, V. (2009). Benign soft tissue
lesions. In Tumors of the mammary gland (FIP Atlas of
mimic breast malignancy, clinically, radiographi-
tumor pathology, series 4, p. 281). Washington, DC: cally (Fig. 1), and cytologically upon fine-needle
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the Armed Forces Institute of Pathology.
Torous, V., Schnitt, S. J., & Collins, L. C. (2017). Benign
breast lesions that mimic malignancy. Pathology, 49(2),
181–196. Clinical Features
• Incidence
IGM is rare, encountered in less than 0.5% of
Granulomatous Mastitis breast samples (Fazzio et al. 2016).
• Age
Noëlle Weingertner and Jean-Pierre Bellocq IGM mainly affects childbearing age women,
Department of Pathology, Strasbourg University most often in postpartum or breastfeeding
Hospital, Strasbourg, France mothers (Fazzio et al. 2016). The age at
Granulomatous Mastitis 123
Granulomatous Mastitis,
Fig. 1 Idiopathic
granulomatous mastitis –
mammographic features.
Mammography shows
nodular opacities (stars).
Courtesy of Dr Sébastien
Molière, Department of
Radiology, Strasbourg
University Hospital
diagnosis is generally 20–50 years (age range, (Lai et al. 2005). Treatment of IGM
11–83 years) (Seo et al. 2012). is not standardized, but corticosteroids and
• Sex methotrexate are generally used, as primary
Mainly females. Males may rarely be affected treatment or after surgery to prevent recur-
(Seo et al. 2012). rences. Steroids can be used before surgery to
• Site shrink the mass (Cheng et al. 2015). Topical
IGM equally affects the right or left breast, corticosteroids may be effective (Tahmasebi
bilaterality being exceptionally rare. Oran et al. 2016) and prevent systemic adverse
et al. found the most frequent site of the lesion effect. Antibiotics are sometimes used in com-
was the upper outer quadrant, followed by the bination with these treatments (D’Alfonso
inferior outer quadrant, the areola, the inferior et al. 2015). Surgery is controversial due to
inner quadrant, and the upper inner quadrant poor wound healing, fistula formation, and dis-
(Oran et al. 2013). ease recurrence (Tahmasebi et al. 2016), with
• Treatment reported recurrence rates after surgery as high
Spontaneous resolution occurs in 50% as 50% (Pereira et al. 2012). It is usually
of patients after a mean duration of 14.5 months reserved for refractory or aggressive cases. It
is recommended that implants not be used if Therefore, tissue core biopsy with histologic
breast reconstruction is undertaken (Pereira evaluation is the most reliable diagnostic method.
et al. 2012), because the implant may act as a Histologic evaluation demonstrates non-
foreign body and trigger further granulomatous necrotizing granuloma, with an infiltrate of multi-
inflammation. Clinical follow-up is also nucleated giant cells, epithelioid histiocytes,
recommended. plasma cells, and lymphocytes. A neutrophilic
• Outcome infiltrate may also occur with formation of micro-
Variable recurrence rates (5.5–50%) are abscesses (Pereira et al. 2012). A histological
reported in the literature (Seo et al. 2012) pattern of neutrophil aggregates surrounding
with complications including sinuses requiring microcystic spaces associated with the granulo-
draining and abscess formation. The patients matous inflammation has been called “cystic neu-
often have to undergo multiple surgical pro- trophilic granulomatous mastitis”. This subset of
cedures. Upon resolution, common sequelae granulomatous mastitis is reported to be linked to
include scarring, retraction of skin and nipple, Corynebacterium species infection in some cases
and shrinkage of breast tissue (Pereira et al. (Gautham et al. 2019) (Figs. 2 and 3). Eosinophils
2012). Therefore, IGM is disfiguring and pain- can also be seen. The inflammation is centered on
ful but does not pose a threat to general health. lobules (Fig. 4), but extensive inflammation may
There is no evidence that this condition obliterate this feature.
increases the incidence of breast carcinoma The diagnosis of IGM should be made after
(Pereira et al. 2012). exclusion of all other possibilities and specific
etiological features (Differential Diagnosis).
Necrosis (apart from microabscesses occasion-
Macroscopy ally), foreign body material, infective agents, or
vasculitis should not be present. Proper evaluation
The most common clinical/macroscopic presenta- of the specimen requires special stains to search
tion is one or multiple firm, unilateral, and palpa- for mycobacteria and a variety of other organisms
ble breast mass(es), often associated with and also requires that samples for microbial exam
inflammation of the overlying skin, with “peau and cultures are obtained in specific conditions.
d’orange” appearance being possible. The mass
can vary in size from 1 to 10 cm (Pereira et al.
2012) and is gray-tan and irregular. The lesion is Immunophenotype
painful in approximately 25% of cases (Korkut
et al. 2015). Skin ulceration, nipple discharge There are no particular immunohistochemical
or nipple retraction, abscesses, sinus formation, features in IGM. A pankeratin immunostaining
fistulas, and axillary lymphadenopathy may be may be helpful to exclude underlying breast
seen, this latter in approximately 15% of patients carcinoma.
(Seo et al. 2012; Korkut et al. 2015). Bilateral
involvement has been described. Rare patients
are asymptomatic, with an abnormality detected Molecular Features
on mammography (Fazzio et al. 2016).
Mammography may show nodular opacities To date, no particular molecular feature has been
(Fig. 1). described for IGM.
Microscopy Differential Diagnosis
IGM can mimic breast malignancy cytologically One of the most important clinical differential
(Al-Khaffaf et al. 2008; Oran et al. 2013). diagnoses of IGM is breast carcinoma. Indeed, in
Granulomatous Mastitis,
Fig. 2 Cystic neutrophilic
granulomatous mastitis –
microscopic features
(microbiospy, H&E 10):
inflammatory infiltrate with
epithelioid cells,
macrophages and
neutrophil leucocytes
forming non-necrotizing
granulomas (stars). This
type of granulomatous
mastitis has association
with Corynebacteria
Granulomatous Mastitis, Fig. 3 Cystic neutrophilic Granulomatous Mastitis, Fig. 4 Idiopathic granuloma-
granulomatous mastitis – microscopic features tous mastitis – microscopic features (microbiospy,
(microbiospy, H&E 20). The inflammatory infiltrate is H&E 20): Multinucleated giant-cells (arrow)
in contact with a lobule and shows a cyst-like space
surrounded by neutrophil leucocytes
Non-tuberculous Infectious Granulomatous
Mastitis
more than 50% of cases, the initial diagnosis was Infection is the first possibility to consider when
suspected to be breast cancer (Seo et al. 2012). faced with an inflammatory granulomatous
Furthermore, a granulomatous inflammation may infiltrate of the breast. Infectious granulomatous
occasionally accompany an infiltrating carci- mastitis can be due to mycobacteriosis,
noma, and this situation must be ruled out before bartonellosis (cat scratch disease), brucellosis,
a diagnosis of granulomatous mastitis is made, corynebacteriosis, and salmonella typhi, as well
particularly in postmenopausal women. as fungal agents such as histoplasma and parasites
Once malignancy is excluded, pathologists such as filariasis. These granulomatous inflamma-
have to think about other causes of mammary tions are often necrotizing. Therefore, special
granulomatous inflammation before a diagnosis stains are essential in considering granulomatous
of IGM can be made. mastitis, including PAS, Grocott, Ziehl-Neelsen,
and Gram. When possible, some tissue should be well-circumscribed, non-necrotizing granulomas
sent to bacteriology, mycology, and parasitology with epithelioid histiocytes and multinucleated
laboratories. giant cells, which may contain asteroid or
Schaumann bodies.
Tuberculosis of the Breast Mammary localization of vasculitis is rare,
Tuberculosis of the breast is rare in Western coun- with approximately 40 cases described in the
tries, accounting for less than 1% of tuberculous literature. Suggestive clinical context is often
cases, and is most frequent in endemic zones. present. Nevertheless, patients often present a
Its incidence can increase in immunosuppressed breast mass, and biopsies of these lesions are
patients. Patients are mostly female, 20 to 50 years therefore taken to exclude malignancy. With
old. Breast tuberculosis is most frequently sec- microbiopsies, when the vasculitis is not known,
ondary to a generalized tuberculous infection the diagnosis is very difficult to ascertain and can
(Korkut et al. 2015). It may infrequently be often only be suggested. Therefore, pathologists
primary, due to main galactophorous duct lesion, have to analyze the vessels carefully in cases of
linked to a trauma during pregnancy or lactation. granulomatous mastitis.
Patients present in general with a breast mass, or Granulomatosis with polyangiitis mainly
an abscess, sometimes associated with satellite affects the respiratory tract and the kidneys, but
axillary lymphadenopathy. Histological aspects rarely the breast. Patients are mostly females, aged
are similar to its appearance in other organs, 40 to 50. In general, breast lesions are accompa-
with an inflammatory infiltrate of epithelioid his- nied by respiratory tract and kidney involvement,
tiocytes, with Langhans-type multinucleated giant associated with biological inflammatory syn-
cells accompanied by lymphocytes and occasion- drome and ANCA antibodies. Breast lesions pre-
ally by neutrophils. Caseous necrosis is character- sent as one or multiple breast lump(s), uni- or
istic and is the main pathologic aspect bilaterally, measuring 2–6 centimeters (Pereira
differentiating IGM from tuberculous mastitis et al. 2012). The skin may be retracted, ulcerated,
(Pereira et al. 2012). As in other organs, Ziehl- or with “peau d’orange” effect, and axillary
Neelsen staining rarely identifies acid-fast bacilli. lymphadenopathy may be present.
Histologically, non-well-circumscribed epithe-
Granulomatous Mastitis Associated with lioid and giant-cell granulomas are associated
Systemic Diseases with large geographic zones of “blue necrosis”
Granulomatous mastitis can be part of systemic (due to the large amounts of basophilic nuclear
diseases such as sarcoidosis, granulomatosis with debris) and vasculitis of small- and medium-sized
polyangiitis (Wegener’s granulomatosis), giant- vessels. Eosinophils may be encountered.
cell arteritis (Horton disease), rheumatoid arthri- Giant-cell arteritis (Horton’s disease) has been
tis, necrobiotic xanthogranuloma, etc. Extranodal described in all branches of the subclavicular
Rosai-Dorfman disease of the breast has also been artery. The breast is vascularized by the internal
reported (Chen et al. 2016) and may appear as a mammary artery and lateral thoracic artery, which
granulomatous process. are branches of the subclavicular artery.
The histological features of systemic disease- Patients are 50 to 80 years old. It presents as
associated granulomatous mastitis are quite clas- one or several, frequently painful breast lumps
sic, similar to the histology seen in other organs. (Pereira et al. 2012). Bilaterality is encountered
Sarcoidosis-related mastitis is rare (less than in approximately 50% of cases. General symp-
1% of sarcoidosis) and, in the large majority of toms are often present, with arthralgias, anorexia,
cases, occurs in the context of generalized disease asthenia, fever, myalgia, biological inflammatory
with pulmonary, cutaneous, lymph node, articular, syndrome, and headache. Histologically, an
and ocular manifestations (Pereira et al. 2012). inflammatory infiltrate centered on small- and
Patients present with one or several breast medium-sized arterial vessels is composed of
masses. Histology is characterized by small, macrophages and giant cells with lymphocytes
and neutrophils. The inflammatory infiltrate is often refracting under polarized light) or second-
segmental and focal, with fragmentation of ary to macrobiopsy or to breast implant (Oran
the internal elastic lamina. et al. 2013).
Necrobiotic xanthogranuloma displays degen- Breast implants are in general composed of
eration of collagen fibers and foam cells besides silicone. A fibrous capsule develops surrounding
the granulomas (Cheng et al. 2015). Benign the implant. The pocket of the implant can fissure
monoclonal gammopathy or myeloma is associ- with a clinical aspect of skin fixation and retrac-
ated with 80% of cases. tion. Axillary lymphadenopathy may be encoun-
tered. Periprosthetic capsules may be addressed
Granulomatous Mastitis Associated with to the pathologists. The inflammatory infiltrate
Trauma, Surgery, or Foreign Body Material is composed mainly of macrophages, with a
Cytosteatonecrosis (▶ Breast Fat Necrosis) is in “pseudo-synovial” palisaded disposition on the
general secondary to a trauma or a surgery internal side of the capsule. Multinucleated for-
(Pereira et al. 2012), but may be spontaneous, eign body giant cell may be seen sometimes asso- G
especially in older women. Clinical presentation ciated with optically clear holes corresponding to
may be worrisome, particularly if the trauma is not silicone, which is non-refracting. Lymphocytes
known or forgotten. The forms of trauma are may be associated. Pathologists have to examine
many: traumas of everyday life, massage, pressure these specimens carefully, to exclude a carcinoma
related to mammography, cyst aspiration, core and a breast implant-associated lymphoma
biopsy, mammoplasty, implant removal, radiation (▶ Breast Implant-Associated Malignant Lym-
therapy, etc. The lesion may persist several phoma), the latter being recently described
months or years after the trauma. Women with (Laurent et al. 2016).
large (adipous) breasts are particularly at risk. Rarely, nodular deposition of amyloid can
Fat necrosis presents as a breast mass, sometimes cause granulomatous reaction in the breast,
with skin retraction. Cystic zones may be seen on which will be diagnosed with special stains
ultrasonography, and there may be calcifications (Cheng et al. 2015).
on mammography (D’Alfonso et al. 2015).
The macroscopic aspect is characteristic, with Other Conditions
adipose tissue appearing pale yellow. Fibrosis, Other conditions may be associated with a granu-
pseudocysts, and calcifications are seen in lomatous inflammation of the breast tissue, such
old lesions. Histologically, an inflammatory infil- as subareolar abscesses, duct ectasia, or
trate is centered on adipose tissue, composed of hidradenitis suppurativa.
foamy macrophages, multinucleated giant cells, Subareolar abscess (SA) is also known as
lymphocytes, and plasma cells. Hemorrhage may Zuska’s disease, mastitis obliterans, or lactiferous
be seen in the acute phase. Immunohistochemistry fistula (Pereira et al. 2012). It results from obstruc-
can be helpful to rule out a carcinoma (particularly tion, distension, inflammation, and rupture of the
a lipid-rich carcinoma or a carcinoma with lactiferous ducts. SA occurs when the normal
“histiocytoid” morphology), which would be pos- epithelium of the distal ducts undergoes squa-
itive in fat necrosis for histiocytic markers such mous metaplasia and keratin obstructs the duct
as CD163 and CD68 and negative for pankeratin lumen. The duct may then rupture, and release of
(D’Alfonso et al. 2015). Lipid pseudocysts, calci- keratin into the breast parenchyma leads to an
fications, and ossifications can be seen in old inflammatory response. Granulomatous inflam-
lesions. When cytosteatonecrosis is secondary to mation is a common histologic feature in the
radiotherapy, cytological atypia in fibroblasts, chronic stage of SA. Nipple discharge is common,
endothelial cells, or mammary epithelial cells usually non-bloody, whereas it is not a common
may be seen. feature in IGM. Smoking is a major risk factor for
Foreign body granulomas may be encountered SA, in contrast to IGM, which is often associated
and associated with surgical thread (which is with pregnancy and lactation. The SA abscess
involves the main lactiferous ducts and occurs just Cheng, L., Reddy, V., Solmos, G., Watkins, L.,
below the nipple and areola, whereas IGM involves Cimbaluk, D., Bitterman, P., Ghai, R., & Gattuso,
P. (2015). Mastitis, a radiographic, clinical, and Histo-
the breast lobules at the periphery of the breast. pathologic review. The Breast Journal, 21, 403–409.
Fistulas from SA involve the nipple and areola, D’Alfonso, T. M., Ginter, P. S., & Shin, S. J. (2015).
whereas fistulas from IGM can occur in any part A review of inflammatory processes of the breast
of the breast. Histologically, keratinizing squamous with a focus on diagnosis in Core biopsy samples.
Journal of Pathology and Translational Medicine,
epithelium can be observed in SA, and the inflam- 49, 279–287.
mation is localized around the ducts. These features Fazzio, R. T., Shah, S. S., Sandhu, N. P., &
are not observed in IGM. Glazebrook, K. N. (2016). Idiopathic granulomatous
In duct ectasia, subareolar ducts are dilated, mastitis: Imaging update and review. Insights Imaging,
7, 531–539.
full of milk-like or butter-like secretion, Gautham, I., Radford, D. M., Kovacs, C. S., Calhoun, B.
surrounded by fibrosis of variable intensity, and C., Procop, G. W., Shepardson, L. B., Dawson, A. E.,
accompanied by a chronic inflammatory infiltrate Downs-Kelly, E. P., Zhang, G. X., Al-Hilli, Z., Fan-
also of variable intensity that may sometimes ning, A. A., Wilson, D.A., Sturgis, C. D. (2019) Cystic
neutrophilic granulomatous mastitis: The Cleveland
become granulomatous (periductal mastitis, Clinic experience with diagnosis and management.
comedomastitis). The Breast Journal, 25, 80–85.
Hidradenitis suppurativa can involve the Kessler, E., & Wolloch, Y. (1972). Granulomatous masti-
breast, but the breast localization is usually asso- tis: A report of seven cases. American Journal of Clin-
ical Pathology, 58, 642–646.
ciated with axillary and inguinal involvement Korkut, E., Akcay, M. N., Karadeniz, E., Subasi, I. D., &
(Pereira et al. 2012). Granulomatous inflamma- Gursan, N. (2015). Granulomatous mastitis: A ten-year
tion is present in the chronic stages. experience at a university hospital. The Eurasian Jour-
In conclusion, when dealing with a granulo- nal of Medicine, 47, 165–173.
Lai, E. C., Chan, W. C., Ma, T. K., Tang, A. P., Poon, C. S.,
matous inflammation in breast specimens, pathol- & Leong, H. T. (2005). The role of conservative treat-
ogists have to: ment in granulomatous mastitis. The Breast Journal.
11, 454–456.
• Rule out an underlying breast carcinoma Laurent, C., Delas, A., Gaulard, P., Haioun, C.,
Moreau, A., Xerri, L., Traverse-Glehen, A., Rousset,
• Search for foreign body material T., Quintin-Roue, I., Petrella, T., Emile, J. F., Amara,
• Think about a possible infection, and therefore N., Rochaix, P., Chenard-Neu, M. P., Tasei, A. M.,
search for necrosis and use special stains or, Menet, E., Chomarat, H., Costes, V., Andrac-Meyer,
more especially, microbiologic analyses on L., Michiels, J. F., Chassagne-Clement, C.,
De Leval, L., Brousset, P., Delsol, G., & Lamant,
fresh tissue if possible L. (2016). Breast implant-associated anaplastic large
• Analyze vessels carefully, searching for cell lymphoma: Two distinct clinicopathological vari-
vasculitis ants with different outcomes. Annals of Oncology, 27,
• Of course be aware of the clinical context 306–314.
Oran, E. S., Gürdal, S. Ö., Yankol, Y., Öznur, M., Calay, Z.,
Tunaci, M., & Soybir, G. R. (2013). Management of
idiopathic granulomatous mastitis diagnosed by core
biopsy: A retrospective multicenter study. The Breast
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Pereira, F. A., Mudgil, A. V., Macias, E. S., &
Al-Khaffaf, B., Knox, F., & Bundred, N. J. (2008). Karsif, K. (2012). Idiopathic granulomatous lobular
Idiopathic granulomatous mastitis: A 25-years experi- mastitis. International Journal of Dermatology, 51,
ence. Journal of the American College of Surgeons, 142–151.
206, 269–273. Seo, H. R., Na, K. Y., Yim, H. E., Kim, T. H., Kang, D. K.,
Bani-Hani, K. E., Yaghan, R. J., Matalka, I. I., & Oh, K. K., Kang, S. Y., An, Y. S., Chun, M., Kim, W.,
Shatnawi, N. J. (2004). Idiopathic granulomatous mas- Park, R. W., Jung, Y. S., & Kim, K. S. (2012).
titis: Time to avoid unnecessary mastectomies. The Differential diagnosis in idiopathic granulomatous
Breast Journal, 10, 318–322. mastitis and tuberculous mastitis. Journal of Breast
Chen, Y. P., Jiang, X. N., Lu, J. P., Zhang, H., Li, X. Q., & Cancer, 15, 111–118.
Cheng, G. (2016). Clinicopathologic analysis of extra- Tahmasebi, S., Karami, M. Y., & Maalhagh, M. (2016).
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Gynecomastia 129
Approximately 50% of adult are affected, pre-

Gynecomastia dominantly by pseudogynecomastia.
• Age
Celien Vreuls and Paul J. van Diest In general gynecomastia there are three peaks
Department of Pathology, University Medical described during life, the neonatal, pubertal,
Center Utrecht, Utrecht, The Netherlands and aging gynecomastia. In neonates,
estrogen levels are high due to exposure to
maternal estrogens. In puberty there is a
Definition relative increase in estrogen production, and
in aging men there is an imbalance with
Gynecomastia is derived from the Greek terms increasing estrogen and decreasing testos-
“gyne” meaning feminine and “masto” meaning terone levels.
breasts. Gynecomastia is defined as an increase in • Sex and Site
the size (hypertrophy) of male breast tissue. Gynecomastia by definition occurs only in G
Gynecomastia is subdivided into a “genuine” men. The breast region is the preferred site of
form with increase in glandular tissue and a occurrence, although very rare cases of axillary
“pseudo” form with increase in fat or a benign gynecomastia have been described (Vega
tumor (pseudogynecomastia). et al. 2015).
• Treatment and Outcome
In male patients with new onset of gynecomas-
Clinical Features tia, the underlying cause (medications, occu-
pational exposure to estrogens or
Gynecomastia presents as a benign uni- or bilat- hyperthyroidism) should be determined and
eral swelling of the breast and is often seen in treated. Usually, within a few weeks there is
newborn male infants, adolescent, and elderly improvement of the gynecomastia. If there is
men. Gynecomastia is not a separate disease entity no improvement after several months, medical
but rather a symptom. Hormonal imbalance treatment for gynecomastia can be tried
between stimulation of estrogens and inhibition (Narula and Carlson 2014).
of androgens is the key factor in the pathogenesis Medical treatment is probably most effec-
of gynecomastia, although the most common tive in the early stage (florid type) of gyneco-
cause for this is idiopathic (Braunstein 1993). mastia, since in the later stage the stroma
Underlying medical conditions such as obesity, becomes fibrotic, making medical therapy
hypogonadism, adrenal disease, thyroid disease, largely ineffective in men with long-standing
cirrhosis, renal failure, and malnutrition may con- gynecomastia. Medical therapy for gyneco-
tribute to this condition. Tumors of the adrenal mastia is based on decreasing estrogen pro-
glands, pituitary, lungs, and testicles can induce duction and/or increasing the levels of
hormonal changes resulting in imbalances and androgens.
ultimately gynecomastia. Medications that have Surgery can be considered in men with
been shown to contribute to this condition include long-standing, symptomatic gynecomastia, if
digoxin, thiazides, estrogens, phenothiazines, and the patient does not respond to medical ther-
theophylline (Sansone et al. 2017). apy, or if the patient prefers surgery for cos-
metic reasons or wants immediate correction of
• Incidence gynecomastia (Narula and Carlson 2014). Sur-
At least 30% of all males will be affected gery may consist of suction lipectomy or
during their life. Gynecomastia is seen in up removal of glandular breast tissue through a
to 90% of newborns, 40–70% during puberty, periareolar or axillary incision. If the underly-
and 30–40% of the general adult male ing cause of gynecomastia is not ruled out,
population, usually mild manifestations. recurrence is possible after surgery.
130 Gynecomastia
Macroscopy Gynecomastia can be divided into three types,

reflecting stages of development: the florid type,
The tissue is soft, firm, and gray/white on the cut reflecting recent onset; the fibrous (quiescent or
surface. The specimens have a unifying shape of a inactive) type, probably the end stage of gyneco-
head, body, and tail. The head is semicircular in mastia (>6–12 months); and the intermediate
shape and is located more medially toward the type, with features of both florid and fibrous types.
sternum. The majority of the glandular tissue con- The florid type shows increased periductal
sists of a body located immediately deep to the stromal cellularity, with often prominent vascular-
nipple areolar complex. The tail appears to taper ity and edema (Fig. 1a), concentrically forming
off of the body more laterally and toward the around the rudimentary ducts that show ductal
insertion of the pectoralis major muscle onto the epithelial hyperplasia; this can be of usual type
humerus (Blau et al. 2016). or with papillary projections. In the intermediate
type, radially expanding concentric fibrosis
around individual ducts starts to merge (Fig. 1b).
Microscopy In the fibrous (end stage) type, usually after
12 months, the lesion is quiescent, and the ubiq-
The male breast is composed of rudimentary ducts uitously confluent fibrous collagen-rich compo-
usually without lobule formation. If exposed to nent dominates, and edema and epithelial
high levels of endogenous or exogenous estrogen, proliferation are less prominent (Fig. 1c).
for example, in male-to-female transsexuals in Pseudoangiomatous stromal hyperplasia
whom progestative chemical castration is com- (PASH) (▶ Pseudoangiomatous Stromal Hyper-
bined with feminizing estrogen therapy, full aci- plasia) is often present in gynecomastia, particu-
nar and lobular formation occurs with hormonally larly in the florid type (Milanezi et al. 1998).
stimulated nuclei and pseudolactational changes PASH has a characteristic growth pattern of
(Kanhai et al. 2000). inter-anastomosing clefts that are, as the name
Gynecomastia, Fig. 1 (H&E) Low-power hematoxylin intermediate type shows increasing concentric fibrosis
and eosin stains illustrate the three types of gynecomastia. around the individual ducts which start to merge (b). The
The florid type shows edematous increased periductal stro- fibrous type shows confluent fibrous collagen-rich stroma
mal cellularity concentrically forming around the rudimen- and less prominent epithelial proliferation (c)
tary ducts that show ductal epithelial hyperplasia (a). The
Gynecomastia 131
Gynecomastia, Fig. 2 Medium-power hematoxylin and Gynecomastia, Fig. 3 High-power hematoxylin and
eosin stain illustrates pseudoangiomatous stromal hyper- eosin stain illustrates gynecomastoid hyperplasia. The
plasia (PASH). The inter-anastomosing clefts are angulated duct is lined by several layers that tuft into the lumina;
and slit-like, lined by myofibroblasts and surrounded by note the pyramid shape of the tufts (H&E)
wavy, acellular collagenous stroma (H&E)
Atypical ductal hyperplasia (ADH) G
suggests, lined by myofibroblasts and not by (▶ Atypical Ductal Hyperplasia) and ductal carci-
endothelium, thereby positive for stromal markers noma in situ (DCIS) (▶ Ductal Carcinoma In
like vimentin only and not for (lympho)vascular Situ), two known clonal precursor lesions for
markers. The spaces are angulated and slit-like breast cancer in females, have rarely been
and surrounded by wavy, acellular collagenous reported in male breasts with gynecomastia
stroma. The myofibroblasts are spindle to ovoid (Hamady et al. 2005; Doebar et al. 2017). DCIS
but are not atypical (Fig. 2). Multinucleated giant is the most commonly observed precursor lesion
cells can be seen. in male breast cancer, and its presence seems to be
The rudimentary ducts in gynecomastia are associated with favorable outcome (Doebar et al.
lined by at least three cell layers: an outer layer 2017). It usually concerns the papillary variant or
of myoepithelial cells and two layers of epithelial low-grade DCIS (▶ Intraductal Papillary Carci-
cells. The myoepithelial cells may have clear noma), although all the subtypes described in
cytoplasm. The intermediate luminal layer con- women can occur in men. DCIS is mainly associ-
sists of cuboidal to columnar vertically orientated ated with invasive breast cancer.
cells, with regular oval nuclei and occasional The presence of lobular carcinoma in situ
small nucleoli. The cytoplasm is eosinophilic (▶ Lobular In Situ Neoplasia) has also been
with indistinct cell borders, and these cells often described but is very rare, in line with the rarity
show luminal tufts. The inner luminal layer com- of invasive lobular cancer (▶ Invasive Lobular
prised slightly smaller and more horizontally ori- Carcinoma) in men (Doebar et al. 2005).
entated cells, most often arranged in a single layer,
with regular to slightly irregular small nuclei and
sporadic small nucleoli (Kornegoor et al. 2012b). Gynecomastia and Invasive Cancer
More layers may be present, resembling the
sloppy ductal hyperplasia of usual type of the The role of gynecomastia in the development of
female breast, with flat peripheral layers or a mildly male breast cancer (▶ Male Breast Cancer)
cribriform architecture with irregular lumina with remains uncertain. Gynecomastia is often seen
regard to spacing, shape, and size, or a central sea alongside invasive breast cancer, but gynecomas-
of epithelium with slit-like peripheral residual tia is also frequently encountered in healthy men
lumina. Some tufting into the lumina may be pre- (Braunstein 1993; Fentiman et al. 2006). How-
sent, and micropapillae showing a pyramid shape ever, other studies found a significant correlation
instead of the rod shape of micropapillae of clonal between gynecomastia and male breast cancer
female breast epithelial proliferations usually (Brinton et al. 2010).
denoted gynecomastoid hyperplasia (Fig. 3). It has been suggested that there is a difference
Microcalcifications and secretions are very rare. in carcinogenesis between male and female breast
132 Gynecomastia
cancer. One of the largest series of male breast SMA+ and CD34- staining are not specific to malig-
cancers demonstrates that luminal type A is by far nancy because such findings are also encountered in
the most common breast cancer subtype in males. reactive fibrosis (Kalekou et al. 2005).
Luminal type B breast cancer is less common and In most cases moderate to strong Bcl-2
represents a subgroup of ER-positive tumors with staining is seen in stromal cells, especially in
highly malignant phenotype. HER2-driven, basal- florid and intermediate types. p21 shows spo-
like, and unclassifiable triple-negative breast can- radic positive cells in the surrounding stroma,
cers in men seem to be very rare. This distribution and p53 shows wild-type expression. Prominent
of breast cancers subtypes in men is different stromal staining is often seen for EGFR, espe-
compared with females (Kornegoor 2012a). cially in the presence of PASH (Kornegoor et al.
2012a). PASH areas do not stain with (lympho)
vascular makers like D2–40 (podoplanin),
Immunophenotype LYVE-1, and CD31.
Epithelium
The normal ductal male breast epithelial cells are Molecular Features
very often ER and Bcl-2 positive (>69%), and PR
and AR expression is also common (>39%). As Until now no chromosomal abnormalities have been
described above, gynecomastia appears to show a detected in cases of gynecomastia with no other
consistent three-layered pattern. The immunohis- concomitant breast disease. For male DCIS and
tochemical pattern is distinctive as the outer invasive cancer, however, a clonal relationship has
myoepithelial layer shows expression of CK5, been described, based on similar copy number pro-
CK14, and p63. The two epithelial cell layers file for 21 out of 22 interrogated breast cancer-related
differ from each other. The intermediate luminal genes, underlining that DCIS is a true precursor for
layer, consisting of vertically oriented cuboidal to male invasive breast cancer (▶ Male Breast Cancer)
columnar cells, is hormone receptor positive and (Vermeulen et al. 2017). Doebar et al. showed iden-
expresses Bcl-2 and CyclinD1. The inner luminal tical genomic aberrations, including PIK3CA,
layer is composed of smaller cells expressing CK5 GATA3, TP53, and MAP2K4 mutations, based on
and often CK14 but are usually negative for hor- next-generation sequencing (Doebar et al. 2017). For
mone receptors and Bcl-2. All epithelial cells male breast cancer it has been suggested that the
show strong staining with CK7 and E-cadherin. X chromosome gain plays a role in the neoplastic
HER2 staining is completely negative in the epi- transformation of male breast epithelial cells and that
thelium, and BRST2 and EGFR are also almost the gain of chromosome 5, loss of the
always negative. Only wild-type p53 staining is Y chromosome, loss of chromosome 17, and del
seen in ductal epithelium (Kornegoor (18)(q21) are described as nonrandom abnormalities
et al. 2012b). (Di Oto et al. 2015).
Male DCIS is consistently ER positive and
CK5/CK14 negative. Ki67-positive cells are
rarely seen in the intermediate and inner luminal Differential Diagnoses
layers (Kornegoor et al. 2012a).
The main most important differential diagnosis is to
Stroma discriminate gynecomastia from male breast cancer
The immunophenotype of periductal connective tis- (▶ Male Breast Cancer), especially if it is a unilat-
sue stroma in gynecomastia appears to parallel the eral, fixed palpable mass with nipple discharge
phenotype of normal breast stroma. In male breast (Johnson and Murad 2009). Mammography and
carcinoma the stromal cell immunophenotype is high-resolution ultrasound can be helpful to distin-
similar to that of its female counterpart showing guish between these breast lesions (Munoz
myofibroblastic differentiation. However, alpha- Carrasco et al. 2010). Also pseudogynecomastia
Gynecomastia 133
and other benign lesions, such as lipoma, hema- Johnson, R. E., & Murad, M. H. (2009). Gynecomastia:
toma, fat necrosis (▶ Breast Fat Necrosis), dermoid Pathophysiology, evaluation, and management. Mayo
Clinic Proceedings, 84, 1010–1015.
cyst, sebaceous cyst, or lymphoplasmacytic inflam- Kalekou, H., Kostopoulos, I., Milias, S., & Papadimitriou,
mation, should be considered. C. S. (2005). Comparative study of CD34, alpha-SMA
and h-caldesmon expression in the stroma of
gynaecomastia and male breast carcinoma. Histopa-
thology, 47, 74–81.
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H
Hamartoma Clinical Features
Catherine N. Chinyama • Incidence

Department of Pathology, Princess Elizabeth In the premammographic era, breast hamar-
Hospital, St Martins, Guernsey, tomas went largely unrecognized. With the
Channel Islands, UK introduction of screening mammography, the
Brighton and Sussex Medical School, realization that a hamartoma is a stand-alone
Brighton, UK pathological entity is on the rise. The incidence
of hamartomas is reported to be between 0.4
and 1.15% and constitutes about 4.8% of all
Synonyms benign breast tumors (Wu et al. 2003).
Hamartomas have been reported in Cauca-
Adenolipofibroma; Adenolipoma; Fibroade- sians, Asian, and African patients (Herbert
nolipoma; Lipofibroadenoma et al. 2002).
• Age
The age of patients with mammary
Definition hamartomas ranges from 18 to 89 years with
a mean age of 45 years and a median age of
Hamartoma is from Greek hamartia meaning 43 years (Daya et al. 1995); typical presenta-
“fault, defect” and -oma denoting a tumor or tion is in the third to fifth decade.
neoplasm. (Seth 2017). The pathological • Sex
definition of a hamartoma, irrespective of Mammary hamartomas affect predominantly
site of origin, is an abnormal proliferation women although a case has been reported in a
of tissue indigenous to the organ to create a man (Amir and Sheikh 2016).
mass or tumor. In the breast, the constitu- • Presentation
ents of the mass include fat, fibrous tissue, When symptomatic, a hamartoma presents with
and epithelial elements. Although previously a painless soft to firm palpable lump with the
described, Arrigoni and colleagues are given clinical diagnosis of a fibroadenoma but not as
credit for increasing the awareness of the firm as a fibroadenoma (Tse et al. 2002). The
existence of a breast hamartoma (Arrigoni lump is usually present for a long duration with
et al. 1971). little or no change in size. Screen-detected

https://doi.org/10.1007/978-3-319-62539-3
136 Hamartoma
hamartomas tend to be small and

asymptomatic. However, there are reported
cases of hamartomas that grow slowly to pro-
duce giant lesions associated with breast asym-
metry and pressure symptoms such as
discomfort and lymphedema as in the case
reports of giant hamartomas which weighed
450 g and 1497 g, (Cazorla and Arentz 2015).
Most patients present with single lesions but a
patient with two hamartomas has been reported
(Herbert et al. 2002).
• Site
Hamartomas affect the left and right breasts
equally; however, some reports document a
higher prevalence in the right breast than the
left (Amir and Sheikh 2016).
• Mammographic Features
The mammographic features of a hamartoma
are considered “fairly characteristic.” The
lesion is well-defined, oval shaped, with a
smooth margin and consists of a mixture of
fat and fibroglandular tissue with or without a Hamartoma, Fig. 1 A mammorgram of a 41-year-old
pseudocapsule (Wu et al. 2003). Lobulated woman shows relatively well-circumscribed mass
densities may be present within the encapsu- 100 mm in diameter. There is little or no variation in the
lated fat and are referred to as “slices of salami hormogencity of the lesion. The histology showed a
harmatoma consisting of predominantly fibrous compo-
or sausages.” These densities may be associ- nent with minimal fat depostion
ated with benign round microcalcification
(Erdem et al. 2011). The main defining feature
is the presence of fat which gives the lesion. The histology showed a hamartoma
hamartoma a heterogeneous appearance. with a predominantly fibrous component with
Because the constituents of the hamartoma minimal fat deposition. In contrast a screen-
resemble normal breast tissue, the lesion is detected hamartomas tend to be small as illus-
sometimes referred to as a “breast in breast” trated in Fig. 2 in a 50-year-old woman. The
(Erdem et al. 2011). The hamartoma can con- lesion was 19 mm in diameter and located
tain excess fat, equal mixture of fat and above the nipple with a typical fatty halo.
fibroglandular tissue or minimal fat with This was a follow-up mammogram 6 months
excess fibroglandular tissue. The mammo- later and the lesion had not increased in size.
graphic density varies according to the amount Microcalcification is rare in hamartomas
of fat and fibroglandular tissue in the lesion; and when present raises the possibility of
more fat will induce radiolucency to the lesion. malignancy. However, benign dystrophic cal-
The different mammographic features are cification has been reported in some
illustrated in Figs. 1 and 2. Figure 1 is a mam- hamartomas (Park et al. 2003).
mogram of a 41-year-old woman who pre- • Sonographic Features
sented with a mass in the right breast, The characteristic sonographic feature of a
clinically suspicious of a large fibroadenoma hamartoma is compressibility with transducer
(▶ Fibroadenoma) or phyllodes tumor pressure (Park et al. 2003; Chao et al. 2007).
(▶ Phyllodes Tumor). The mammogram This gives the tumors a longer transverse dimen-
shows a 10 cm dense well-circumscribed sion than the anteroposterior diameter i.e. an
Hamartoma 137
Hamartoma, Fig. 3 Ultrasonogrphic features of screen- H

detected hamartoma in a 50-year-old woman; the charac-
teristic oval shape is due to the compressibility of the lesion
Hamartoma, Fig. 2 Screen-detected hamartoma in a

50-year-old woman. The lesion is 19 mm in diameter
with a characteristic fatty halo. This was a repeat
mammogramm at 6 months and the lesion had not grown
in size
‘oval shaped’ or ‘lens shaped’ appearance. The

oval shape of the hamartoma due to compress-
ibility under ultrasound scan is illustrated in
Fig. 3 in a screen-detected lesion. The majority
of hamartomas have well-circumscribed smooth
margins. The internal echo texture is variable
consisting of hyperechoic, mixed heteroge-
neous echogenicity or isoechoic. Some tumors
have heterogenous echogenicity with mixed
isoechogenecity and hyperechogenicity. The
variable echo texture depends on the proportion Hamartoma, Fig. 4 Symptomatic 20 mm hamartoma in
of fat and fibroglandular tissue in the a 88-year-old woman illustrating variable echogenecity on
hamartoma. Variable echogenicity is illustrated ultrasonography; note the irregular border
in Fig. 4 in a symptomatic hamartoma in an
88-year-old woman. The hamartoma in charac- phenomenon which is a feature in a malignant
terized by irregular borders and heterogeneous lesion. Cystic areas are frequent in sonographic
internal contents. Echogenic halos or anechoic images (Wu et al. 2003).
halos are present in some hamartomas due to • Magnetic Resonance Imaging (MRI)
compression between the hamartoma and the Features
surrounding breast tissue. The majority of Because hamartomas generally display benign
hamartomas lack retro-tumor acoustic features on mammography and ultrasound,
138 Hamartoma
patients are rarely referred for MRI. Conventional • Treatment

T1 and T2 weighted MRI of mammographically Asymptomatic, screen-detected biopsy con-
and sonographically proven hamartomas demon- firmed hamartomas can be left in situ and the
strates heterogeneous intensities due to the fatty patient is subjected to close surveillance.
and fibroglandular content of the lesions plus a Symptomatic patients are offered surgery
thin capsule. Enhancement of lesions is grad- because the diagnosis is not always conclusive.
ual on dynamic contrast-enhanced (DCE)- • Outcome
MRI. Although not routinely used in the work Surgery is usually curative and patients have
up of hamartomas, MRI can be a useful ancil- an excellent prognosis; however a patient with
lary investigation where the mammographic recurrent hamartoma has been reported. The
and sonographic features are inconclusive, recurrence was due to incomplete surgical
and there is need to exclude cancer (Erdem excision (Tse et al. 2002).
et al. 2011).
• Diagnosis
Macroscopy
Similar to any other breast lesion, the definitive
diagnosis of a hamartoma should be attained
Hamartomas tend to be single, well-
following triple assessment consisting of clin-
circumscribed lesions ranging in size from 1 to
ical examination, radiological assessment, and
10 cm (McGuire and Cohn 1991). The cut surface
pathological evaluation. Fine needle aspiration
may be grey-white in color. The surface may be
cytology is rarely diagnostic in hamartomas,
glistening. The lesion may be encapsulated. There
because the material yield is usually inade-
is no hemorrhage or necrosis. Fat may or may not
quate or may sample normal breast epithelium
be readily apparent on naked eye examination.
with no diagnostic features. Needle core biop-
There is no lobulation usually seen in
sies can be diagnostic if supported by radiolog-
fibroadenoma (▶ Fibroadenoma). Small cysts
ical findings. Because of the resemblance to
may be present.
normal breast tissue, pathologists can easily
overlook this lesion as normal breast tissue.
Figure 5 illustrates a needle core from a
mammographically detected hamartoma Microscopy
showing a variable mixture of fibroglandular
tissue and fat. In the absence of a localized When supported by mammographic and sono-
radiological abnormality, this can be errone- graphic features, the needle core biopsy of a
ously reported as nonspecific fibrosis or nor- hamartoma can be diagnostic and this can spare
mal breast tissue. the patient surgery in screen-detected lesions. As
illustrated in Fig. 5, the needle core biopsy from a
hamartoma consists of a variable mixture of fat
and fibrous tissue containing benign ducts and
lobular units.
The true characteristics of a hamartoma are
better appreciated in the excised specimen. The
proliferation of mostly fibrous stroma obliterates
the normal interlobular architecture. The fibrous
stroma can exhibit variable degrees of
hyalinization and may resemble scar tissue. The
most common feature which differentiates
Hamartoma, Fig. 5 A needle core biopsy from a
hamartomas from other well-circumscribed
mammographically detected hamartoma showing a mix-
ture of fibrofatty tissue with benign ducts and lobular units benign lesions is the presence of fat in the fibrous
resembling normal breast tissue (H&E) stroma. The amount of fat is variable. The fat can
Hamartoma 139
be present as isolated adipocytes, in clusters or as and CD31. Pseudoangiomatous hyperplasia is a

diffusely in a large area. The epithelial component common feature in the stroma of hamartomas
can also be heterogeneous. The ducts and lobular (Tse et al. 2002). Figure 7 illustrates pseudo-
units can be normal depending on the age of the angiomatous hyperplasia in a needle core biopsy
patient, hence the “breast in breast” concept. The from the same patient in Fig. 6. The needle core
epithelial component can be atrophic or exhibit biopsy was reported as suspicious of PASH.
hyperplasia without atypia, cystic change with or However, on excision the lesion was a
without apocrine metaplasia. Figure 6 illustrates hamartoma with pseudoangiomatous changes in
the heterogeneous microscopic features in an the stroma. Other features noted in hamartomas
excised hamartoma, but with a predominantly on microscopic examination include micro-
fibrous component, sparsely distributed benign calcification. Smooth muscle can also be present
ducts, lobular units, cystic change, mucin filled in hamartomas and when present in excess, the
ducts, and myxoid degeneration of the stroma. lesion is termed a myoid hamartoma (Amir and
Rare adipocytes are scattered in the stroma. Sheikh 2016).
Pseudoangiomatous hyperplasia (PASH)
(▶ Pseudoangiomatous Stromal Hyperplasia) in H
the stroma is characterized by irregular slit-like Pathogenesis
spaces which resemble capillaries but are nega-
tive for endothelial markers such as factor VIII The pathogenesis of hamartomas is unclear. It is
thought to be a developmental abnormality rather
than a true neoplasm. Initially the abnormality
was thought to be related to pregnancy and lacta-
tion (Hogamen and Ostberg 1968). However, sub-
sequent studies did not support this hypothesis as
hamartomas also arise in nulliparous women.
Although pregnancy and lactation may influence
the growth of a hamartoma, there is no evidence of
pathogenetic relationship.
Immunophenotype
Hamartoma, Fig. 6 Symptomatic hamartoma consisting
of a predominantly dense hyalinized stroma with atrophic One of the characteristic immunophenotypic fea-
sparsely distributed ducts and lobular units (H&E) tures of hamartomas is that both the stroma and
epithelial elements are positive for estrogen recep-
tors and progesterone receptors, i.e., ER and PR
positive (Herbert et al. 2002). This differentiates
hamartomas from normal breast tissue which is
usually ER and PR positive in the epithelium, but
ER and PR negative in the stroma. This suggests
simultaneous response to hormonal stimulation of
the constituents of the hamartoma (Fig. 8). As
expected the epithelial elements are positive for
cytokeratins and the stroma for vimentin similar to
normal breast tissue. Hamartomas do not express
HER2 or p53 and the Ki67 proliferation activity is
Hamartoma, Fig. 7 Pseudoangiomatous hyperplasia in a
needle core biopsy from a hamartoma in Fig. 6 which could usually low (Herbert et al. 2002). Markers such as
have led to erroneous diagnosis of primary PASH (H&E) desmin highlight smooth muscle fibers in the
140 Hamartoma
Hamartoma, Fig. 8 The hamartoma from the patient in Fig. 6 expresses estrogen receptors (a) and progesterone
receptors (b) in the stroma and epithelial components. The PR appears stronger than the ER
hamartoma or support the diagnosis of a myoid gastrointestinal tract, bone, central nervous sys-
hamartoma. tem, eyes and genitourinary tract (Fiala (2016)
Medscape). Cowden syndrome is associated with
malignancy in particular breast cancer and thyroid
Genetic Aberrations cancer. Gomez et al. (2012) reported a carcinoma
of the breast arising in a calcified hamartoma. The
As the breast hamartoma is not considered neo- case was unusual in that although Cowden syn-
plastic there are very few genetic studies on this drome is a multiple hamartoma syndrome, breast
lesion. Aberrations involving 12q12-15 in a breast hamartomas are not even in the minor criteria for
hamartoma were reported independently by dif- diagnosis of this condition, but breast cancer is a
ferent authors (Dietrich et al. 1994 and Rohen major diagnostic criterion. Furthermore, the patient
et al. 1995). Using FISH studies, the authors had bilateral breast microcalcification which on
reported aberrations involving 12q12-15 which mammography involved over two-thirds of the
was mapped to the multiple aberration region breasts. Massive calcification is not one of the
(MAR). The MAR is a major cluster region of features of hamartomas. This link between PTEN
chromosome 12 breakpoints of benign solid mutations and breast hamartoma confirmed an ear-
tumors such as uterine leiomyoma, lipoma and lier study by the same authors (Sabate et al. 2006)
pleomorphic adenoma of the salivary gland. The which reported hamartomas in two patients with
authors identified the aberrations in the stroma Cowden syndrome.
and not the epithelial cells and concluded that
hamartomas arose due to mutated mesenchymal
stromal cells, and therefore adenolipomas or Differential Diagnosis
hamartomas of the breast were not due to
entrapped epithelial cells and mesenchymal cells The most common lesion which mimics a
with proliferating adipocytes but mutated mesen- hamartoma clinically is a fibroadenoma
chymal cells capable of differentiating into stro- (▶ Fibroadenoma). Fibroadenomas tend to affect
mal cells as well as adipocytes. younger women in the 20–30 age groups. Although
Breast hamartomas have also been linked to clinically and radiologically fibroadenomas resem-
Cowden disease. Cowden disease also termed ble hamartomas, pathologically the two lesions are
Cowden syndrome or multiple hamartoma syn- very different, more significantly, fibroadenomas
drome is an autosomal dominant condition with lack fat infiltration. Furthermore the epithelial com-
variable expression associated with the mutation ponent of a fibroadenoma can be very heteroge-
of the PTEN suppressor gene on 10q23.3 neous to include: sclerosing adenosis (▶ Sclerosing
(Liaw et al. 1997). Cowden disease causes Adenosis), fibrocystic change (▶ Fibrocystic Breast
hamartomatous neoplasms of the skin, mucosa, Changes) with apocrine metaplasia, columnar cell
Hamartoma 141
change (▶ Columnar Cell Lesions), epithelial detected. The well-circumscribed lesions could
hyperplasia of usual type (▶ Usual Ductal Hyper- be difficult to differentiate from a hamartoma
plasia (UDH)) without atypia. The fibroadenoma radiologically. However, the lack of sonographic
is lobulated and the epithelial proliferation exhibits compressibility in the fibrous tumor should dis-
the so called intracanalicular or pericanalicular tinguish this lesion from a hamartoma. Fibrous
growth patterns. In older patients, fibroadenomas tumors can be clinically palpable but radiologi-
become hyalinized with reduced cellularity but cally occult, which is not the case with a
with preservation of the lobular architecture. The hamartoma. In the absence of appropriate radio-
stroma in fibroadenoma is also prone to myxoid logical studies, a fibrous tumor can be difficult to
degeneration. If these features are present, the diag- differentiate from a hamartoma in a needle core
nosis of hamartoma would be questionable. biopsy (Fig. 9). In the presence of fat, a fibrous
Fibroadenomatoid hyperplasia is thought to be tumor can mimic a hamartoma with a predomi-
a harbinger of a fibroadenoma and can be difficult nantly fibrous component. The cause of a fibrous
to differentiate from a hamartoma on a needle core tumor is unknown but transforming growth factor
biopsy. This lesion consists of small lobules of beta (TGF-beta) is implicated in promoting spin-
hyalinized stroma admixed with benign ducts and dle cell proliferation (Gold 1999). H
lobular units. Inclusion of fat in the needle core Diabetic mastopathy can mimic a hamartoma
biopsy may give rise to erroneous diagnosis of radiologically. Histologically, the diagnosis
hamartoma. However, the lobulated architecture should be clear because of the presence of lobular
of a fibroadenomatoid hyperplasia plus the radio- mastitis in the background of fibrotic stroma with
logical findings should exclude a hamartoma. or without islands of mature adipocytes
Tubular adenoma (▶ Tubular Adenoma of the (▶ Diabetic Mastopathy).
Breast) which belongs to the same family as Pseudoangiomatous stromal hyperplasia
fibroadenoma can mimic a hamartoma clinically (PASH) (▶ Pseudoangiomatous Stromal Hyper-
and radiologically, but the histological appearance plasia) can be present as a primary lesion of the
of crowded tubules usually with luminal secre- breast but can arise in the stroma of other breast
tions with no intervening stroma has no resem- lesions such as gynecomastia or hamartoma. The
blance to a hamartoma. Coincidentally, a patient main pathological appearance of PASH is the
with a tubular adenoma of the breast and Cowden presence of slit-like structures which resemble
disease was reported in the same study which capillaries in the stroma. If a needle core biopsy
reported two patients with PTEN mutation in samples the pseudoangiomatous component in a
hamartomas (Sabate et al. 2006). hamartoma, as illustrated in Fig. 7, it is almost
Phyllodes tumors (▶ Phyllodes Tumor) arise in impossible to exclude primary PASH; more so
the same age groups as hamartomas. A giant
hamartoma (Cazorla and Arentz 2015) would be
clinically indistinguishable from a phyllodes
tumor. However, histologically the increase in
cellularity of the stroma with associated clefting
would distinguish a phyllodes tumor from a
hamartoma (▶ Phyllodes Tumor).
Fibromatosis of the breast may clinically and
radiologically mimic a hamartoma, but the pre-
dominance of a cellular infiltrative fibrous prolif-
eration with no epithelial elements is
characteristic of this lesion and clearly differenti- Hamartoma, Fig. 9 Needle core biopsy from a palpable
but mammorgraphically and sonographically occult
ates it from a hamartoma.
fibrous tumor. The stroma is hyalinized with a scar-like
Fibrous mastopathy or fibrous tumor can be appearance. The presence of fat and benign ducts and
present symptomatically or mammographically lobular units resembles a hamartoma (H&E)
142 Hamartoma
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hamartoma (Fig. 10). literature. Korean Journal of Radiology, 11, 687–691.
Daya, D., Trus, T., D'Souza, T. J., Minuk, T., & Yemen, B.
(1995). Hamartoma of the breast, an underrecognized
breast lesion: A clinicopathologic and radiographic
Breast Cancer Risk study of 25 cases. American Journal of Clinical Pathol-
ogy, 103, 685–689.
Hamartomas have no documented risk of progres- Dietrich, C. U., Pandis, N., Andersen, J. A., & Heim, S.
(1994). Chromosome abnormalities in adenolipomas of
sion to malignancy nor are they a marker for
the breast: Karyotypic evidence that the mesenchymal
breast cancer. A review of the literature component constitutes the neoplastic parenchyma.
documented several case reports of breast cancers Cancer Genetics and Cytogenetics, 72, 146–150.
arising in patients with known hamartomas on a Erdem, G., Karakas, H. M., Isik, B., & Firat, A. K. (2011).
Advanced MRI findings in patients with breast
surveillance program or cancer arising in a
hamartomas. Diagnostic and Interventional Radiology,
hamartoma identified during the investigation of 17, 33–37.
mass, either radiologically or pathologically Fiala, K. H. (2016) Cowden disease (multiple hamartoma
(Choi and Ko 2010). The important message syndrome). emedicine.medscape.com/article/1093383-
overview. Accessed 18 Nov 2017.
from this review is for the clinician to take heed
Gold, L. I. (1999). The role for transforming growth factor-
of changing radiological features during surveil- beta (TGF-beta) in human cancer. Critical Reviews in
lance of a biopsy proven hamartoma in particular, Oncogenesis, 10, 303–360.
the presence of new calcification. Breast cancer Gómez García, E. B., Lobbes, M. B., van de Vijver, K.,
Keymeulen, K., van der Ent, F., Yntema, H. G., et al.
arising in a calcifying hamartoma in patients with
(2012). Occult breast cancer due to multiple calcified
Cowden disease was previously described in this hamartomas in a patient with Cowden syndrome. Case
chapter (Gomez et al. 2012). In this case, the Reports Radiology, 638725.
Hemangioma of the Breast 143
Herbert, M., Sandbank, J., Liokumovich, P., Yanai, O., Definition

Pappo, I., Karni, T., et al. (2002). Breast hamartomas:
Clinicopathological and immunohistochemical studies
of 24 cases. Histopathology, 41, 30–34. Hemangioma is a benign proliferation of endothe-
Hogamen, K., & Ostberg, G. (1968). Three cases of post- lial cells that tend to vasoformation, a generic term
lactational breast tumour of peculiar type. Acta for a variety of hamartomatous lesions comprising
Pathologica et Microbiologica Scandinavica, vascular tissue. Hemangiomas in the breast are a
73, 169–176.
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L., Wang, S. I., benign group of lesions with a broad morphologic
Zheng, Z., et al. (1997). Germline mutations of the spectrum (Table 1).
PTEN gene in Cowden disease, an inherited breast
and thyroid cancer syndrome. Nature Genetics,
16, 64–67.
McGuire, L.I., & Cohn, D. (1991). Hamartoma of the Clinical Features
breast. Aust NZ J Surg, 61, 713–716.
Metcalf, J. S., & Ellis, B. (1985). Choristoma of the breast. • Incidence
Human Pathology, 16, 739–740. Breast hemangiomas are rare entities,
Park, S. Y., Oh, K. K., Kim, E. K., Son, E. J., &
Chung, W. H. (2003). Sonographic findings of breast accounting for 0.4% of all breast tumors,
hamartoma: Emphasis on compressibility. Yonsei and occur more often in the breast skin. H
Medical Journal, 44, 847–854. They have to be differentiated from atypical
Rohen, C., Caselitz, J., Stern, C., et al. (1995). vascular lesions (▶ Atypical Vascular
A hamartoma of the breast with an aberration of 12q
mapped to the MAR region by fluorescence in situ Lesions). Coexistence of hemangiomas with
hybridization. Cancer Genetics and Cytogenetics, other breast lesions (e.g., ▶ Fibroadenoma)
84, 82–84. can occur.
Sabaté, J. M., Gómez, A., Torrubia, S., Blancas, C., • Age
Sánchez, G., Alonso, M. C., et al. (2006). Evaluation
of breast involvement in relation to Cowden syndrome: At any age, from birth to late age. Younger
A radiological and clinicopathological study of patients patients mainly have capillary hemangiomas
with PTEN germ-line mutations. European Radiology, in the breast skin.
16, 702–706. • Sex
Seth, R. Hamartoma. emedicine.medscape.com/article/
1254012-overview. Accessed 27 Oct 2017. Slight female predilection. Estrogens may be
Tse, G. M. K., Law, B. K. B., Ma, T. K. F., Chan, A. B. W., implicated in its development.
Pang, L. M., Chu, W. C. W., & Cheung, H. S. (2002). • Site
Hamartoma of the breast: A clinicopathological review. Most often in the breast skin, followed by
Wu, C. Y., Lin, S. H., Tu, S. H., Huang, C. S., & Jeng, hemangiomas in the subcutaneous fatty tissue.
C. M. (2003). Hamartoma of the breast. Chinese They can also develop in the breast paren-
Journal of Radiology, 28, 143–148. chyma, including the intralobular and peri-
ductal connective tissue. Perilobular
hemangiomas can be bilateral (Tavassoli and
Eusebi 2009).
Hemangioma of the Breast • Size
From a microscopic size up to 18 cm large
Anikó Kovács1 and Ute Krüger2 mass over 1000 g in weight. Angiomatosis
1
Department of Clinical Pathology, Sahlgrenska may measure 9–22 cm. Microscopic heman-
University Hospital, Gothenburg, Sweden giomas are incidental histological findings
2
Department of Pathology, County Hospital, which represent capillary hemangiomas any-
Kalmar, Sweden where in the breast, even in the perilobular
and periductal stroma. These lesions can be
unifocal or mutifocal, which usually remain
Synonym clinically occult and unapparent. Macro-
scopic hemangiomas are mostly cavernous
Angioma hemangiomas that can reach a palpable size
144 Hemangioma of the Breast
Hemangioma of the Breast, Table 1 Classification of mammary hemangiomas
Hemangiomas
of the breast:
localized: diffuse:
angiomatosis
nonparenchymal: parenchymal:
cutaneous
hemangiomas
cavernous: non-cavernous: complex:

• sinusoidal • perilobular • cavernous
• atypical • capillary and capillary
• venous
• epitheloid
• atypical
and can be revealed by mammography mammograms and with high density or

(Fig. 1. Radiogram, ultrasound, and histolog- equal to the density of the breast parenchyma.
ical features of cavernous hemangioma). At ultrasonography, hemangiomas appear as
Hemangiomas of larger size may cause swell- hypoechoic, oval, lobulated masses with
ing and deformity of the breast simulating circumscribed and sharp margins. MRI of
inflammatory carcinoma. breast hemangioma may show a lesion with
• Diagnostics internal slow flow and draining vessels,
Difficult to diagnose preoperatively using areas of hemorrhage, thrombosis, and
conventional imaging modalities since breast venous lakes. The differentiation from
hemangiomas lack pathognomonic character- angiosarcomas (▶ Angiosarcoma of the
istics. A high percentage of hemangiomas Breast) can be difficult. Minority of vascular
are diagnosed incidentally during imaging neoplasms contain microcalcification,
analysis. The diagnosis of hemangioma phleboliths, and thrombosis. Anamnesis
should be verified by histopathological exam- about previous irradiation of the breast is
ination after a clinical diagnosis made by important.
ultrasound and mammography, along with • Treatment
magnetic resonance imaging (MRI). They Local excision or follow-up with imaging
are diagnostically challenging in small core examination. A complete excision is
biopsies (Howitt and Nascimento 2012). recommended for angiomatosis, as it has
Hemangiomas in the breast parenchyma a potential for local recurrence. In
produce round opacities and lobular-shaped children, both surgery and radiotherapy of
masses with circumscribed, microlobulated, cutaneous breast hemangiomas may result
and well-circumscribed margin on in mammary hypoplasia (Tavassoli and
Hemangioma of the Breast, Fig. 1 A 10 mm large septa between them (c H&E, 100 magnification). Mam-
cavernous hemangioma of the breast in a 52-year-old mography (a) and ultrasonography picture (b) by courtesy
female patient. The tumor is composed of dilated, blood- of Dr. Eva Molnar, Department of Radiology, Sahlgrenska
filled spaces of different sizes and shape with thin fibrous University Hospital, Gothenburg, Sweden
Eusebi 2009). Any vascular lesion with instability or ulceration and should prevent
atypical morphology on a needle core or correct deformity.
biopsy should be completely excised, • Outcome
regardless of the degree of Ki-67, to exclude Favorable, but hemangiomas can grow over time.
an underlying angiosarcoma. Treatment of Malignant transformation is rare; they are not
hemangiomas should avoid hemodynamic likely precursors of angiosarcoma.
Macroscopy In patients with Kasabach-Merritt syndrome

(hemangioma-thrombocytopenia syndrome),
Hemangiomas are usually soft, lobulated, well- hemangiomas can be multiple and of variable
circumscribed lesions, albeit unencapsulated size. Moreover, they may become progressively
with red or dark-brown, spongy, and hemorrhagic larger over time.
appearance on cut surface. Discoloration of the Perilobular hemangioma is the most common
skin may occur if the lesion is near the skin surface vascular lesion in the breast comprising incidental
or it is located in the subareolar region. microscopic findings smaller than 5 mm with
a reported frequency of 1–12%. These capillary
hemangiomas in the intra- or the extralobular
Microscopy stroma form vessels as delicate capillary-
like spaces (Fig. 2a, b H&E) Rarely, perilobular
All vascular lesions of the skin and soft hemangioma is associated with lobular carcinoma
tissue can be diagnosed in the breast. Mammary in situ (LCIS) (Fig. 2c and 2d). The endothelial
hemangiomas represent benign vascular lesions cells lining the spaces are flat without hyper-
which are well circumscribed and lack endothelial chromasia or atypia. Hemangiomas are not encap-
hyperplasia and atypia without interanastomos- sulated and sometimes show anastomosing small
ing vascular channels like in angiosarcoma. vessels. These features may produce diagnostic
Hemangioma of the Breast, Fig. 2 (a, b) Perilobular (H&E staining, 40 and 100 magnification). (c) Neg-
hemangioma as an incidental finding in a 57-year- ative E-cadherin immunostaining in LCIS (200 magnifi-
old female patient. The coexistence of perilobular cation). (d) Positive 34bE12 immunostaining in LCIS
hemangioma and lobular carcinoma in situ (LCIS) (100 magnification)
pitfalls. Furthermore, some vascular channels Sinusoidal hemangioma is a distinctive variant

may show a dissecting growth pattern (Howitt of acquired cavernous hemangioma (Calonje and
and Nascimento 2012). Perilobular hemangiomas Fletcher 1991). It is a well-circumscribed tumor in
may be multiple and bilateral, which require no the deep dermis and the subcutaneous tissue
treatment (Tavassoli and Eusebi 2009; Howitt and which shows intercommunicating vascular chan-
Nascimento 2012). nels arranged in sinusoidal patterns and back-to-
Capillary hemangiomas are composed of back arrangements without much intervening
proliferating capillary-sized blood vessels and stroma and with pseudopapillary growth. Vessel
usually remain clinically occult. They are charac- walls are lined by flattened endothelial cells with
terized by compact or lobular collections of focal pleomorphism and hyperchromatic nuclei.
small blood vessels that resemble a pyogenic Interconnected blood vessels with the presence of
granuloma. pseudopapillae has been described not only in
Cavernous hemangiomas are composed of sinusoidal hemangiomas but focally in spindle
dilated, blood-filled spaces of different sizes and cell hemangioma and juvenile hemangioma.
shapes with thin fibrous septa between them Venous hemangiomas consist of large venous
(Fig. 3 Cavernous Hemangioma: (a) Ultrasono- channels with variably thickened muscular walls H
graphic picture; (b) H&E). Areas of thrombosis, lined by a flat endothelial layer without atypia
infarction, and revascularization may be present. (Rosen et al. 1985).
Within these areas, an increase in the number of Epithelioid hemangioma (angiolymphoid
mitoses and calcification may be present. Micro- hyperplasia with eosinophilia) shows a prolifera-
papillary structures are consistent with recanaliza- tion of blood vessels surrounded by varying
tion. These findings hamper the diagnosis of amounts of inflammatory cells that encircle
preexisting hemangioma and can lead to the diag- but do not destroy the native breast epithelium.
nosis of an intravascular papillary endothelial The endothelial cells can be cuboidal or dome-
hyperplasia (Masson’s tumor) (Howitt and shaped with papillary tufting (Brodie and
Nascimento 2012). Provenzano 2008).
Complex hemangiomas are composed of a Atypical hemangiomas show conspicuous
mixture of both dilated vessels and small vessels, vascular anastomoses, papillary endothelial
as seen in cavernous and capillary hemangiomas, hyperplasia, ill-defined borders, cytological
respectively. abnormalities with mild degree of pleomorphism,
Hemangioma of the Breast, Fig. 3 A 3 mm large courtesy of Dr. Bronislava Vályová, Department of
cavernous hemangioma in a 64-year-old female Radiology, Sahlgrenska University Hospital, Gothenburg,
patient, in the mastectomy scar (b H&E staining, Sweden
100 magnification). Ultrasonography picture (a) by
occasional mitoses, and microthrombi. They can Erythrocyte-type glucose transporter protein
be categorized into four groups according to their 1 (GLUT1) immunoreactivity is found in
growth pattern: (a) cavernous, (b) compact capil- all phases of hemangiomas and can be helpful
lary, (c) capillary budding type, and (d) combined for differential diagnosis. Pericytes are a-SMA-
atypical hemangiomas with a combination of cav- positive, whereas most angiosarcomas lack this
ernous (a) and compact capillary subtype (b). marker.
There are no signs of destructive invasion, solid
areas, hemorrhage, or necrosis. Atypical heman-
giomas have no greater risk to develop into Differential Diagnosis
angiosarcoma.
Angiomatosis is an extensive, acquired, or Hemangiomas should be differentiated from
congenital vascular lesion in young women, angiosarcoma, atypical vascular lesions (AVLs),
which may involve large areas (9–22 cm) in the pseudoangiomatous stromal hyperplasia
breast growing as non-anastomosing cystic (PASH), Mondor’s disease, angiolipoma,
spaces in between but not infiltrating the breast papillary endothelial hyperplasia (Masson’s
glandular structures. The vascular spaces are tumor), Kaposi-form hemangioendothelioma,
lined by flat endothelial cells without atypia and hemangiopericytoma, epithelioid hemangioen-
mitotic activity. The presence of pericytes can be dothelioma, benign lymphangioendothelioma,
detected by a-smooth muscle actin (a-SMA) and lymphangioma.
positivity. Because of lacking the circumscrip- Cutaneous hemangioma should be differenti-
tion that characterizes mostly the other benign ated from low-grade, postradiation cutaneous
vascular lesions, distinction from a low-grade angiosarcoma in the breast (▶ Angiosarcoma of
angiosarcoma can be difficult. However, the Breast). Angiosarcomas are located usually in
angiomatosis surrounds the ducts and the lobules the breast parenchyma and are usually larger than
without invading them. Hormonal replacement 3 cm (Howitt and Nascimento 2012). They appear
therapy with the use of exogenous estrogen may as hemorrhagic masses which involves both the
favor the appearance of angiomatosis. mammary parenchyma and the overlying skin.
Angiosarcomas usually lack a-SMA. MYC gene
amplification has been detected in secondary,
Immunophenotype postradiation angiosarcomas but not in AVLs.
Amplification of FLT4 gene (which encodes
Endothelial markers are overexpressed for CD31, VEGFR-3 and belongs to the tyrosine kinase
CD34, factor VIII, and Fli-1. However, Fli-1 is a receptor family) was found in 25% of secondary
marker for both benign and malignant vascular angiosarcomas but not in AVLs.
tumors. The Ki-67 proliferation marker is rarely Atypical vascular lesions (AVLs) (▶ Atypical
>5% in breast hemangiomas, whereas in Vascular Lesions) are limited to the upper dermis
angiosarcomas, it is usually >20%. Ki-67 may in patients with prior exposure to radiation ther-
help to highlight proliferative activity in border- apy. Two distinct morphological patterns exist: a
line vascular lesions. However, increased Ki-67 lymphatic type and a vascular type. Occasionally,
immunoreactivity can be seen in a hemangioma at both types may be seen simultaneously within
the site of a prior core biopsy and in thrombi; the same lesion. The vascular type of the lesion
therefore, fields with these reactive lesions should shows round to linear, capillary-sized vessels
be avoided during assessment of Ki-67 index. The which grow irregularly within the superficial or
absence of cell cycle regulatory protein Skp2 can deep dermis. Moderate nuclear atypia may be
be used in combination with Ki-67 for hemangi- encountered, but no mitotic figures. The lesions
oma diagnoses. Androgen receptor expression frequently show endothelial hobnailing and anas-
may be seen in hemangiomas. tomosing vascular channels.
Pseudoangiomatous stromal hyperplasia malignant” behavior, often associated with

(PASH) (▶ Pseudoangiomatous Stromal Hyper- Kasabach-Merritt syndrome in children. The lesion
plasia) is frequently a microscopic incidental shows endothelial-derived spindle cell prolifera-
finding mimicking a vascular lesion. In a dense tion with dense hyaline stromal response, forming
collagenous stroma, there are slit-like, elongated, irregular nodules which contain glomeruloid nests
and regular interanastomosing spaces without of rounded or epithelioid endothelial cells with
red blood cells. Fibroblasts at the edges of these abundant eosinophilic cytoplasm. A lymphatic ori-
spaces resemble endothelial cells. They can be gin is evidenced by the expression of VEGFR-3
flat or plump, sometimes multinucleated, or can and D2–40.
aggregate into fascicles. Typically, PASH shows Hemangiopericytoma shows irregular,
immunostaining for vimentin and CD34, nuclear staghorn, and slit-like vascular channels within a
staining for progesterone receptor, but not for cellular stroma composed of mildly pleomorphic
estrogen receptor, factor VIII, and CD31. In round, oval, or elongated spindle cells with infre-
more cellular fascicular lesions, the stromal quent mitoses. The lesion may be partially encap-
cells acquired a-SMA and desmin positivity. sulated (Brodie and Provenzano 2008).
PASH can be seen in male patients with Epithelioid hemangioendothelioma comprises H
gynecomastia. epithelioid pleomorphic cells in cords and short
Mondor’s disease appears as a cord-like, tender strands with infiltrative margins within a
subcutaneous mass that comprises a phlebitis of the myxohyaline matrix. Intracytoplasmic lumina
vena thoracoepigastrica accompanied by peri- are present, occasionally containing erythro-
phlebitis and thrombosis (Fig. 4. (a, b) H&E. cytes. These tumors express not only vascular
(c, d, e) Masson trichrome). antigens such as CD31, CD34, and factor VIII,
Angiolipomas are diagnosed mostly in the skin but even cytokeratin 7 and 18, but not
as often painful and multiple lesions (Tavassoli cytokeratin 14 (Brodie and Provenzano 2008).
and Eusebi 2009). Histologically, they are an A cutaneous form of epithelioid hemangioen-
admixture of mature adipose tissue and capillary dothelioma presented as an ulcerated areolar
hemangioma often with hyaline microthrombi. As mass with recurrence 1 year after surgery.
hemangiomas, they also lack cellular atypia and CAMTA1 is useful for diagnosing epithelioid
show low mitotic activity. Vascular-predominant hemangioendothelioma.
cellular angiolipoma may be mistaken for heman- Benign lymphangioendothelioma shows large
giomas, but hemangioma shows vessels of vari- irregular empty spaces within stromal collagen and
ous calibers with no fibrin microthrombi (Howitt adipose tissue with lymphoid aggregates around the
and Nascimento 2012). vascular spaces (Tavassoli and Eusebi 2009).
Papillary endothelial hyperplasia (Masson’s Mammary lymphangiomas are uncommon,
tumor) is composed of vascular spaces lined by and they can occur both in children and adults,
endothelial cells without atypia, necrosis, or involving most commonly the upper-outer quad-
mitotic activity that surrounds hyalinized cores rant of the breast or the axillary tail.
representing organized and recanalized thrombus, Lymphangiomas constitute malformations with
measuring usually less than 2 cm in diameter with congenital weakness of lymphatic vessel walls
circumscribed margins. The papillary appearance causing blockage of the lymphatic channels
results from numerous elongated and branching that are unable to communicate with the
papillary fronds composed of dense and relatively venous network. They are poorly demarcated
acellular collagenous stroma. Papillary endothe- vascular lesions in the breast parenchyma with
lial hyperplasia arising in an irradiated breast has irregular spaces containing lymph and lympho-
been described. cytes. The vascular spaces are lined by a single
Kaposi-form hemangioendothelioma is a layer of D2–40-positive flattened endothelial
locally aggressive vascular tumor with “borderline cells.
Hemangioma of the Breast, Fig. 4 Mondor’s disease. lesion. (a, b) H&E staining (200 magnification). (c–e)
A 48-year-old female patient with abscess in the right Masson trichrome staining (100 , 200 and
breast. There was thrombophlebitis at the periphery of the 100 magnification)
References and Further Reading Howitt, B., & Nascimento, A. F. (2012). Vascular lesions
of the breast. Surgical Pathology, 5, 645–659.
Brodie, C., & Provenzano, E. (2008). Vascular prolifera- Rosen, P. P., Jozefczyk, M. A., & Boram, L. H. (1985).
tions of the breast. Histopathology, 52, 30–44. Vascular tumors of the breast. IV. The venous heman-
Calonje, E., & Fletcher, C. D. M. (1991). Sinusoidal hem- gioma. The American Journal of Surgical Pathology, 9,
angioma. A distinctive benign vascular neoplasm within 659–665.
the group of cavernous hemangiomas. The American Tavassoli, F. A., & Eusebi, V. (2009). Tumors of the mammary
Journal of Surgical Pathology, 15, 1130–1135. gland (AFIP atlas of tumor pathology, series 4, fascicles
10, pp. 283–290). Silver Spring, Maryland, USA.
HER2 in Breast Cancer 151
patients affected by an invasive carcinoma in

HER2 in Breast Cancer the neoadjuvant, adjuvant, and metastatic set-
tings. Other agents have been developed over
Laura Annaratone2, Ivana Sarotto1 and the years and are used in the metastatic setting
Caterina Marchiò1,2,3 or within the context of randomized clinical
1
Unit of Pathology, Candiolo Cancer Institute trials.
FPO-IRCCS, Candiolo, Italy After more than 15 years of translational
2
Department of Medical Sciences, research in HER2-positive breast cancer, several
University of Turin, Turin, Italy markers with prognostic value have been identi-
3
Institut Curie, Paris, France fied; however, the best predictive factor for
likeliness of response to anti-HER2 agents
remains HER2 overexpression/amplification.
Synonyms Recently, the NRG trial B-47 (ClinicalTrials.gov
identifier: NCT01275677) has confirmed the lack
ERBB2 of benefit from adjuvant trastuzumab for patients
whose tumors show a score 1+ or 2+ in immuno- H
histochemistry and lack of gene amplification
Definition (Fehrenbacher et al. 2018). Therefore, as stated
by the American Society of Clinical Oncology
HER2, whose official name is “erb-b2 receptor (ASCO) and College of American Pathologists
tyrosine kinase 2,” is a tyrosine kinase receptor (CAP) 2018 recommendations (Wolff et al.
belonging to the human epidermal growth factor 2018), HER2 gene amplification assessed by in
receptor family. It represents the second member situ hybridization (ISH) and protein over-
of this family (and therefore called HER2), and it expression assessed by immunohistochemistry
is an orphan receptor, meaning that no specific (IHC) remain the primary predictors of respon-
ligands are known for this receptor. siveness to HER2-targeted therapies in breast
cancer.
More recently, studies based on massively
Features parallel sequencing have unveiled the presence
of activating mutations affecting regions coding
About 15% of all invasive breast carcinomas pre- for the tyrosine kinase domain or for the trans-
sent HER2 overexpression and/or HER2 gene membrane domain. More frequently these muta-
amplification, thus identifying a subset of breast tions are found in the context of breast
carcinomas that can be treated in a targeted fash- carcinomas lacking HER2 overexpression
ion. It has been shown that HER2-positive breast and/or amplification. Currently the potential
carcinomas are often poorly differentiated and benefit of targeted anti-HER2 therapies is being
of no special types (NST) (▶ Invasive Carcinoma explored in clinical trials (Hyman et al. 2018; Ma
NST). et al. 2017).
Ductal carcinoma in situ (DCIS) of high
nuclear grade with comedonecrosis (▶ Ductal
Carcinoma In Situ) is frequently HER2-positive Application
and may be associated with an invasive carci-
noma. However, HER2 overexpression in DCIS Current HER2 Testing
is not considered for anti-HER2 therapy. Cells
of Paget disease of the nipple (▶ Paget Disease Approach
of the Nipple) are typically HER2-positive. Each newly diagnosed invasive breast cancer is
The monoclonal antibody trastuzumab subjected to HER2 testing, and so are relapses and
(Herceptin ®) directed against HER2 is currently metastatic deposits. Identification of patients with
administered together with chemotherapy in a HER2-positive tumor relies on the identification
152 HER2 in Breast Cancer
of the target (HER2) by either frontline in situ ISH (SISH). ISH tests, either in dark or in bright
hybridization (ISH) or immunohistochemistry field, can be performed with a single-color probe
(IHC) followed by ISH in borderline cases. (HER2 gene probe) or with a dual-color probe
When applying a two-step approach, IHC is (probes for the HER2 gene and the centromere
applied first and scored according to a three-tier of the chromosome 17 (CEP17)).
scoring system according to the ASCO/CAP 2018 Alternative probes mapping to the chromo-
guidelines (score 0/1+, score 2+, score 3+; see some 17 have been used and proposed by several
Fig. 1a–c, respectively) (Wolff et al. 2018). When- groups; however, it is important to note that chro-
ever an equivocal overexpression (score 2+) is mosome 17 is highly recurrently altered in breast
encountered, the sample must be subjected to cancers (Arriola et al. 2008; Isola et al. 2004;
ISH to verify the presence of HER2 gene Marchio et al. 2009; Rondon-Lagos et al. 2014);
amplification. therefore this approach should be strongly
discouraged.
Cleared Methods Alternative techniques to assess the HER2 sta-
Three methods of ISH have been introduced in tus, such as mRNA assays (e.g., RT-PCR), did not
breast pathology and are FDA approved for HER2 reach sufficient evidence to warrant inclusion, at
gene assessment in breast cancer: fluorescence least when dealing with unselected patients (Wolff
ISH (FISH), chromogenic ISH (CISH), and silver et al. 2018).
HER2 in Breast Cancer, Fig. 1 HER2 immunohisto- membrane staining in >10% of tumor cells (score 2+). (c)
chemistry. (a) weak, incomplete membrane staining in strong, complete membrane staining in the vast majority of
>10% of tumor cells (score 1+). (b) moderate, complete tumor cells (score 3+)
Methodology of ISH Scoring HER2/CEP17 ratio is calculated, and then the

The evaluation of HER2 expression by immuno- HER2 copy number values are examined. For
histochemistry or HER2 gene status by ISH is not each category of ISH results, additional work-
univocal, and slight differences can apply ups may be needed to adjudicate the final result.
depending on the use of American or European Here below, following the ASCO/CAP 2018 rec-
recommendations. However, the majority of ommendations, categories for positive and nega-
countries agreed upon those edited by the tive test results are illustrated.
ASCO/CAP. The 2013 ASCO/CAP guidelines
have introduced the so-called ISH algorithm HER2 Positive
(Table 1), and this has been confirmed by the By IHC: score 3+, circumferential membrane
recently updated recommendations (Wolff et al. staining that is complete, intense, and in >10%
2013, 2018). By following the algorithm, first the of tumor cells (this is readily appreciated using a
HER2 in Breast Cancer, Table 1 Summary of changes of HER2 evaluation by ISH over the ASCO/CAP guideline
updates (2007, 2013, 2018). FDA-recommended thresholds are also reported H
NOT
Guideline Method AMP/positive Equivocal AMP/negative
FDA/ HER2/ 2 // <2
EMA CEP17
ratio
HER2 >4 4
copy
number
ASCO/ HER2/ >2.2 1.8–2.2 <1.8
CAP CEP17
2007 ratio
HER2 >6 4–6 <4
copy
number
ASCO/ ISH (a) HER2/CEP17 ratio 2, regardless of HER2/CEP17 <2 with HER2/CEP17
CAP algorithm HER2 copy number HER2 copy number 4 and <2 with HER2
2013 (b) HER2/CEP17 <2 but HER2 copy <6 copy number
dual- number 6 <4
color
ASCO/ HER2 6 4 and <6 <4
CAP copy
2013 number
single-
color
ASCO/ ISH (a) HER2/CEP17 ratio 2, regardless of HER2/CEP17 <2 with HER2/CEP17
CAP algorithm mean HER2 copy number (but additional HER2 copy number 4 and <2 with HER2
2018 work-up needed in case HER2 copy <6 (additional work-up copy number
dual- number mean is <4) needed) <4
color (b) HER2/CEP17 <2 but HER2 copy
number 6 (but additional work-up
needed)
ASCO/ HER2 6 4 and <6 (additional <4
CAP copy work-up needed)
2018 number
single-
color
AMP Amplified, ASCO American Association of Clinical Oncology, CAP College of American Pathologists, EMA
European Medicines Agency, FDA Food and Drug Administration, NOT AMP Not Amplified
low power objective and observed within a homo- Additional work-up for scenarios in which the
geneous and contiguous invasive cell population). tumor cell population shows HER2/CEP17 ratio
2.0 and average HER2 copy number <4.0 sig-
By ISH:
nals/cell.
This is a challenging scenario in which, for
– Dual-probe assay: HER2/CEP17 ratio 2.0
instance, tumors harboring monosomy of chro-
and average HER2 copy number 4.0 sig-
mosome 17 easily lead to ratio values >2 despite
nals/cell (Fig. 2a).
a not high absolute HER2 copy number (mean of
– Dual-probe assay: HER2/CEP17 ratio 2.0
2 or 3). Importantly, Press and colleagues have
and average HER2 copy number <4.0 sig-
recently shown that these patients seem not to
nals/cell: additional work-up needed.
benefit from trastuzumab treatment (Press
– Dual-probe assay: HER2/CEP17 ratio <2.0
et al. 2016).
and average HER2 copy number 6 signals/
The updated guidelines suggest that, if not
cell: additional work-up needed.
already assessed by the institution or laboratory
– Single-probe assay: average HER2 copy num-
performing the ISH test, IHC testing for HER2
ber 6.0 signals/cell: concurrent score 3+ in
should be performed (using sections from the
IHC should be documented, otherwise dual
same tissue sample used for ISH) and the slides
colour ISH should be performed.
HER2 in Breast Cancer, Fig. 2 Dual-probe HER2 fluo- CEP17 copy number of 3 (green signals) leading to a
rescence in situ hybridization (FISH). (a) nuclei of tumor HER2/CEP17 ratio of 1.4. (c) tumor cells harbor a mean
cells homogeneously show multiple red signals (HER2 HER2 copy number of 2 (red signals) and a CEP17 copy
signals) clustering together. (b) tumor cells display a number of 1.9 with a HER2/CEP17 ratio of 1.05
mean HER2 copy number of 4.1 (red signals) and a
from both ISH and IHC should be reviewed The ISH algorithm in this case has allowed
together to guide the selection of areas to score HER2 gene amplification not to be
by ISH: underestimated in a subset of tumors harbor-
ing high HER2 copy numbers together with
(a) IHC result is 3+: diagnosis is HER2-positive. CEP17 gain or amplification, a scenario that
(b) If the IHC result is 0 or 1+: diagnosis is would lead to a HER2/CEP17 ratio <2 even in
HER2-negative with a comment*. the presence of a high HER2 copy number.
(c) If IHC result is 2+, recount ISH by having an The phenomenon of CEP17 gain/amplifica-
additional observer, blinded to previous ISH tion has been demonstrated by the study of
results, and count at least 20 cells that include microarray-based comparative genomic
the area of invasive cancer with IHC 2+ hybridization (array CGH) (Marchio et al.
staining: 2009; Moelans et al. 2010; Yeh et al. 2009)
– If reviewing the count by the additional and further confirmed by other indirect
observer changes the result into another methods (Ercolani et al. 2017; Sapino et al.
ISH category, the result should be adjudi- 2014). Although these carcinomas account for
cated per internal procedures to define the a minority of cases, they are also the most H
final category. challenging in diagnostic practice.
– If the count remains an average of <4.0 Now, in the 2018 updated recommenda-
HER2 signals per cell and the HER2/ tions, the recommended additional work-up
CEP17 ratio is >2.0, diagnosis is HER2- is as follows: if not already assessed by the
negative with a comment*. institution or laboratory performing the ISH
test, IHC testing for HER2 should be
*The Expert Panel recommends the fol- performed (using sections from the same tis-
lowing comment: “Evidence is limited on the sue sample used for ISH), and the slides from
efficacy of HER2-targeted therapy in the both ISH and IHC should be reviewed
small subset of cases with a HER2/CEP17 together to guide the selection of areas to
ratio of 2.0 and an average HER2 copy score by ISH:
number of <4.0 per cell. In the first generation (a) IHC result is 3+: diagnosis is HER2-positive.
of adjuvant trastuzumab trials, patients in this (b) If the IHC result is 0 or 1+, diagnosis is
subgroup who were randomly assigned to the HER2-negative with a comment**.
trastuzumab arm did not seem to derive an (c) If the IHC result is 2+, recount ISH by having
improvement in disease-free or overall sur- an additional observer, blinded to previous
vival, but there were too few such cases to ISH results, and count at least 20 cells that
draw definitive conclusions. IHC expression include the area of invasion with IHC 2+
for HER2 should be used to complement ISH staining:
and define HER2 status. If the IHC result is – If reviewing the count by the additional
not 3+ positive, it is recommended that the observer changes the result into another
specimen be considered HER2 negative ISH category, the result should be adjudi-
because of the low HER2 copy number by cated per internal procedures to define the
ISH and the lack of protein overexpression.” final category.
(Type, evidence based; evidence quality, – If the HER2/CEP17 ratio remains <2.0
intermediate; strength of recommendation, with >6.0 HER2 signals per cell, diagnosis
strong) is HER2-positive.
Additional work-up for scenarios in which **The Expert Panel recommends the fol-
the tumor cell population shows HER2/ lowing comment: “There are insufficient data
CEP17 ratio <2.0 and average HER2 copy on the efficacy of HER2-targeted therapy in
number 6.0 signals/cell. cases with a HER2 ratio of <2.0 in the
absence of protein overexpression because By ISH:

such patients were not eligible for the first
generation of adjuvant trastuzumab clinical – Single-probe assay: average HER2 copy num-
trials. When concurrent IHC results are nega- ber 4.0 and <6.0 signals/cell – If IHC results
tive (0 or 1+), it is recommended that the score 2+ (equivocal), it is recommended to also
specimen be considered HER2 negative.” perform dual-probe ISH (and follow related
(Type, evidence based; evidence quality, recommendations).
intermediate; strength of recommendation, – Dual-probe assay: HER2/CEP17 ratio <2.0
strong) and average HER2 copy number 4.0 and
<6.0 signals/cell (Fig. 2b): additional work-
An additional remark must be made regarding up needed.
HER2 heterogeneity. A matter of debate is
represented by the pattern of heterogeneity to be Additional work-up for scenarios in which the
considered clinically meaningful to report an ISH tumor cell population shows HER2/CEP17 ratio
result as positive featuring a heterogeneous pat- <2.0 and HER2 copy number 4 and <6.0 sig-
tern of tumor population. At present, the experts nals/cell.
of the ASCO/CAP guidelines (Wolff et al. 2013, If not already assessed, IHC testing for HER2
2018) contend that only spatially clustered hetero- should be performed (using sections from the
geneity is significant and should be recorded same tissue sample used for ISH), and the slides
(Wolff et al. 2013, 2018); however, scattered from both ISH and IHC should be reviewed
HER2-amplified cells, although of unknown clin- together to guide the selection of areas to score
ical relevance, are more frequent (Sapino et al. by ISH:
2014) and usually represent a source of inter-
observer disagreement. (a) IHC result is 3+: diagnosis is HER2-positive.
Regarding heterogeneity, we draw the readers’ (b) IHC result is 0 or 1+: diagnosis is HER2-
attention to a potential pitfall in ISH testing that can negative with a comment***.
be encountered in residual carcinomas following (c) If IHC result remains 2+, recount ISH by
taxane-based neoadjuvant chemotherapy: reports having an additional observer, blinded to pre-
are on record on the possible presence of giant vious ISH results, and count at least 20 cells
syncytial multinucleated-looking neoplastic cells that include the area of invasion with IHC 2+
harboring a very high number of HER2 signals staining:
scattered within a background of tumor cells lacking – If reviewing the count by the additional
HER2 amplification. A polyploidy status induced by observer changes the result into another
chemotherapy rather than a focal amplification of ISH category, the result should be adjudi-
the HER2 locus has been advocated as the phenom- cated per internal procedures to define the
enon underlying this pattern, as suggested by the final category.
presence of additional copies of CEP17 as well as of – If the count remains a HER2/CEP17 ratio
many regions in other chromosomes (Valent et al. <2.0 and average HER2 copy number
2013). A word of caution should be voiced in order 4.0 and <6.0 signals/cell, diagnosis is
not to misinterpret this phenomenon as heteroge- HER2-negative with a comment***.
neous HER2 amplification.
***Comment recommended by the Expert
HER2 Equivocal Panel: “It is uncertain whether patients with an
By IHC: score 2+, weak to moderate complete average of 4.0 and <6.0 HER2 signals per
membrane staining observed in >10% of tumor cell and a HER2/CEP17 ratio of <2.0 benefit
cells. In this scenario a reflex test (same specimen from HER2 targeted therapy in the absence of
using ISH) or a new test (new specimen if avail- protein overexpression (IHC 3+). If the spec-
able, using IHC or ISH) must be ordered. imen test result is close to the ISH ratio
threshold for positive, there is a high likeli- and usually display a relatively high mean of
hood that repeat testing will result in different Ki67 indices (Ballard et al. 2017; Ragazzi et al.
results by chance alone. Therefore, when IHC 2017; Sapino et al. 2014). If compared to HER2-
results are not 3+ positive, it is recommended negative disease, these tumors display a signifi-
that the sample be considered HER2 negative cantly higher prevalence of grade 3 carcinomas,
without additional testing on the same harbor significantly higher proliferation indices,
specimen.” and show a significantly higher proportion of
(Type, evidence based; evidence quality, lymph node metastases at presentation (Ballard
intermediate; strength of recommendation, et al. 2017; Ragazzi et al. 2017; Sapino et al.
strong) 2014). If compared to HER2-positive disease,
HER2 double-equivocal carcinomas show a sig-
The experts also suggest that clinical correlation nificantly higher rate of ER positivity and a sig-
with other factors in a particular case (such as grade nificantly lower prevalence of histological grade
and special histologic subtypes) or repeat testing of 3 carcinomas (Ballard et al. 2017; Ragazzi et al.
other tissue samples from the patient may also be 2017; Sapino et al. 2014). Data on the efficacy of
appropriate in this setting. In particularly challeng- response to anti-HER2 therapy are not available at H
ing cases or if the results are in question, expert present, and we only know that these carcinomas
consultation may be appropriate and may include do not do worse than HER2-negative breast car-
alternative probes or other genetic methods. How- cinomas treated with anthracycline- and taxane-
ever, alternative probes should not be used as stan- based chemotherapy (Press et al. 2016). Recently,
dard practice due to limited data on outcomes for an extensive genomic analysis has revealed that
this subset of patients. Regarding the latter, the double-equivocal carcinomas are preferentially
experts acknowledge that this group of carcinomas luminal B also at the transcriptomic level. In addi-
has been frequently tested by ISH using multiple tion, in these cases, HER2 mRNA levels are more
chromosome 17 probes at once, many not analyti- widely overlapping with HER2-negative rather
cally or clinically validated. Such indiscriminate than with HER2-positive breast carcinomas.
testing often results in four or more ISH ratios However, they display a high risk of recurrence
being described in a single test report and a final by Prosigna ® assay, even when they present good
designation of HER2 gene amplified if just a single prognostic features (unifocal, <2 cm, node nega-
ratio is >2.0. After careful consideration of this tive/micrometastatic carcinomas) (Marchio et al.
practice and available data, the Expert Panel 2018). Interestingly, a subset of double-equivocal
strongly recommends against this as a routine test- cases is classified as HER2-enriched by gene
ing strategy. expression analysis in spite of their double-
According to this work-up, the equivocal result equivocal status, opening the possibility to
is in a way “sorted out” as negative; nevertheless, explore the beneficial effect of anti-HER2 agents
the experts acknowledge that data on this sub- in this subgroup of patients (Marchio et al. 2018).
group of patients are scant. Cases as such would In addition, at the mutational level, double-
be defined as HER2 double-equivocal breast car- equivocal carcinomas show PIK3CA and TP53
cinomas, i.e., breast carcinomas with an equivocal mutation rates more similar to ER-positive/
expression of the HER2 protein (score 2+ by IHC) HER2-positive rather than to ER-positive/HER2-
and mean HER2 copy numbers in the equivocal negative carcinomas, supporting the theory that
range (i.e., HER2/CEP17 ratio <2.0 and mean these cases represent an aggressive subgroup of
HER2 copy numbers 4 and <6 by ISH). These ER-positive carcinomas (Marchio et al. 2018).
breast carcinomas fall into the luminal B subtype The responses to chemotherapy and
when using the IHC surrogate proposed by the trastuzumab in this category of patients are still
St. Gallen Consensus (▶ Invasive Carcinoma unclear. In a cohort of patients treated in the neo-
NST), as they are typically estrogen receptor pos- adjuvant setting with trastuzumab-containing che-
itive (▶ Hormone Receptors in Breast Cancer) motherapy, double-equivocal carcinoma patients
HER2 in Breast Cancer, Table 2 Prevalence of HER2 derived from the TCGA study by Curtis et al. (2012) and
mutations in the distinct PAM50-defined molecular sub- from Ciriello et al. (2015))
types (TCGA data from www.cbioportal.org). (Data
Frequency of HER2 mutations
N %
Luminal (A/B) 5/321 1.6
Luminal A 3/235 1.3
ILC Luminal A 4/106 4
Luminal B 2/133 1.5
HER2-enriched 2/58 3
Basal-like 0/81 0
ILC invasive lobular carcinoma, N number of cases
had low rates of pathologic complete response et al. 2013; Lee et al. 2006). These cases account
(pCR), but a great proportion reached near-pCR: for about 1.3–4% of all breast cancers, depending
when these two categories were grouped, the dif- on the molecular subtype and the histologic type.
ference in terms of response rate was not statisti- They represent an important subgroup of HER2-
cally significant between double-equivocal and activated cancers that may be missed by standard
HER2-positive carcinomas (Marchio et al. HER2 positivity assessment (IHC or ISH).
2018). However, larger studies are warranted to Indeed, these mutations are found in breast carci-
ascertain the real impact of chemotherapy and nomas regardless of the presence of HER2 ampli-
anti-HER2 therapy in this specific subset of breast fication, occurring in both ER-positive/HER2-
carcinomas. negative diseases and HER2-enriched cancers
(Table 2) (Petrelli et al. 2017). For this reason,
HER2 Negative Result they represent tumors considered to be HER2-
By IHC: negative (by the routinely used methods and algo-
– Score 1+: incomplete membrane staining rithms at present) but with active HER2 signaling
that is faint/barely perceptible and in that can be targeted by anti-HER2 agents.
>10% of tumor cells. In breast cancer, HER2 mutations are clustered
– Score 0: (i) no staining is observed or mainly in two different regions: the extracellular
(ii) membrane staining that is incomplete domain, at exon 8, and the kinase domain, at exons
and is faint/barely perceptible and in 19 and 20. The majority of HER2 mutations
10% of tumor cells. described so far in the context of breast cancer
By ISH: affect codons belonging to the kinase domain.
– Single-probe assay: average HER2 copy The most frequent HER2 mutations are L755S,
number <4.0 signals/cell: double-check V777L, and D769H or D769Y: all of them are
whether concurrent IHC 0, 1+ and/or con- activating mutations, likely driving tumorigene-
current dual-probe ISH with a result of sis. In preclinical studies, L755S is related to
HER2 copy number <4.0 signals/cell. resistance to the reversible HER2 inhibitor
– Dual-probe assay: HER2/CEP17 ratio <2.0 lapatinib, but it is sensitive to the irreversible
and average HER2 copy number <4.0 sig- HER2 inhibitor, neratinib (Bose et al. 2013;
nals/cell (Fig. 2c). Kancha et al. 2011), while the other two mutations
(V777L, and D769H or D769Y) are associated
with sensitivity to trastuzumab, lapatinib, and
HER2 Mutations neratinib (Bose et al. 2013; Petrelli et al. 2017).
Different studies have suggested that invasive
Studies based on massively parallel sequencing lobular carcinomas (▶ Invasive Lobular Carci-
have unveiled the presence of a subgroup of breast noma) are enriched in HER2 mutations (Ciriello
carcinomas harboring HER2 mutations (Bose et al. 2015; Lien et al. 2015; Ross et al. 2013).
A high HER2 mutation rate has also been reported cancer: A multi-institutional study. Modern Pathology,
in metastatic breast cancer. Interestingly, in this 30, 227–235.
Bose, R., Kavuri, S. M., Searleman, A. C., Shen, W., Shen,
subset of tumors, mutations are more frequent in D., Koboldt, D. C., Monsey, J., Goel, N., Aronson,
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(Fang et al. 2014). In addition, HER2 mutations Ellis, M. J. (2013). Activating HER2 mutations in
can represent a marker of resistance to anti-HER2 HER2 gene amplification negative breast cancer. Can-
cer Discovery, 3, 224–237.
therapy in this subset of patients (Park et al. 2015). Ciriello, G., Gatza, M. L., Beck, A. H., Wilkerson, M. D.,
Using a basket-trial approach, Hyman et al. Rhie, S. K., Pastore, A., Zhang, H., McLellan, M., Yau,
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R. E., Collins, L. C., Allison, K. H., Chen, Y. Y., Jensen,
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H
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cal Cancer Research, 23, 5687–5695. some 17 centromere by karyotyping, FISH and
Marchio, C., Lambros, M. B., Gugliotta, P., Di Cantogno, M-FISH in breast cancer cells. BMC Cancer, 14, 922.
L. V., Botta, C., Pasini, B., Tan, D. S., Mackay, A., Ross, J. S., Wang, K., Sheehan, C. E., Boguniewicz, A. B.,
Fenwick, K., Tamber, N., Bussolati, G., Ashworth, A., Otto, G., Downing, S. R., Sun, J., He, J., Curran, J. A.,
Reis-Filho, J. S., & Sapino, A. (2009). Does chromo- Ali, S., Yelensky, R., Lipson, D., Palmer, G., Miller,
some 17 centromere copy number predict polysomy in V. A., & Stephens, P. J. (2013). Relapsed classic
breast cancer? A fluorescence in situ hybridization and E-cadherin (CDH1)-mutated invasive lobular breast
microarray-based CGH analysis. Journal of Pathology, cancer shows a high frequency of HER2 (ERBB2)
219, 16–24. gene mutations. Clinical Cancer Research, 19,
Marchio, C., Dell’Orto, P., Annaratone, L., Geyer, F. C., 2668–2676.
Venesio, T., Berrino, E., Verdun di Cantogno, L., Sapino, A., Maletta, F., Verdun di Cantogno, L., Macri, L.,
Garofoli, A., Rangel, N., Casorzo, L., dell’Aglio, C., Botta, C., Gugliotta, P., Scalzo, M. S., Annaratone, L.,
Gugliotta, P., Trisolini, E., Beano, A., Pietribiasi, F., Balmativola, D., Pietribiasi, F., Bernardi, P., Arisio, R.,
Hormone Receptors in Breast Cancer 161
Viberti, L., Guzzetti, S., Orlassino, R., Ercolani, C., Definition

Mottolese, M., Viale, G., & Marchio, C. (2014). Gene
status in HER2 equivocal breast carcinomas: Impact of
distinct recommendations and contribution of a poly- Estrogen receptor a, progesterone receptor,
merase chain reaction-based method. The Oncologist, androgen receptor, estrogen receptor b.
19, 1118–1126.
Valent, A., Penault-Llorca, F., Cayre, A., & Kroemer,
G. (2013). Change in HER2 (ERBB2) gene status
after taxane-based chemotherapy for breast cancer: Description
Polyploidization can lead to diagnostic pitfalls with
potential impact for clinical management. Cancer Hormone receptors are members of the steroid
Genetics, 206, 37–41. receptor family. They encompass estrogen
Wolff, A. C., Hammond, M. E., Hicks, D. G., Dowsett, M.,
McShane, L. M., Allison, K. H., Allred, D. C., Bartlett, receptor (ERa), progesterone receptor (PR),
J. M., Bilous, M., Fitzgibbons, P., Hanna, W., Jenkins, androgen receptor (AR), and estrogen receptor
R. B., Mangu, P. B., Paik, S., Perez, E. A., Press, M. F., b (ER b).
Spears, P. A., Vance, G. H., Viale, G., Hayes, D. F., PR receptors exist in two isoforms, namely,
American Society of Clinical Oncology, & College of
PRA and PRB. The levels are equally
American Pathologists. (2013). Recommendations for
human epidermal growth factor receptor 2 testing in distributed in normal breast, but during carcino- H
breast cancer: American Society of Clinical Oncology/ genesis there is often an imbalance (toward
College of American Pathologists clinical practice increase in PRA).
guideline update. Journal of Clinical Oncology, 31,
3997–4013. ERb was identified 10 years after the description
Wolff, A. C., Hammond, M. E. H., Allison, K. H., Harvey, of ERa. Since then five ERb isoforms have been
B. E., Mangu, P. B., Bartlett, J. M. S., Bilous, M., described, of which three (ERb1, ERb2, and
Ellis, I. O., Fitzgibbons, P., Hanna, W., Jenkins, R. B., ERb5) are expressed in the breast.
Press, M. F., Spears, P. A., Vance, G. H., Viale, G.,
McShane, L. M., & Dowsett, M. (2018). Human epi-
dermal growth Factor receptor 2 testing in breast can-
cer: American Society of Clinical Oncology/College Clinical Features
of American Pathologists Clinical Practice Guideline
Focused Update. Journal of Clinical Oncology, 36,
2105–2122. • Incidence of ER/PR positive carcinoma
Yeh, I. T., Martin, M. A., Robetorye, R. S., Bolla, A. R., Overall, over two thirds of breast cancers
McCaskill, C., Shah, R. K., Gorre, M. E., Mohammed, are ER positive. Low grade no special
M. S., & Gunn, S. R. (2009). Clinical validation of an type cancers (▶ Invasive Carcinoma NST)
array CGH test for HER2 status in breast cancer reveals
that polysomy 17 is a rare event. Modern Pathology, and special histological types including tubu-
22, 1169–1175. lar (▶ Tubular Carcinoma), mucinous
(▶ Invasive Mucinous Carcinoma),
and classical lobular carcinoma (▶ Invasive
Lobular Carcinoma) are often positive.
Hormone Receptors in Breast Data from a UK National Biomarker audit
Cancer of over 40,000 cancers showed ER positivity
in 83.7% of primary breast cancer and 69.7%
Abeer M. Shaaban1 and Valerie Speirs2 of metastatic breast cancer. PR was positive in
1
Department of Cellular Pathology, Queen 68.8% and 44.6% of primary and metastatic
Elizabeth Hospital Birmingham and University of breast cancers, respectively (Guidelines
Birmingham, Birmingham, UK Working Group of the UK National Coordi-
2
Leeds Institute of Cancer and Pathology, nating Committee for Breast Pathology
University of Leeds, Leeds, UK 2016).
• Effect of age
In the female breast, the expression of ER
Synonyms in normal mammary epithelial cells increases
with age. This age effect is not seen in the
AR; ER; ER b; PR male breast.
162 Hormone Receptors in Breast Cancer
• Effect of sex While the majority of hormone receptors in their

The vast majority of male breast cancers active state reside in the nucleus, there is evidence
are hormone receptor positive with a for a small pool (~5%) which is located in the cell
positivity rate of 82–84% for ER and membrane (Levin and Hammes 2016). This was
71–74% for PR (Shaaban et al. 2012; described initially as non-genomic ER activity but
Humphries et al. 2017) (▶ Male Breast is now more commonly referred to as membrane-
Cancer). initiated steroid signaling (MISS) (Nemere et al.
• Effect of treatment on hormone receptor 2003). MISS is also shown in Fig. 1. Here, ligand-
expression receptor binding at the cell membrane initiates a
Change in the level of expression and hor- rapid activation of the nonclassical signaling path-
mone receptor status following neoadjuvant way, typically occurring in minutes. The impact of
chemotherapy has been observed in a small extranuclear hormone receptor signaling via
proportion of cases (2.5–17% for ER and MISS is still at an experimental stage and has yet
5.9–51.7% for PR). This includes change to translate into the clinic.
from positive to negative status and vice
versa (van den Ven et al. 2011; Gahlaut
et al. 2016). The impact on management is Immunohistochemical Interpretation
not clear, but this may provide new options
for therapy in previously hormone receptor Hormone receptors are expressed in the nuclei of
negative tumors that switch to a positive cancer cells. Cytoplasmic and/or membranous
status. staining should be discarded. Normal breast tissue
shows scattered positive luminal cells among a
majority of negative cells. These serve as a posi-
Mechanism of Action and Function tive internal control.
It is essential that all laboratories providing
Hormone receptors are ligand-activated transcrip- immunohistochemical staining and reporting of
tion factors. There are two principal modes of ER/PR as predictive/prognostic markers
activation, summarized schematically in Fig. 1 should participate in an appropriate external
using ER as an example. The traditional mecha- quality assurance program, an example of
nism of action is ligand-dependent transcription. which is the UK National External Quality
Upon entering the cell, hormones bind to their Assessment Scheme for Immunocytochemistry
cognate receptors in the cytoplasm. Following and in situ hybridization (UK NEQAS ICC
binding they dissociate from their inhibitory chap- and ISH).
erone complexes and then translocate to the
nucleus. Gene activation is accomplished through
binding to consensus ER response elements Scoring
(EREs), as in the classical mode of action, or by
tethering, via Fos and Jun (components of AP-1 There are several recognized systems for ER/PR
transcription factor), to other DNA-bound scoring with variation in the cutoff value for
transcription factors such as AP-1 (activator ER/PR positivity internationally. The current
protein 1) and SP1 (specificity protein 1) CAP/ASCO/RCPath guidelines by the College
(nonclassical pathway). Hormone receptors can of American Pathologists, American Society
also be activated indirectly through growth factor of Clinical Oncology, and the Royal College
binding which triggers the nonclassical pathway of Pathologists, UK, respectively, recommend a
via activation of MAP kinase (mitogen-activated cutoff value of 1% of any intensity to indicate
protein kinase) signaling. Typically this involves positivity (Guidelines Working Group of the UK
epidermal growth factor, insulin growth factor-1, National Coordinating Committee for Breast
or transforming growth factor a (Lee et al. 2001). Pathology 2016; Hammond et al. 2010).
Growth factor
E2
ER ER
HSP MAP kinase

activation
ER Inactive
Cytoplasm
ER
ER P
Fos
Foss JJun
un
n
H
Nucleus AP1/SP1
P P
ER ER ER
ER P
Fos
Foss Jun
n
ERE
Classical pathway AP1/SP1
Non-classical pathway
mRNA
Protein
Estrogen action
Hormone Receptors in Breast Cancer, traditional ligand- dependent transcription pathway and
Fig. 1 Mechanism of action of estrogen receptor. The the indirect activation through growth factor binding
receptor can be activated via two mechanisms; the
The most widely used scoring system is the possibility is to evaluate the percentage of any
Allred (Quick) score. The score is a sum of the nuclear staining, independently from the intensity.
intensity (0, 1, 2, 3) and percentage (scores 0, 1, 2,
3, 4, 5) scores giving a final score ranging from
zero (negative) to 8/8 (strongly positive) (Harvey Relevance for Breast Pathology
et al. 1999). Another commonly used system is
the H-score which is obtained by adding the sum ER is routinely assessed on all newly diagnosed
of multiplying the percentage by intensity scores primary breast cancers, and this is mandated
(including different staining intensities within in the pathology and management guidelines
the tumor, thus accounting for heterogeneity). (Guidelines Working Group of the UK National
The final score ranges from 0 to 300. Another Coordinating Committee for Breast Pathology
164 Hormone Receptors in Breast Cancer
2016; National Institute for Health and Care The prognostic significance of ERb protein
Excellence 2009). Depending on the guidelines, and mRNA expression in breast carcinoma
PR assessment is optional or mandatory has been conflicting. A recent meta-analysis
(American Society of Clinical Oncology/College of 21 studies of 6769 patients for ERb1, 2295
of American Pathologists guideline 2010). Both patients for ERb2, and 2271 patients for ERb5
receptors are increasingly tested in recurrent concluded that ERb1 protein expression corre-
and metastatic breast cancers to aid management lated with favorable survival (DFS, OS)
decisions. AR and ERb are not analyzed in the and ERb2 with improved DFS only, whereas
routine setting. ERb5 was not associated with DFS (Liu
Traditionally, testing for ER/PR was et al. 2016).
performed on surgical resection specimens. With AR has been shown to be an independent
increasing demands for early availability of prognosticator (when tumor size, grade, and
results to help select patients for neoadjuvant ther- nodal status were included in the model) of favor-
apy and preoperative trials, testing is currently able outcome not only in ER-positive breast car-
performed on core biopsies in the majority of cinoma but also in ER-negative tumors
cases. Studies have shown excellent concordance (Aleskandarany et al. 2016).
of receptor results between core and excision A prognostic index (ERPI) was created using
samples (Hodi et al. 2007). AR status (positive or negative) together with
Repeat testing on surgical specimens is advised tumor size and lymph node status that clearly
in the presence of multiple tumors, tumor hetero- separated patients with luminal-A and luminal-B
geneity, if tumor cells on core biopsy were scanty, breast cancer into good and poor prognosis groups
or if the staining on core sections was technically (Castellano et al. 2013).
suboptimal/failed.
ER/PR as Predictive and Prognostic Markers

ER/PR status is a predictor for response to endo-
crine therapy. Tumors that express the highest Aleskandarany, M. A., Abduljabbar, R., Ashankyty, I.,
protein content are most likely to respond to Elmouna, A., Jerjees, D., Ali, S., Buluwela, L.,
anti-hormonal treatment such as tamoxifen Diez-Rodriguez, M., Caldas, C., Green, A. R.,
Ellis, I. O., & Rakha, E. A. (2016). Prognostic signif-
(Harvey et al. 1999).
icance of androgen receptor expression in invasive
The aromatase inhibitor “anastrozole” has breast cancer: Transcriptomic and protein expression
been shown to be superior to tamoxifen in the analysis. Breast Cancer Research and Treatment, 159,
management of postmenopausal breast cancer 215–227.
Castellano, I., Chiusa, L., Vandone, A. M., Beatrice, S.,
(Howell et al. 2005; Riemsma et al. 2010). More-
Goia, M., Donadio, M., Arisio, R., Muscara, F.,
over, the protective effect of endocrine therapy Durando, A., Viale, G., Cassoni, P., & Sapino, A.
has been shown to last well beyond the 5 years of (2013). A simple and reproducible prognostic index in
standard therapy. Hormone receptor-positive luminal ER-positive breast cancers. Annals of Oncol-
ogy, 24, 2292–2297.
breast cancers are often indolent and relapse
Gahlaut, R., Bennett, A., Fatayer, H., Dall, B. J.,
late. A proportion of those tumors, however, Sharma, N., Velikova, G., Perren, T., Dodwell, D.,
develop resistance to endocrine therapy during Lansdown, M., & Shaaban, A. M. (2016). Effect of
the course of treatment. neoadjuvant chemotherapy on breast cancer pheno-
type, ER/PR and HER2 expression – Implications for
the practising oncologist. European Journal of Cancer,
Prognostic Significance of Other Hormone 60, 40–48.
Receptors Guidelines Working Group of the UK National Coordinat-
It has recently been shown that a high PRA/PRB ing Committee for Breast Pathology. (2016). Pathology
reporting of breast disease in surgical excision speci-
ratio is associated with early relapse on
mens incorporating the dataset for histological
tamoxifen in the ATAC trial cohort (Mote reporting of breast cancer. London: The Royal College
et al. 2015). of Pathologists.
Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. receptors. Nature Reviews Molecular Cell Biology,
American Society of Clinical Oncology/College of 17, 783–797.
American Pathologists Guideline Recommendations Liu, J., Guo, H., Mao, K., Zhang, K., Deng, H., & Liu, Q.
for Immunohistochemical testing of estrogen and pro- (2016). Impact of estrogen receptor-beta expression
gesterone receptors in breast cancer. J Oncol Pract. on breast cancer prognosis: A meta-analysis. Breast
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assay for predicting response to adjuvant endocrine discriminator of benefit from endocrine therapy in the
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I
Infarct of Breast Tissue • Age

Wide age distribution depending on underlying
Peter Regitnig lesion. Primary infarction is more typical in
Diagnostic- and Research Institute of Pathology, pregnant women.
Medical University of Graz, Graz, Austria • Sex
Only females, no reported male case.
• Site
Definition No site preference.
• Treatment
An infarct is a coagulative necrosis of (breast-) Due to clinical presentation of an infarct, core
tissue, caused by ischemia. This is mostly not a needle biopsy is most often performed. Local
primary event in breast tissue but rather a sec- excision of the infarcted area is necessary most
ondary one, typically occurring after an invasive of the time due to pain and depending on the
procedure or within a breast lesion such as a underlying lesion itself.
fibroadenoma, papilloma, or large neoplasm. In • Outcome
rare events, it can occur during late pregnancy or It depends on the infarcted lesion and the pri-
lactation. mary cause.
Clinical Features Macroscopy
• Incidence Infarction typically presents as a palpable mass

Primary breast infarction is rare. Only a that may be painful and varies between soft and
few case reports exist about breast infarction hard in consistency. In this case, it can be mistaken
during the third trimester of pregnancy or lacta- for a carcinoma due to the firm consistency of the
tion (Han et al. 2015; Hasson and Pope 1961). lesion. Infarcts usually occur as single lesions,
Secondary breast infarction sometimes localized to a breast lesion, or to hyperplastic
occurs as a complication following core needle lactating breast tissue during the puerperal period.
biopsy, fine needle aspiration biopsy (FNAB), The infarcted area can be well circumscribed (Han
or a surgical procedure by altering the blood et al. 2015). Hemorrhage can be seen within most
vessels of a breast lesion, which then undergoes infarcts and sometimes a hyperemic outer border
infarction. can also be observed.

https://doi.org/10.1007/978-3-319-62539-3
168 Infarct of Breast Tissue
Microscopy Typical breast lesions that tend to undergo

(partial) infarction are fibroadenoma
On routine H&E sections, infarcted tissue is, like in (▶ Fibroadenoma), papilloma (▶ Intraductal Pap-
other areas of the body, typically recognizable by the illoma), adenosis (▶ Adenosis, Other Types), and
loss of nuclear staining with ghostlike nuclear con- highly proliferative breast carcinoma, mostly
tours in an early phase, independent of the underly- basal-like carcinoma.
ing structures. Epithelial structures are more affected Similar to an infarct is hemorrhagic necrosis of
compared to mesenchymal areas. Structural integ- the skin and subcutis, which can occur as a side effect
rity of an underlying breast lesion is in most cases or complication of anticoagulant therapy. Most often,
still preserved. Localized hemorrhages and small this situation occurs subsequent to thrombophlebitis
groups of granulocytes and lymphocytes can be treated with warfarin. A hypersensitivity reaction
included, and thrombotic small vessels can be seen. affecting small vessels might be the pathogenic rea-
After days to weeks, the infarcted area can son. Another explanation could be heterozygous
undergo different changes depending on the protein C deficiency promoting paradoxical coagu-
remaining surrounding tissue and its capability to lation under warfarin (Isenberg et al. 1996).
repair the infarcted area. This mainly depends on
the cause of the infarct and whether the surrounding
tissue is well oxygenized by blood vessels. In the Immunophenotype
latter case, the infarct will be organized by a typical
granulation tissue, which contains macrophages, Although not applicable to an infarct by itself, it
fibroblasts, and capillaries, finally resulting in a can be helpful to reconstruct infarcted breast
fibrotic scar with more or less remaining macro- lesions. Sometimes myoepithelial markers can
phages or siderophages. In the opposite case, if the be helpful, even in less preserved areas.
surrounding tissue is less oxygenized, then the
infarcted area will undergo a more acellular, long-
lasting degenerative process leading to a pseudo- Molecular Features
cyst with macro- or microcalcifications.
In a chronic ischemic healing process, epithe- Not applicable
lial structures can be entrapped and can be
distorted within marked fibrosis, which might
be mistaken for a carcinoma. The appearance of Differential Diagnosis
squamous metaplasia has also been described
(Flint and Oberman 1984). Clinically, a breast infarct can simulate a carci-
When an infarct in the breast is seen, it is most noma through its tenderness, and even enlarged
important to think about a possible infarcted neo- axillary lymph nodes may coexist due to the reac-
plasm, which might be recognized only in its sil- tive inflammatory process as a result of the infarct.
houettes. Therefore, a thorough clinical history or Nipple discharge of an infarcted papilloma is
additional information is also very important. In bloody and thus raises suspicion. In FNAB,
every infarcted area, it is critical to also evaluate infarcted areas can show highly reactive and thus
the general architectural aspects within the infarct atypical cells, which may be misleading.
and to evaluate the margin toward unaffected areas. On H&E, highly fibrotic areas containing high
These two steps may lead to the recognition of an collagen content and low cellularity can be mistaken
underlying lesion or neoplasm, respectively. Find- for an infarct, but there are still some remaining
ings of the core needle biopsy should be cautiously bland fibroblasts and typical collagen bundles.
interpreted if the sample size is small and only Difficulties sometimes arise because of the
central areas are visible. Ultimately surgical exci- presence of complete necrotic material of a highly
sion should be performed to confirm the diagnosis proliferative carcinoma or another breast lesion in
of an underlying breast lesion. the background.
Inflammatory Myofibroblastic Tumor of the Breast 169
References and Further Reading tendency to recur in up to 25% of the cases and
with a slight risk of distant metastasis. This is
Flint, A., & Oberman, H. A. (1984). Infarction and squa- especially true if IMT typically arises in the lung
mous metaplasia of intraductal papilloma: A benign
and abdomen of children/adolescents (Coffin
breast lesion that may simulate carcinoma. Human
Pathology, 15, 764–767. and Fletcher 2013). As future studies are needed
Han, B., Zhang, H., Jiang, P., Zheng, C., Bi, L., Lu, L. U., to better define the boundaries between a reac-
& Fan, Z. (2015). Breast infarction during pregnancy tive and a neoplastic process, the combined
and lactation: A case report. Experimental and Thera-
diagnosis of “inflammatory pseudotumor/
peutic Medicine, 10, 1888–1892.
Hasson, J., & Pope, C. H. (1961). Mammary infarcts asso- inflammatory myofibroblastic tumor,” specify-
ciated with pregnancy presenting as breast tumors. ing the presence or not of ALK-1 expression
Surgery, 49, 313–316. (see below), seems actually to be more appropri-
Isenberg, J. S., Tu, Q., & Rainey, W. (1996). Mammary
ate for these lesions.
gangrene associated with warfarin ingestion. Annals of
Plastic Surgery, 37, 553–555.
Clinical Features
Inflammatory Myofibroblastic • Incidence

I
Tumor of the Breast The terms IMT or IP of the breast have been
used interchangeably over time, and only
Gaetano Magro and Lucia Salvatorelli 24 cases have been reported in English litera-
Department of Medical and Surgical Sciences and ture so far (Haj et al. 2003; Vecchio et al. 2011;
Advanced Technologies, G.F. Ingrassia, Azienda Zhao et al. 2013; Bosse et al. 2014; Choi et al.
Ospedaliero-Universitaria “Policlinico-Vittorio 2015; Markopoulos et al. 2015; Talu
Emanuele,” Anatomic Pathology Section, School et al. 2016).
of Medicine, University of Catania, Catania, Italy • Age
IMT/IP can occur at any age including adoles-
cents (16–86 years), but it is more frequently
Synonyms observed between the third to sixth decades.
• Sex
Inflammatory pseudotumor; Plasma cell The majority of cases seems to occur sponta-
granuloma neously in women. Only rarely IMT has been
described in male patients, following local
mechanical trauma (Vecchio et al. 2011).
Definition • Clinical presentation
Patients usually present with a painless nodule
Inflammatory myofibroblastic tumor (IMT) is ranging in size from 1.0 to 8 cm in its greatest
currently classified by WHO as a soft tissue diameter, without associated constitutional
tumor composed of spindly myofibroblasts symptoms (fever, malaise, weight loss) as usu-
admixed with inflammatory cells such as plasma ally seen in pediatric patients with lung and
cells, lymphocytes, and eosinophils (Coffin and abdominal tumors.
Fletcher 2013). IMT can occur in adults at sev- • Radiographic findings
eral anatomic sites, including the breast. Imaging features (ultrasound; mammogra-
Although initially thought to be an exaggerated phy) are non-specific and usually reveal a
inflammatory local response to various stimuli, solitary, less frequently multifocal, round to
and thus variably labeled as “inflammatory oval mass which may show either well-
pseudotumor (IP) or plasma cell granuloma,” circumscribed (Zhao et al. 2013) or ill-defined
there is growing evidence that a subset of these margins with the suspicion of malignancy
lesions are truly neoplastic in nature with the (Haj et al. 2003).
170 Inflammatory Myofibroblastic Tumor of the Breast
• Treatment Inflammatory Myofibroblastic Tumor of the Breast,

Complete surgical excision is the adequate treat- Table 1 Clinicopathologic features
ment. Most cases have an indolent clinical Inflammatory myofibroblastic tumor/inflammatory
course (Vecchio et al. 2011), but local recurrence pseudotumor
can be documented in a minority of cases Clinical features
Females (only rarely males)
(15–20% of cases) (Zhao et al. 2013; Choi Age: 16–86 years
et al. 2015). Only rarely IMT of the breast may Painless nodule (1–8 cm) arising spontaneously
show metastatic potential (Zhao et al. 2013; Imaging
Choi et al. 2015). However, some tumors Nodule with well-circumscribed or ill-defined
labeled as “inflammatory myofibroblastic margins
Gross pathology
tumors” are not convincing based on the Poorly circumscribed mass
illustrations provided by the authors, and they Firm in consistency
could represent low- to intermediate-grade Gray whitish in color
myofibroblastic sarcomas (Choi et al. 2015). Histological features
Margins: Well- or poorly circumscribed
Patients with IMT/IP of the breast need a long-
Cells: Plump, bland-looking spindle cells
term follow-up. admixed with lymphocytes, plasma cells, and
eosinophils
Growth pattern: Interlacing short fascicles; focal
Macroscopy storiform or swirling pattern
Mitotic count: 0–3 mitoses per 10 high power field
Grossly, IMT/IP presents as a round to oval mass, Stroma: Fibrous to focally edematous
sometimes lobulated, with well or often ill- Immunohistochemistry
Positive markers: Vimentin and a-smooth muscle
defined margins. The size is variable, ranging actin
from 1.5 to 8.0 cm (average tumor size of Variable expression: Desmin; ALK-1 (40–50% of
3.1 cm). The cut surface reveals a tumor mass cases)
Negative markers: Cytokeratins, EMA, CD34, S-100
firm in consistency and gray whitish in color.
protein, b-catenin, STAT6
Necrosis and hemorrhage are absent.
Cytogenetics
FISH analysis: ALK-gene rearrangements/
amplification
Microscopy
IMT/IP shows morphological and immunohisto-

chemical features similar to those reported at other Cellularity is quite variable and tumor stroma is
sites (Table 1). At low magnification, a tumor fibrous to loose. A minority of cases shows exten-
mass with infiltrative margins into the surround- sive hypocellular and hyalinized areas, closely
ing fibro-fatty breast tissue is observed. It consists resembling scar-like tissue. Rarely the tumor
of a proliferation of plump, bland-looking spindle cells may exhibit moderate/severe cytological
cells with the features of myofibroblasts, showing atypia consisting of large vesicular or hyper-
pale to slightly eosinophilic cytoplasm and ovoid chromatic nuclei (Fig. 2c H&E) with one or two
to tapering vesicular nuclei with inconspicuous prominent nucleoli. Necrosis and atypical mitoses
nucleoli (Fig. 1a, b H&E). These cells are usually are absent. Macrophages and a few multi-
arranged in interlacing short bundles with nucleated giant cells can be occasionally seen.
focal swirling and/or storiform growth pattern
(Fig. 1a, b H&E). Mitotic count is extremely Immunophenotype
variable, ranging from few (1–2) to 10 mitoses
per 10 high power fields. Characteristically the IMT/IP shows a myofibroblastic profile with
spindle cells are closely admixed with inflamma- immunoreactivity for vimentin, a-smooth muscle
tory cells, especially lymphocytes (Fig. 2a H&E), actin (Fig. 2d Immunostaining with a-smooth
plasma cells (Fig. 2b H&E), and eosinophils. muscle actin), and variably with desmin. The
Inflammatory Myofibroblastic Tumor of the Breast, Fig. 1 (a) Proliferation of bland-looking spindle cells with
fascicular and swirling growth patterns. (b) Higher magnification showing the cytological details
expression of ALK-1 protein has been demon- and/or ALK gene rearrangement does not seem
strated in three cases (Zhou et al. 2013; Bosse to predict clinical course. In this regard, only a
et al. 2014), proving that, at least, a subset of few cases, regardless of ALK-1 expression and/or
these lesions could represent true IMT. Occasion- ALK rearrangements, develop local recurrence or
ally immunostaining for cytokeratins has been more rarely distant metastases (Zhao et al. 2013;
described. No immunoreactivity is reported for Bosse et al. 2014; Choi et al. 2015; Markopoulos
CD34, CD21, CD35, S100, and estrogen/proges- et al. 2015; Talu et al. 2016).
terone receptors (Table 1).
Molecular Features Differential Diagnosis
The role of ALK gene is still unclear in the path- The diagnosis of IMT/IP arising in the breast is
ogenesis of IMT. The distinction between IMT challenging, especially on a core needle biopsy.
and IP still remains arbitrary, especially in the The pathologists facing with a bland-looking
absence of a proven immunohistochemical spindle cell lesion of the breast should keep in
expression of ALK-1 or rearrangements of ALK mind a wide variety of benign and malignant
gene by means of FISH. Some investigators prefer lesions, including reactive spindle cell nodule,
the diagnosis of IP when dealing with ALK- nodular fasciitis, IgG4-related sclerosing mastitis,
negative lesions arising at unusual sites, including myofibroblastoma (▶ Mammary Myofibro-
the breast, of adult patients (Vecchio et al. 2011). blastoma), solitary fibrous tumor, desmoid-type
Among the cases of IMT/IP of the breast tested by fibromatosis, low-grade (fibromatosis-like) spin-
FISH, only four cases have been found to be dle cell carcinoma (▶ Invasive Metaplastic Carci-
ALK-rearranged. Notably ALK1 expression noma), low-grade myofibroblastic sarcoma, and
Inflammatory Myofibroblastic Tumor of the Breast, some areas the spindle cells may exhibit moderate nuclear
Fig. 2 Proliferating spindle cells are closely admixed with atypia (c) (H&E). Immunostaining with alpha-smooth
lymphocytes (a) (H&E) and plasma cells (b) (H&E). In muscle actin is a common finding (d)
dermatofibrosarcoma protuberans (Table 2). Immunoglobulin (IgG)4-related sclerosing

A history of a previous biopsy or fine-needle mastitis is rare with only a few cases reported in
aspiration (FNA), as well as the recognition of the breast to date (Cheuk et al. 2009). Histologi-
entrapped/displaced epithelial mammary struc- cally the breast masses usually contain prominent
tures, stromal hemosiderin deposition, foamy stromal sclerosis with a variable number of
and hemosiderin-laden macrophages, lympho- spindle fibroblast-like cells, a dense lympho-
cytes and plasma cells, fat necrosis, and foreign plasmacytic infiltrate, and loss of breast lobules
body giant cell reaction, favors the diagnosis of (Cheuk et al. 2009). This lesion differs from
reactive spindle cell nodule. IMT/IP in that fibrosis and inflammation predom-
Nodular fasciitis shares with IMT/IP irregular inate over the spindle cell component. Diagnostic
margins, at least focally, and the presence of var- clue is the presence of numerous (range from
iable myxoid matrix, mitoses, and inflammatory 272 to 495 per high power field) IgG4-expressing
cells. However lymphocytes and plasma cells in plasma cells (Cheuk et al. 2009).
the latter are more prominent and closely Myofibroblastoma (▶ Mammary Myofibro-
intermingling with the spindle cells. Unlike nod- blastoma), a benign tumor of the mammary
ular fasciitis, IMT/IP lacks the typical tissue- stroma which presents as a nodule with well-
culture/granulation-like appearance. circumscribed margins, is usually composed of
Inflammatory Myofibroblastic Tumor of the Breast, Table 2 Differential diagnosis

Differential diagnosis of inflammatory myofibroblastic tumor/inflammatory pseudotumor
Inflammatory Imaging features: Well-circumscribed or ill-defined margins
myofibroblastic tumor/ Histology: Interlacing short fascicles of spindle cells, closely intermingling with
inflammatory lymphocytes, plasma cells, and eosinophils
pseudotumor Immunohistochemistry: Staining with vimentin and a-smooth muscle actin; variable
staining with desmin and ALK-1; CD34, CD21,CD35, b-catenin, and STAT6 are
negative
Reactive spindle cell Imaging features: Nodule with circumscribed margins, following biopsy or FNAC
nodule Histology: Short fascicles; focal storiform pattern; hemosiderin deposition; foamy and
hemosiderin-laden macrophages, lymphocytes, and plasma cells; fat necrosis and foreign
body giant cell reaction
Immunohistochemistry: Staining with a-smooth muscle actin; CD34, desmin,
b-catenin, and pancytokeratins are negative
Nodular fasciitis Imaging features: Ill-defined margins, at least focally
Histology: Short, focally intersecting fascicles; foci of extravasated red blood cells and
lymphocytes; tissue culture-like appearance
Immunohistochemistry: Staining with a-smooth muscle actin; CD34, desmin,
b-catenin, and pancytokeratins are negative
IgG4-related sclerosing
mastitis
Imaging features: Multiple nodular masses with ill-defined or circumscribed margins
Histology: Fibro-sclerotic tissue with prominent inflammation of lymphocytes (nodular
I
aggregate of lymphoid cells; lymphoid follicle formation) and plasma cells; variable
number of fibroblast-like cells
Immunohistochemistry: IgG4-expressing plasma cells
Myofibroblastoma Imaging features: Well-circumscribed nodule
Histology: Short, haphazardly intersecting fascicles interrupted by keloid-like collagen
fibers
Immunohistochemistry: Staining with desmin, CD34, estrogen, and progesterone
receptors; variable expression of a-smooth muscle actin, bcl2, CD10, CD99;
pancytokeratins, S100 protein, b-catenin, and STAT6 are negative
Solitary fibrous tumor Imaging features: Well-circumscribed nodule
Histology: Short fibroblast-like spindle to round/ovoid cells, haphazardly arranged; focal
storiform pattern
Immunohistochemistry: Staining with CD34 and STAT6; desmin, a-smooth muscle
actin, and pancytokeratins are negative
Desmoid-type Imaging features: Ill-defined, often infiltrative margins
fibromatosis Histology: Long fascicles, focally intersecting; fibrous stroma
Immunohistochemistry: Staining with a-smooth muscle actin and b-catenin; CD34,
desmin, pancytokeratins, and STAT6 are negative
Low-grade Imaging features: Ill-defined or frankly infiltrative margins
(fibromatosis-like) Histology: Proliferation of spindle cells with, at least focally, mild to moderate nuclear
spindle cell carcinoma atypia; scattered clusters of epithelioid to polygonal cells; occasionally small squamous-
glandular structures and/or foci of in situ or invasive carcinoma
Immunohistochemistry: Staining with pancytokeratins and p63; variable expression of
a-smooth muscle actin and desmin; CD34, b-catenin, and STAT6 are negative
Low-grade Imaging features: Poorly circumscribed nodule
myofibroblastic sarcoma Histology: Proliferation of spindle cells with fascicular arrangement; low to focally
moderate nuclear pleomorphism; occasionally severe nuclear pleomorphism
Immunohistochemistry: Staining with a-smooth muscle actin; desmin,
pancytokeratins, b-catenin, CD34, and STAT6 are negative
Dermatofibrosarcoma Imaging features: Ill-defined margins
protuberans Histology: Proliferation of spindle cells with diffuse storiform pattern; infiltration of
adipose tissue in a “honeycomb” pattern
Immunohistochemistry: Staining with CD34 and STAT6; desmin, a-smooth muscle
actin, b-catenin, and pancytokeratins are negative
eosinophilic spindle cells arranged in short, hap- Finally, dermatofibrosarcoma protuberans may
hazardly intersecting fascicles with interspersed share with IMT/IP the storiform/swirling growth
keloid-like collagen fibers. Unlike IMT/IP, pattern which can be focally encountered in the
myofibroblastoma contains mast cells but not latter. Unlike IMT/IP, dermatofibrosarcoma pro-
lymphocytes, plasma cells, or eosinophils in the tuberans exhibits a diffuse storiform pattern and is
stroma. In addition myofibroblastoma usually diffusely positive for CD34, while myogenic
co-expresses diffusely CD34, desmin, and markers (desmin, a-smooth muscle actin) are
a-smooth muscle actin, while ALK1 immunore- absent.
activity is absent.
In contrast to IMT/IP, solitary fibrous tumor
characteristically shows short fibroblast-like cells References and Further Reading
haphazardly arranged and medium-sized blood
vessels with hyalinized walls and branching con- Bosse, K., Ott, C., Biegner, T., Fend, F., Siegmann-Luz,
K., Wallwiener, D., & Hahn, M. (2014). 23-year-old
figuration. In addition solitary fibrous tumor is
female with an inflammatory Myofibroblastic tumour
diffusely positive for CD34 and STAT6, which of the breast: A case report and a review of the
are not expressed in IMT/IP. literature. Geburtshilfe und Frauenheilkunde, 74,
wDesmoid-type fibromatosis usually exhibits 167–170.
Cheuk, W., Chan, A. C., Lam, W. L., Chow, S. M.,
extensive infiltrative margins with fingerlike pro-
Crowley, P., Lloydd, R., Campbell, I., Thorburn, M.,
jections into the adjacent fibro-fatty tissue and & Chan, J. K. (2009). IgG4-related sclerosing mastitis:
breast parenchyma. The diagnosis of desmoid- Description of a new member of the IgG4-related scle-
type fibromatosis is based on the presence of rosing diseases. The American Journal of Surgical
Pathology, 33, 1058–1064.
long, sweeping fascicles set in a variable fibrous
Choi, E. J., Jin, G. Y., Chung, M. J., Moon, W. S., &
stroma. Spindle cells are aligned parallel and their Youn, H. J. (2015). Primary inflammatory
nuclei are spaced, without overlapping. Inflamma- myofibroblastic tumors of the breast with metastasis:
tory cells admixed with the proliferating spindle Radiographic and histopathologic predictive factors.
Journal of Breast Cancer, 18, 200–205.
cells are lacking in desmoid-type fibromatosis.
Coffin, C. M., & Fletcher, J. A. (2013). Inflammatory
Although desmoid-type fibromatosis may myofibroblastic tumour. In C. D. M. Fletcher, J. A.
share with IMT/IP the immunohistochemical Bridge, P. C. W. Hogendoorn, & F. Mertens (Eds.),
expression of a-smooth muscle actin, the former WHO classification of tumours of soft tissue and bone
(4th ed., pp. 83–84). Lyon: WHO Press.
is typically positive for b-catenin in about 80% of
Haj, M., Weiss, M., Loberant, N., & Cohen, I. (2003).
cases. Inflammatory pseudotumor of the breast: Case report
Low-grade (fibromatosis-like) spindle cell car- and literature review. The Breast Journal, 9, 423–425.
cinoma (▶ Invasive Metaplastic Carcinoma) is Markopoulos, C., Charalampoudis, P., Karagiannis, E.,
Antonopoulou, Z., & Mantas, D. (2015). Inflammatory
included in the differential diagnosis because neo-
myofibroblastic tumor of the breast. Case Reports in
plastic cells adopt a spindle cell morphology. Surgery, 2015, 705127.
Detection of epithelioid-polygonal cells arranged Talu, C. K., Çakır, Y., Hacıhasanoğlu, E., Leblebici, C.,
in small cohesive clusters, in addition to spindle Aksoy, Ş., & Nazlı, M. A. (2016). Inflammatory
myofibroblastic tumor of the breast coexisting with
cell component, and immunoreactivity for
pseudoangiomatous stromal hyperplasia. The Journal
cytokeratins and myoepithelial markers, espe- of Breast Health, 12, 171–173.
cially p63, supports the diagnosis of carcinoma. Vecchio, G. M., Amico, P., Grasso, G., Vasquez, E., La
Low-grade myofibroblastic sarcoma shares with Greca, G., & Magro, G. (2011). Post-traumatic inflam-
matory pseudotumor of the breast with atypical mor-
IMT/IP the expression of a-smooth muscle actin.
phological features: A potential diagnostic pitfall.
However, its presentation (nodule with well- Report of a case and a critical review of the literature.
circumscribed margins); presence, at least focally, Pathology, Research and Practice, 207, 322–326.
of moderate nuclear atypia; and high mitotic count Zhao, H. D., Wu, T., Wang, J. Q., Zhang, W. D., He, X. L.,
Bao, G. Q., Li, Y., Gong, L., & Wang, Q. (2013).
(from 7 to 35 mitoses per 10 HPF), along with
Primary inflammatory myofibroblastic tumor of the
absence of inflammatory cells, favor the diagnosis breast with rapid recurrence and metastasis: A case
of low-grade myofibroblastic sarcoma. report. Oncology Letters, 5, 97–100.
Intraductal Papillary Carcinoma 175
Zhou, Y., Zhu, J., Zhang, Y., Jiang, J., & Jia, M. (2013). • Incidence
An inflammatory myofibroblastic tumour of the breast The incidence of DCIS has dramatically
with ALK overexpression. BMJ Case Reports,
2013. https://doi.org/10.1136/bcr-07-2011-4474, pii: increased since the introduction of population-
bcr0720114474. based breast cancer screening. Nowadays,
approximately 20–25% of all breast neoplastic
lesions are DCIS. A pure or predominant papil-
lary growth pattern is however rare.
Intraductal Papillary • Age
Carcinoma The reported age range of the patients with
malignant papillary lesions in general is
Emma Josephine Groen and Jelle Wesseling 27–89 years with a mean age of 60 (Tse 2005).
Department of Pathology, The Netherlands • Sex
Cancer Institute-Antoni van Leeuwenhoek Predominantly in women.
Hospital, Amsterdam, The Netherlands • Site
The vast majority is asymptomatic and
is detected by screening mammography. Symp-
Synonyms toms such as nipple discharge, Paget’s disease of
I
the nipple, or a palpable mass sometimes occur.
Noninvasive papillary carcinoma; Papillary duc- There is no preferential site for intraductal pap-
tal carcinoma in situ illary carcinoma.
• Treatment
Treatment is similar to DCIS in general. Cur-
Definition rently almost all lesions are being treated to
prevent the development of breast cancer.
In literature, an unambiguous definition and uni- Breast conserving treatment followed by radio-
form criteria of intraductal papillary carcinoma therapy or in case of extensive lesions a mas-
is lacking. Often, it is described as a luminal tectomy with or without immediate
epithelial neoplastic proliferation of the breast reconstruction are generally recommended.
confined to the mammary ducts and lobules There is no consensus on the value of adjuvant
(also known as ductal carcinoma in situ, DCIS hormonal treatment.
(▶ Ductal Carcinoma In Situ)), characterized by • Outcome
a papillary growth pattern. It is considered a The natural course of intraductal papillary car-
potential precursor lesion for breast cancer. cinoma or papillary DCIS is largely unknown,
Whether these lesions represent de novo malig- as almost all lesions are treated. Fifteen years
nant papillary epithelial proliferations or malig- after DCIS diagnosis, including all subtypes,
nant epithelial populations transforming and cumulative incidence of ipsilateral breast can-
replacing benign papillomas (▶ Intraductal Pap- cer was 1.9% after mastectomy, 8.8% after
illoma) remains unclear. breast conservative surgery (BCS) plus radio-
therapy, and 15.4% after BCS alone (Elshof
et al. 2016).
Clinical Features Despite the increased detection and treat-
ment of these potential precursor lesions for
As intraductal papillary carcinoma is a morpho- breast cancer, the incidence of breast cancer
logical subtype of DCIS, the following features has not declined, suggesting overdiagnosis
are derived from literature based on DCIS in gen- exists resulting in overtreatment. Unfortu-
eral, combined with data specifically focusing on nately, we cannot, at present, distinguish inno-
intraductal papillary carcinoma (also known as cent from aggressive DCIS lesions regarding
papillary DCIS). their capacity to progress to invasive breast
176 Intraductal Papillary Carcinoma
cancer. Therefore, biomarker studies in order and Neubecker 1962; Yamaguchi et al. 2014).
to enable risk stratification and prospective The neoplastic epithelium often consists of one
trials investigating the safety of a wait-and- or more layers of uniform cuboidal to columnar
see strategy for low-risk ductal carcinoma in epithelium with hyperchromatic nuclei of low
situ have emerged. to intermediate grade (Fig. 1b, Fig. 2-plate A2).
Myoepithelial cells are absent within the fibrovas-
cular cores but are seen at the periphery of the
Macroscopy
involved spaces, in line with an in situ process. It
should be noted that a pure papillary architecture
As DCIS in general, intraductal papillary
is rarely seen; often it is seen intermixed with
carcinoma is a segmental disease that can be asso-
other growth patterns, such as micropapillary,
ciated with an impeccable breast parenchyma.
cribriform, or solid DCIS.
Occasionally, dilated mammary ducts filled with
necrotic debris and calcifications with or without
Pitfalls
fibrosis can be seen.
In some cases, intraductal papillary carcinoma
constitutes of a dimorphic epithelial cell popula-
tion, in which an often basally located second
Microscopy population of cells with abundant pale cytoplasm
(“globoid cells”) is seen. These cells may be
Intraductal papillary carcinoma is characterized incorrectly interpreted as myoepithelial cells
by a segmental disease distribution. Involved (Collins and Schnitt 2007). Immunohistochemical
spaces show intraluminal arborizing fibrovascular staining for epithelial and myoepithelial cells can
cores covered by neoplastic epithelium (Fig. 1a, resolve this issue and confirm the epithelial nature
Fig. 2-plate A1). In 1962, delicate and relatively of these cells.
inconspicuous fibrovascular cores were described Dislodgement and displacement of fragments
as characteristic for malignant lesions such as from papillary lesions into the surrounding
intraductal papillary carcinoma (Kraus and breast stroma or even within lymphatic vascular
Neubecker 1962). More recently, however, others spaces, especially after a biopsy procedure, is
have refuted this statement, as they found broad a well-known occurrence and should be
fibrovascular cores even more often in malignant interpreted with caution (Collins and Schnitt
papillary lesions and concluded this morphologic 2007; Kraus and Neubecker 1962; Ni and Tse
feature was not a helpful feature to distinguish 2015). In case of displacement into the surround-
between benign and malignant lesions (Kraus ing breast stroma, epithelial components with
Intraductal Papillary Carcinoma, Fig. 1 Intraductal papillary carcinoma, haemotoxylin-eosin stain (H&E),
(a) magnification 25; (b) magnification 200
Intraductal Papillary Carcinoma, Fig. 2 (a) Intraductal involved space; B4 – ER 400, heterogeneous ER expres-
papillary carcinoma: A1 – H&E 50; A2 – H&E 400; sion (mosaic pattern). (c) Encapsulated papillary carci-
A3 – p63 400, showing presence of myoepithelial cells at noma: C1 – H&E 50; C2 – H&E 400; C3 – p63
the periphery of the involved space but not within the 400, showing no myoepithelial cells; C4 – ER 400,
fibrovascular structure; A4 – ER 400, strong diffuse strong diffuse homogeneous ER expression. (d) Solid
homogeneous ER expression. (b) Intraductal benign pap- papillary carcinoma: D1 – H&E 50; D2 – H&E 400;
illoma: B1 – H&E 50; B2 – H&E 400; B3 – p63 400, D3 – p63 400, showing sporadic myoepithelial cells at
showing presence of myoepithelial cells both within the the periphery of the nodules; D4 – ER 400, strong diffuse
fibrovascular structures and at the periphery of the homogeneous ER expression
some degree of degenerative changes are present fat necrosis, and some degree of inflammation.
within the confines of the biopsy tract with Invasion should only be considered when epithe-
concomitant reactive changes such as reactive lial structures are found well away from the
fibrous stroma, signs of associated hemorrhage, biopsy site and show morphological features
178 Intraductal Papillary Carcinoma
consistent with invasive cancer. Likewise, the Whereas LOH at loci 16p13 and 16q21 could
presence of epithelial fragments in lymphatic be detected in malignant as well as paired benign
vascular spaces or even lymph nodes should papillary lesions as obtained from adjacent tissue,
be doubted when no convincing invasive cancer LOH at locus 16q23 and at the TP53 locus was
is found elsewhere within the breast. limited to malignant lesions, suggesting a role
Immunohistochemistry to verify the presence for the latter two in malignant transformation
or absence of myoepithelial cells in the distinction (Di Cristofano et al. 2005; Lininger et al. 1998).
between true invasion and displacement is only LOH at loci 16q12.2 and 16q21 was found
useful when myoepithelial cells can be detected, exclusively in malignant intraductal papillary
because often only the luminal epithelial cells lesions in core needle biopsies. Therefore, these
are displaced. Especially in intraductal papillary loci of LOH might be potential biomarkers in
carcinoma where myoepithelial cells are only the differential diagnosis with benign lesions
found at the periphery, immunohistochemistry is (Yoshida et al. 2012).
of limited value (Collins and Schnitt 2007; Ni and
Tse 2015).
Immunophenotype Other Forms of Ductal Carcinoma In Situ

(▶ Ductal Carcinoma In Situ)
The neoplastic epithelial compartment often There is no evidence to date that the papillary
shows strong homogeneous staining for estrogen growth pattern as seen in intraductal papillary
receptor (ER). To confirm the absence of carcinoma implicates relevant differences in
myoepithelial cells within the papillary fibrovas- terms of clinical or radiological features and out-
cular structures and the presence at the periphery come compared to DCIS lesions comprising other
of the involved spaces, a p63 stain is advised (see growth patterns. Of note, as described above,
also below) (Fig. 2-plate A3, A4). DCIS with a pure papillary growth pattern
is rarely seen, but a clear definition of when to
call a DCIS lesion “intraductal papillary carci-
Molecular Features noma” as a whole is lacking (e.g., which percent-
age of the lesion should consist of a papillary
Few studies have evaluated molecular alterations in growth pattern). Finally, labeling DCIS with
intraductal papillary carcinoma specifically, in line a papillary growth pattern as intraductal papillary
with its rarity and the uncertainty regarding what carcinoma may be relevant when considering
can be considered as such a lesion. In addition, a differential diagnosis with other papillary
most studies have looked at only small lesions; it can also be confusing as DCIS showing
and nonuniform series, variably including atypical other growth patterns are simply diagnosed
papillomas, papillomas with DCIS, intraductal pap- as DCIS.
illary carcinomas, or even invasive papillary carci-
nomas. Taking this into account, numerical or Benign Papilloma (▶ Intraductal Papilloma)
structural alterations in chromosome 17 and Benign papillomas are either localized centrally
the accumulation of numerical alterations in (solitary) or in the periphery (multiple) and show
chromosomes 3, 7, and X have been detected in a a similar papillary growth pattern with variable
low percentage of the cases of papillary carcinoma, degrees of cell proliferation. In benign papillo-
but not in papillomas (Tsuda et al. 1997). mas, however, one cannot only appreciate the
A higher PIK3CA and AKT1 mutation presence of myoepithelial cells along the periph-
frequency was found in papillomas compared to ery of involved lumina but within the fibrovascu-
papillary carcinomas, which might suggest lar structures as well. Also in the proliferative
a different molecular origin of at least some areas, a mixture of luminal epithelial cells and
papillary carcinomas (Troxell et al. 2009). myoepithelial cells is seen, consistent with
a hyperplastic process (Fig. 2-plate B1, B2, B3). expression of neuroendocrine markers such as
A heterogeneous ER expression pattern is often synaptophysin and chromogranin A. Mucin pro-
seen (Fig. 2-plate B4), but homogeneous ER duction or even a mucinous invasive component
expression does not rule out benignancy, espe- can be seen in association with these lesions.
cially when epithelium with columnar cell type Myoepithelial cells can be present or absent
change is encountered (Ni and Tse 2015). Other at the periphery of these lesions while ER is
useful findings are the presence of apocrine meta- homogeneously expressed in epithelial cells
plasia within a papillary lesion and ▶ usual ductal (Fig. 2-plate D1, D2, D3, D4).
hyperplasia and ▶ sclerosing adenosis in the adja- The true nature of both these entities is uncer-
cent breast tissue, which are suggestive of tain. Historically, these lesions were considered
a benign papilloma (Collins and Schnitt 2007; variants of DCIS but given the often lack of
Kraus and Neubecker 1962). myoepithelial cells, these lesions may perhaps be
When an undoubtedly neoplastic epithelial better classified as low grade invasive carcinomas
population with papillary growth has been identi- with pushing growth or intermediates during the
fied one should keep in mind the following. progression from in situ to invasive breast cancer.
A recognizable architecture of a benign papilloma In the absence of a component of frank invasive
in some part of the lesion precludes the diagnosis growth or high-grade morphology, the outcome is
I
of intraductal papillary carcinoma and should excellent.
rather be considered an atypical papilloma or As described above, the presence of
a papilloma with DCIS depending on the myoepithelial cells both at the periphery
classification used. (DD encapsulated/solid papillary carcinoma)
and in the fibrovascular structures and/or cell
Encapsulated Papillary Carcinoma and Solid proliferation (DD benign papilloma) is a key
Papillary Carcinoma distinguishing feature. One should be careful
Encapsulated Papillary Carcinoma (▶ Encapsu- interpreting immunohistochemical stains for
lated Papillary Carcinoma) often have myoepithelial cells as both stromal fibroblasts
a symptomatic presentation with a subareolar and pericytes can show cross-reactivity, and all
mass and/or nipple discharge mostly occurring stains have their inherent sensitivity and specific-
in elderly women. Microscopically, one or several ity. A combination of more than one marker
nodules of often but not exclusively low to inter- is therefore advised. P63 is superior to other
mediate grade papillary neoplasms can be seen myoepithelial markers in the classification of pap-
originating in a cystically dilated duct surrounded illary lesions, as it is a nuclear stain with only
by a thick fibrous capsule (Collins and Schnitt minimal cross-reactivity and high sensitivity.
2007; Ni and Tse 2015). In contrast to intraductal For evaluating the nature of solid epithelial
papillary carcinoma, these lesions do not show proliferations often seen in papillary lesions,
a rim of myoepithelial cells at the periphery and cytokeratin 5/6 is recommended, as among the
ER is homogeneously and strongly expressed high molecular weight cytokeratins (HMWCKs),
(Fig. 2-plate C1, C2, C3, C4). it has the highest sensitivity and specificity
Solid papillary carcinoma (▶ Solid Papillary (Ni and Tse 2015; Tse et al. 2009).
Carcinoma) also tends to present in elderly Classifying papillary lesions on fine-needle
women as a circumscribed mass. As in aspiration is challenging and should generally
intraductal papillary carcinoma a papillary be discouraged, given the necessity to visualize
ground structure can be appreciated in solid pap- not only the presence of myoepithelial cells but
illary carcinoma. In the latter, however, fibrovas- also their exact location within the lesion.
cular cores are often completely surrounded by a
solid epithelial cell proliferation. These epithelial Immunohistochemical Biomarkers
cells often show ovoid to spindle bland cells and Several studies have evaluated the effectivity
can show neuroendocrine features, both morpho- of new immunohistochemical biomarkers to
logically and immunohistochemically, with the distinguish benign from malignant papillary
180 Intraductal Papilloma
lesions. The absence of staining for stem cell Loh, S. F., Cooper, C., Selinger, C. I., Barnes, E. H.,
markers CD44 and CD133 may be useful in iden- Chan, C., Carmalt, H., et al. (2015). Cell cycle marker
expression in benign and malignant intraductal papil-
tifying malignant papillary lesions. Positive CD44 lary lesions of the breast. Journal of Clinical Pathol-
expression has been proposed as a marker to dif- ogy, 68, 187–191. https://doi.org/10.1136/jclinpath-
ferentiate between benign and malignant papillary 2014-202331.
lesions with a reported sensitivity of 45% and Ni, Y.-B., & Tse, G. M. (2015). Pathological criteria and
practical issues in papillary lesions of the breast –
a specificity of 92% (Tse 2005) and CD133 A review. Histopathology, 68, 22–32. https://doi.org/
expression was significantly lower in papillary 10.1111/his.12866.
carcinomas than in benign or atypical papillomas Troxell, M. L., Levine, J., Beadling, C., Warrick, A.,
(p < 0.001) (Lin et al. 2014). Dunlap, J., Presnell, A., et al. (2009). High prevalence
of PIK3CA/AKT pathway mutations in papillary neo-
Cell cycle markers cyclin B1 and cyclin D1 plasms of the breast. Modern Pathology, 23, 27–37.
have been shown to be independently associated https://doi.org/10.1038/modpathol.2009.142.
with malignancy in papillary lesions. Positive Tse, G. M. K. (2005). CD44s is useful in the differentiation
staining for cyclin B1 and cyclin D1 was found of benign and malignant papillary lesions of the breast.
Journal of Clinical Pathology, 58, 1185–1188. https://
to be helpful for identifying malignant papillary doi.org/10.1136/jcp.2005.026906.
lesions with a sensitivity of 80% and a specificity Tse, G. M., Tan, P. H., & Moriya, T. (2009). The role of
of 72.7% for cyclin B1 and a sensitivity of 86.4% immunohistochemistry in the differential diagnosis of
but only a specificity of 32.6% for cyclin D1 (Loh papillary lesions of the breast. Journal of Clinical
Pathology, 62, 407–413. https://doi.org/10.1136/
et al. 2015). The expression was however fre- jcp.2008.063016.
quently heterogeneous and only focal, limiting Tsuda, H., Takarabe, T., Inazawa, J., &
its usefulness in clinical practice. Hirohashi, S. (1997). Detection of numerical alterations
of chromosomes 3, 7, 17 and X in low-grade intracystic
papillary tumors of the breast by multi-color fluores-
References and Further Reading cence in situ hybridization. Breast Cancer, 4, 247–252.
Yamaguchi, R., Tanaka, M., Tse, G. M., Yamaguchi, M.,
Collins, L. C., & Schnitt, S. J. (2007). Papillary lesions of Terasaki, H., Nomura, Y., et al. (2014). Broad
the breast: Selected diagnostic and management issues. fibrovascular cores may not be an exclusively benign
Histopathology, 52, 20–29. https://doi.org/10.1111/ feature in papillary lesions of the breast: A cautionary
j.1365-2559.2007.02898.x. note. Journal of Clinical Pathology, 67, 258–262.
Di Cristofano, C., Mrad, K., Zavaglia, K., Bertacca, G., https://doi.org/10.1136/jclinpath-2013-201749.
Aretini, P., Cipollini, G., et al. (2005). Papillary lesions Yoshida, M., Tsuda, H., Yamamoto, S., Kinoshita, T., Akashi-
of the breast: A molecular progression? Breast Cancer Tanaka, S., Hojo, T., & Fukutomi, T. (2012). Loss of
Research and Treatment, 90, 71–76. https://doi.org/ heterozygosity on chromosome 16q suggests malignancy
10.1007/s10549-004-3003-3. in core needle biopsy specimens of intraductal papillary
Elshof, L. E., Schaapveld, M., Schmidt, M. K., breast lesions. Virchows Archiv, 460, 497–504. https://doi.
Rutgers, E. J., Leeuwen, F. E., & Wesseling, org/10.1007/s00428-012-1200-8.
J. (2016). Subsequent risk of ipsilateral and contralat-
eral invasive breast cancer after treatment for ductal
carcinoma in situ: Incidence and the effect of
radiotherapy in a population-based cohort of 10,090
women. Breast Cancer Research and Treatment, 159, Intraductal Papilloma
553–563. https://doi.org/10.1007/s10549-016-3973-y.
Kraus, F. T., & Neubecker, R. D. (1962). The differential Ales Ryska and Folakemi A. Torgersen
diagnosis of papillary tumors of the breast. Cancer, 15,
444–455. The Fingerland Department of Pathology, Charles
Lin, C.-H., Liu, C.-H., Wen, C.-H., Ko, P.-L., & Chai, C.-Y. University Medical Faculty and University
(2014). Differential CD133 expression distinguishes Hospital, Hradec Kralove, Czech Republic
malignant from benign papillary lesions of the breast.
Virchows Archiv, 466, 177–184. https://doi.org/
10.1007/s00428-014-1695-2.
Lininger, R. A., Park, W. S., Man, Y. G., Pham, T., Synonyms
MacGrogan, G., Zhuang, Z., & Tavassoli, F. A.
(1998). LOH at 16p13 is a novel chromosomal alter- Ductal adenoma; Large duct papilloma; Major
ation detected in benign and malignant microdissected
papillary neoplasms of the breast. Human Pathology, duct papilloma; Microscopic papilloma; Small
29, 1113–1118. duct papilloma
Intraductal Papilloma 181
Definition • Clinical symptoms

Patients with central papillomas frequently
Intraductal papillomas are benign intraluminal present with serous or serosanguinous nipple
neoplastic proliferations characterized by the discharge (Wei 2016). Small retroareolar pap-
presence of arborizing fibrovascular cores lined illomas can be occult on mammography
by bilayered populations of basal (myoepithelial) because of the breast density in the area. Larger
and luminal (epithelial) cells (O’Malley et al. lesions on the other hand appear as well-
2012). Papillomas may be centrally or peripher- circumscribed round or oval masses. Up to a
ally located in the breast. Central papillomas with quarter of central papillomas are associated
predominant glandular differentiation are also with benign appearing mammographic calcifi-
known as ductal adenomas (▶ Ductal Adenoma). cations. On ultrasound, cystic lesions with
Large, often complex papillomas containing a solid components may be observed.
cystic component are sometimes called papillary Galactography (ductography) shows well-
cystadenomas (Wei 2016). defined filling defects and may be useful in
identifying affected ducts prior to excision
(MacGrogan and Tavassoli 2003).
Clinical Features Sclerosing papillomas may mimic malig-
I
nancy both clinically and on imaging. Patients
• Incidence may present with a palpable mass fixed to the
Intraductal papillomas account for less than skin. Radiographically these lesions may pre-
10% of all benign breast tumors. They are sent as stellate soft tissue densities, sometimes
however the most common papillary lesions with microcalcifications.
of the breast. Peripheral papillomas are usually clinically
• Age occult and nipple discharge is rare. Patients
Though there is a wide age distribution, most may present with a palpable mass.
intraductal papillomas occur in the fourth and • Treatment
fifth decades. While central lesions are more Papillary lesions may be heterogeneous; there-
common in perimenopausal women, periph- fore, papillomas with atypia (focal atypical epi-
eral papillomas typically affect slightly youn- thelial proliferation usually with low-grade
ger patients. nuclei) diagnosed on core needle biopsy are
• Sex usually recommended for excision as the likeli-
Vast majority of cases are diagnosed in hood of discovering malignancy on excision is
females. Intraductal papillomas in the male up to 67%. Complete surgical excision is also
breast are extremely rare. Isolated case reports recommended for papillomas without atypia as
exist in the literature of intraductal papillomas no features predictive of upgrading on examina-
occurring in males ranging in age from 11 to tion of the entire lesion have been identified
73 years. (Shiino et al. 2015). Imaging-guided large-
• Site volume vacuum-assisted percutaneous biopsy
Central papillomas are more common (about has been suggested as a possible alternative to
75% of all papillomas) and arise in the surgical excision (Bianchi et al. 2015). When a
lactiferous ducts in the subareolar region of papilloma without atypia is diagnosed with vac-
the breast. They are usually solitary but less uum biopsy, there is a high likelihood that it is
frequently may also be multiple. Peripheral benign; however, if surgical excision is not
or small duct papillomas on the other hand performed, long-term follow-up is still required.
arise in smaller branches or even in the Patients with multiple papillomas are at
terminal ductolobular units and are fre- increased risk of developing malignancy thus
quently multiple. Some papillomas grow long-term follow-up is appropriate. As no sig-
within cystically dilated ducts (intracystic nificant increase of risk of malignancy devel-
papillomas). opment has been demonstrated in patients with
solitary papillomas, their regular follow-up is

not justified.
• Outcome
Intraductal papillomas with no other changes
in the surrounding breast tissue are associated
with a slight increase in relative risk of subse-
quent invasive breast carcinoma, equivalent to
that of florid ductal hyperplasia.
In a study of 193 papillomas diagnosed on
core needle biopsy, Cyr et al. reported that 12%
of the papillomas were upgraded to malignant
on excision; these carcinomas were early stage
and usually hormone receptor positive and thus
likely to have favorable prognosis (Cyr Intraductal Papilloma, Fig. 1 (H&E) Arborizing struc-
ture of intraductal papilloma
et al. 2011).
Macroscopy
Macroscopically, central papillomas may appear

as exophytic shagged masses attached to the wall
within dilated ducts. Papillomas vary greatly in
size, ranging from a few millimeters to several
centimeters. Peripheral papillomas are macro-
scopically unidentifiable.
Microscopy
Intraductal Papilloma, Fig. 2 (H&E) Intraductal papil-
Cytologically, smears from papillomas are loma with complex structure and signs of bleeding
moderately cellular. The fronds of intraductal
papillomas show sharp delineation and cells
in tissue fragments are more cohesive. The papil- hyperchromasia (O’Malley et al. 2012). Regressive
lae feature fibrovascular stalks lined by changes may frequently occur in papillomas, mak-
columnar cells. Frequently, epithelial cells ing them difficult to assess when only a limited
arranged in a honeycomb pattern are seen. amount of tissue is available for histological exam-
Alternatively, columnar cells can be arranged ination (▶ Infarct of Breast Tissue). Such changes
in small papillae and/or can be seen isolated. include bleeding and infarction. These are typically
The presence of apocrine metaplasia and seen in large central lesions and may occur as a
bipolar naked nuclei is very frequent (Gomez- result of torsion of fibrovascular cores or prior
Aracil et al. 2002). sampling. When no residual vital tissue is present,
Histologically intraductal papillomas are the lesion should be simply called an infarcted
characterized by the presence of a complex papillary lesion (Wei 2016).
arborizing structure comprised of fibrovascular Stromal fibrosis or sclerosis is another feature
cores lined by myoepithelial (basally located) commonly associated with intraductal papillomas.
and epithelial (luminal) cell layers (Fig. 1 The sclerosis may distort the tissue to such an
(H&E) (Fig. 2 (H&E). The epithelial cell nuclei extent that a pseudo-infiltrative pattern is observed
vary in shape and size but are lacking (Fig. 3 (H&E). In these sclerosing intraductal
Intraductal Papilloma 183
Intraductal Papilloma, Fig. 3 (H&E) Pseudo-infiltra- Intraductal Papilloma, Fig. 4 (H&E) Peripheral papil-
tive pattern in intraductal papilloma with stromal sclerosis loma with apocrine metaplasia and microcalcifications in
adjacent TDLU
papillomas, immunohistochemistry can be useful

I
for demonstrating the presence of myoepithelial
cells (Tse et al. 2009). Ductal adenomas (▶ Ductal
Adenoma), which are quite rare, show an epithelial
proliferation surrounding a central scar. They are
thought to be sclerosing intraductal papillomas.
Some cases of ductal adenoma may appear in the
context of Carney complex.
Inflammatory cell infiltrate as well as epithelial
and myoepithelial hyperplasia may also be
observed in intraductal papillomas. Metaplastic
changes are quite common, especially apocrine
metaplasia. Squamous-, clear cell-, sebaceous-,
osseous-, chondroid- and mucinous metaplasia Intraductal Papilloma, Fig. 5 p63 stain showing
may also occur. Squamous metaplasia may be pre- myoepithelial cells within papillary fronds
sent more frequently in the vicinity of infarction.
Compared with central papillomas, peripheral
papillomas (Fig. 4 (H&E) are more commonly and uneven in distribution. The myoepithelial
associated with other proliferative changes of the cells may be identifiable at high power, but immu-
breast such as usual- and atypical ductal hyper- nohistochemical staining for myoepithelial markers
plasia (▶ Usual Ductal Hyperplasia (UDH), may be necessary in some cases (Fig. 5 p63 stain).
▶ Atypical Ductal Hyperplasia) and ductal carci- Smooth muscle actin, p63, p40, CD10, calponin,
noma in situ (▶ Ductal Carcinoma In Situ). and high molecular weight keratins like CK 5/6,
CK14, and HMW-CK may be used (Tse et al.
2009). Among these, smooth muscle actin and
Immunophenotype CD10 are the least specific as their expression can
be seen also in some stromal cells. Thus, they have
Demonstration of a continuous myoepithelial cell only limited value in lesions with a pseudo-invasive
layer within the papillary fronds as well as in the growth pattern.
periphery of the duct wall distinguishes benign CK5/6 may also be useful for confirming het-
papillary lesions from the malignant ones. This erogeneity of cell population in a benign lesion
myoepithelial layer may however be attenuated when a patchy staining pattern is observed (Fig. 6.
CK5/6 immunostaining) (Tse et al. 2009). Lack of

CyclinB1 expression was described as a feature of
papillomas, while lack of CD133 expression was
found almost exclusively in malignant papillary
lesions (Ni and Tse 2016).
Molecular Features
Molecular studies are not relevant for routine

diagnosis and assessment of papillary lesions.
However, Volckmar et al. described recurrent mis-
sense mutations affecting AKT1, GNAS, and
PIK3CA in ductal adenomas (▶ Ductal Adenoma) Intraductal Papilloma, Fig. 6 CK5/6 stain demonstrat-
ing the presence of myoepithelial cells in papillary fronds
(Volckmar et al. 2017). They concluded that muta- as well as a mosaic staining pattern in benign hyperplastic
tions in so-called cancer-related genes do not nec- luminal epithelium
essarily indicate malignant behavior but are also
present in benign tumors. for intraductal papilloma with low-grade DCIS
(O’Malley et al. 2012).
Intraductal papillary carcinoma (▶ Intraductal
Differential Diagnosis Papillary Carcinoma) is one of the architectural
patterns of DCIS (▶ Ductal Carcinoma In Situ). It
Papillomas frequently contain foci of benign epi- is not associated with intraductal papillomas. The
thelial proliferation showing features of usual neoplastic intraductal proliferations in intraductal
ductal hyperplasia (UDH) (▶ Usual Ductal papillary carcinomas (papillary DCIS) show slen-
Hyperplasia (UDH)). This includes the presence der, delicate fibrovascular cores lined by stratified
of nuclei of variable shape, often elongated or columnar epithelial cells with palisading nuclei
spindled, without atypia. The cells grow in a arranged perpendicular to the fibrovascular
lace-like pattern with irregular unevenly shaped cores. When diagnosed cytologically, smears
lumina. The cells demonstrate the phenomenon of from malignant papillary lesions are usually
nuclear streaming (Bianchi et al. 2015). more cellular than those from papillomas
Immunohistochemically, it is possible to demon- (Gomez-Aracil et al. 2002).
strate a mosaic co-expression of low (e.g., CK18) The state of the myoepithelial cell layer is a
and high (e.g., CK5/6) molecular weight useful indicator of the nature of the papillary
cytokeratins with variable intensity of staining in lesion. Atypical papillomas show reduced num-
individual cells (Wei 2016). bers of myoepithelial cells, while in intraductal
Atypical epithelial proliferations (▶ Atypical papillary carcinomas, there is a paucity or com-
Ductal Hyperplasia and ▶ Ductal Carcinoma In plete absence of myoepithelial cells in the papil-
Situ) may involve intraductal papillomas, and lary fronds. However, it should be kept in mind
they are usually of low grade. They are typically that the sole absence of demonstrable
characterized by the presence of small, evenly myoepithelial cells does not automatically mean
spaced cells with round, bland, uniform nuclei. a diagnosis of malignancy, as these may be
Intraductal papilloma with ADH and intraductal completely or almost completely absent in papil-
papilloma with DCIS are distinguished from one lomas with apocrine metaplasia (Cserni 2012).
another using quantitative criteria; when the atyp- During different diagnostic interventions for
ical proliferation is smaller than or equal to 3 mm, intraductal papillomas (such as fine-needle aspi-
it is classified as ADH within a papilloma. Atyp- ration cytology, core-cut biopsy, wire placement,
ical proliferations larger than 3 mm fulfill criteria etc.), so-called epithelial displacement may occur
Invasive Carcinoma NST 185
(Nagi et al. 2005). This phenomenon – although Shiino, S., Tsuda, H., Yoshida, M., Jimbo, K., Asaga, S.,
relatively rare – is well known and represents an Hojo, T., & Kinoshita, T. (2015). Intraductal papillo-
mas on core biopsy can be upgraded to malignancy on
important diagnostic pitfall. Displaced benign subsequent excisional biopsy regardless of the presence
epithelial structures are usually represented by of atypical features. Pathology International, 65,
small isolated clusters of cells present in the 293–300.
stroma or lymphatic channels. Unlike truly inva- Tse, G. M., Tan, P. H., & Moriya, T. (2009). The role of
immunohistochemistry in the differential diagnosis of
sive nests of neoplastic cells, displaced epithelial papillary lesions of the breast. Journal of Clinical
clusters are always located within the biopsy tract Pathology, 62, 407–413.
and lack desmoplastic stromal reaction (Ueng >Ueng, S. H., Mezzetti, T., & Tavassoli, F. A. (2009).
et al. 2009). Though the biologic significance of Papillary neoplasms of the breast: A review. The
Archives of Pathology and Laboratory Medicine, 133,
epithelial displacement is unknown, preliminary 893–907.
studies suggest that displaced cells most probably Volckmar, A. L., Leichsenring, J., Flechtenmacher, C.,
do not survive the preceding trauma or eventually Pfarr, N., Siebolts, U., Kirchner, M., Budczies, J.,
die as time progresses (Nagi et al. 2005). Bockmayr, M., Ridinger, K., Lorenz, K., Herpel, E.,
Noske, A., Weichert, W., Klauschen, F., Schirmacher,
P., Penzel, R., Endris, V., & Stenzinger, A. (2017).
Tubular, lactating, and ductal adenomas are devoid
of MED12 Exon2 mutations, and ductal
References and Further Reading adenomas show recurrent mutations in GNAS and I
the PI3K-AKT pathway. Genes, Chromosomes &
Bianchi, S., Bendinelli, B., Saladino, V., Vezzosi, V., Cancer, 56, 11–17.
Brancato, B., Nori, J., & Palli, D. (2015). Non- Wei, S. (2016). Papillary lesions of the breast: An update.
malignant breast papillary lesions – b3 diagnosed on The Archives of Pathology and Laboratory Medicine,
ultrasound – guided 14-gauge needle core biopsy: 140, 628–643.
Analysis of 114 cases from a single institution and
review of the literature. Pathology and Oncology
Research, 21, 535–546.
Cserni, G. (2012). Benign apocrine papillary lesions of the
breast lacking or virtually lacking myoepithelial cells- Invasive Carcinoma NST
potential pitfalls in diagnosing malignancy. Acta
Pathologica, Microbiologica, et Immunologica
Scandinavica, 120, 249–252. Ian Ellis
Cyr, A. E., Novack, D., Trinkaus, K., Margenthaler, J. A., Department of Histopathology, City Hospital
Gillanders, W. E., Eberlein, T. J., Eberlein, T. J., Ritter, Campus, Nottingham University Hospitals,
J., & Aft, R. L. (2011). Are we overtreating papillomas Nottingham City Hospital, Nottingham, UK
diagnosed on core needle biopsy? Annals of Surgical
Oncology, 18, 946–951.
Gomez-Aracil, V., Mayayo, E., Azua, J., & Arraiza, A.
(2002). Papillary neoplasms of the breast: Clues in Synonyms
fine needle aspiration cytology. Cytopathology, 13,
22–30.
MacGrogan, G., & Tavassoli, F. A. (2003). Central atypical Carcinoma simplex; Ductal carcinoma NST; Infil-
papillomas of the breast: A clinicopathological study of trating ductal carcinoma; Invasive carcinoma of
119 cases. Virchows Archiv, 443, 609–617. no specific type (NST); Invasive ductal carcinoma
Nagi, C., Bleiweiss, I., & Jaffer, S. (2005). Epithelial not otherwise specified (ductal NOS); Scirrhous
displacement in breast lesions: A papillary phenome-
non. The Archives of Pathology and Laboratory Med- carcinoma; Spheroidal cell carcinoma
icine, 129, 1465–1469.
Ni, Y. B., & Tse, G. M. (2016). Pathological criteria and
practical issues in papillary lesions of the breast – a
review. Histopathology, 68(1), 22–32. https://doi.org/ Definition
10.1111/his.12866.
O’Malley, F., Visscher, D., MacGrogan, G., & Tan, P. H. Invasive breast carcinoma of no special type
(2012). Intraductal papilloma. In S. R. Lakhani, I. O.
is also commonly known as invasive ductal
Ellis, S. J. Schnitt, P. H. Tan, & M. J. van de Vijver
(Eds.), WHO classification of tumours of the breast carcinoma not otherwise specified, comprises
(pp. 100–102). Lyon: IARC Press. the largest group of invasive breast cancers. It
186 Invasive Carcinoma NST
is a morphologically heterogeneous group which the tumor including the histological grade
does not exhibit the features or purity of tumors (or growth fraction), size, lymph node stage,
of recognized special types of breast cancer, vascular invasion, hormone receptor, and
such as classical invasive lobular (▶ Invasive HER2 receptor status of the cancer. Treatments
Lobular Carcinoma) or tubular carcinoma are more aggressive when the prognosis is
(▶ Tubular Carcinoma). worse or there is a higher risk of recurrence of
the cancer following treatment. Surgery with or
without radiation therapy is the usual initial
Clinical Features treatment in early stage disease, which may
be followed by adjuvant systemic therapy
• Incidence such as endocrine therapy, chemotherapy, and
Invasive carcinoma NST forms a large propor- targeted anti HER2 therapy where appropriate.
tion of mammary carcinomas and its epidemio- Approximately, 70–80% of NST breast can-
logical characteristics are similar to those of cers are estrogen receptor (ER)-positive and
breast cancer as a whole. The WHO currently 12–20% of cases are HER2 positive.
identifies that breast cancer is the most frequent Neoadjuvant chemotherapy (NACT) has
cancer among women, impacting 2.1 million been shown to be effective in downstaging
women each year, and also causes the greatest breast cancer and is now commonly used as
number of cancer-related deaths among women. primary therapy (Early Breast Cancer Trialists’
In 2018, it is estimated that 627,000 women die Collaborative Group 2018). NACT for early
from breast cancer – that is approximately 15% breast cancer can make breast-conserving sur-
of all cancer deaths among women. While gery more feasible. Patients with high-grade,
breast cancer rates are higher among women in hormone receptor-negative tumors are most
more developed regions, rates are increasing in likely to achieve a complete clinical response
nearly every region globally. of the primary tumor after NACT. Pathological
• Age complete response (pCR) of the axilla can
It is rare below the age of 40 years, but be achieved in 41–75% of patients with
the proportion of tumors classified as such in HER2-positive or triple-negative cancer
young women with breast cancer is in general receiving NACT.
similar to that in older women. • Outcome
• Sex Outcomes for breast cancer vary depending on
Breast cancer of NST is a disease predomi- the extent of disease, prognostic characteristics
nantly of females with male breast cancer and response to treatment. Survival rates have
being very rare. Less than 1% of all breast improved significantly in recent years due to
cancer cases develop in men, and only one in multiple variables including early detection,
a thousand men will ever be diagnosed with screening and an increasing range of effective
breast cancer. treatment options. Survival rates in the devel-
• Site oped world are now high, with between 80%
Breast cancer of NST occurs in the parenchyma and 90% of those in Europe and the United
of the breast or very rarely in extra mammary States alive for at least 5 years. In developing
ectopic breast tissue. Approximately 50% of countries survival rates are poorer.
breast cancers arise in the upper outer quadrant Tools and methods have been developed to
of the breast, 15% in the inner upper quadrant, assist in predicting patient outcome and to sup-
and <10% in the inner lower and outer lower port clinical decision making in breast cancer
quadrants respectively. management. Examples of such methods
• Treatment include the Nottingham Prognostic Index (NPI)
The management of breast cancer of NST (Blamey et al. 2007), St Gallen consensus
depends on the prognostic characteristics of criteria, the National Comprehensive Cancer
Network (NCCN) guidelines, and Predict in this chapter illustrate examples of NST histo-
(https://www.predict.nhs.uk). logical type, please note the ranges of non
The NPI is based on a combination of specific appearances). In many of cases, glandular
histopathological examination of tumor size, differentiation may be apparent as tubular or
lymph node stage, and tumor grading assem- acinar structures with central lumina formed by
bled in a prognostic index formula. Prognosis the tumor cell population. Occasionally,
worsens as the NPI numerical value increases areas with single-file infiltration or targetoid
and by using cut-off points patients may be features mimicking invasive lobular carcinoma
stratified into good, moderate and poor prog- (▶ Invasive Lobular Carcinoma) occur but
nostic groups. The NPI has been confirmed lacking its distinct cytomorphological character-
after long-term follow-up, validated indepen- istics. NST carcinoma cells have a variable
dently in large multi-center studies, and revised appearance. Their cytoplasm may be abundant
in order to stratify patients into 5 prognostic and eosinophilic. Nuclei may be regular and uni-
groups (Blamey et al. 2010). form or highly pleomorphic with prominent, often
multiple, nucleoli. Mitotic activity ranges from
virtually absent to frequent. In up to 80% of
Macroscopy
cases, foci of associated ductal carcinoma in situ
I
(DCIS) (▶ Ductal Carcinoma In Situ) will be pre-
Due to their morphological, biological, and
sent. Any associated DCIS is usually of same
behavioral diversity, these tumors have no specific
nuclear grade as the invasive carcinoma. Occa-
macroscopic features. They can range in size from
sionally lobular neoplasia, either ALH or LCIS
<10 mm to >100 mm. They can have a rounded,
may be present (▶ Lobular In Situ Neoplasia).
irregular, stellate, diffuse, or nodular configura-
The stromal component is extremely variable.
tion. The invasive border is variable in appearance
There may be a highly cellular fibroblastic prolif-
but usually moderately or ill-defined and lacks
eration, a scanty element of connective tissue or
sharp circumscription. Classically, NST carcino-
marked hyalinization. Foci of elastosis may also
mas form a mass lesion and are firm or even hard
be present in a periductal or perivenous distribu-
on palpation, and may have a “gritty” feel when
tion. Focal necrosis may be present and this is
cut with a blade. The cut surface appearance is
occasionally extensive with secondary formation
varied but is usually pale and grey to cream white.
of cysts. In a minority of cases, a distinct
lymphoplasmacytoid infiltrate can be identified.
Vascular tumor emboli can be observed within or
Microscopy adjacent to the tumor.
Assignment of a tumor to the NST histological Carcinoma of Mixed Histological Type

type of breast cancer is essentially through a pro- The current UK (Ellis et al. 2016), European
cess of exclusion of recognized special types. As (Perry et al. 2006) and WHO (Lakhani et al.
a consequence, morphological features vary con- 2012) classification systems promote use the
siderably from case to case. All types of tumor mixed tumor type category for tumors which
margins can be observed, from highly infiltrative, lack the purity of a specific special type but
invading nonspecialized mammary stroma, show prominent or dominant but not pure special
and disrupting the normal parenchymal lobular type characteristics. For a tumor to be typed as
architecture to continuous pushing margins. breast carcinoma NST, it must have a non-
Architecturally, the tumor cells may be arranged specialized pattern in >50% of its mass as
in cords, clusters, and trabeculae, while some judged by thorough examination of representa-
tumors are characterized by a predominantly tive sections. If the NST pattern comprises
solid or syncytial infiltrative pattern with little between 10% and 49% of the tumor, the rest
associated stroma (Fig. 1a, b, c: all the figures being of a recognized special type, then it
Invasive Carcinoma NST, Fig. 1 (H&E) (a, b, c) Exam- morphological appearances seen in the NST tumor type.
ples of three invasive carcinomas of NST type showing no Please note that all the figures in this chapter are of NST
specific characteristics and a range of morphological tumors, with the exception of Fig. 2 which shows a tumour
appearances. Note the lack of special characteristic of mixed type with both NST and Tubular features
exhibited by each tumor and also the range of
will fall into one of the mixed groups: carcinoma, carcinoma with osteoclast-like stro-
mixed NST and special type (Fig. 2) or mal giant cells, carcinoma with choriocarci-
mixed NST and lobular carcinoma. Apart nomatous features, and carcinoma with
from these considerations, there are very melanotic features. There is also a current debate
few lesions that should be confused with NST whether to include medullary like cancers within a
carcinomas. group of NST cancers with associated
lymphocyte-rich stroma rather than as a distinct
separate morphological type.
Rare Morphological Variants of NST
Carcinoma Pleomorphic carcinoma. The 2012 WHO
The 2012 WHO classification of breast tumors classification defines pleomorphic carcinoma
(Lakhani et al. 2012) recognizes a number of as a rare variant of high-grade NST carcinoma,
morphological forms of breast cancer that are which is characterized by a proliferation of
not currently recognized as distinct special types pleomorphic and bizarre, sometimes multi-
of invasive breast cancer but as variants of nucleated, tumor giant cells comprising
NST breast cancer. These include pleomorphic >50% of the tumor cells in a background
Invasive Carcinoma NST, Fig. 2 (H&E) (a, b) An Note the presence of a normal lobular unit (b) for compar-
example of a tumor of mixed type with focal (>50% and ison of tumor cells’ nuclear size. The carcinoma has similar
<90%) tubular carcinoma characteristics with background sized nuclei and score 1 for nuclear pleomorphism. There
(<50%) non specialised, NST, features. Please note that is marked tubule/gland formation, score 1 and no visible
this tumour shows grade 1 histological characteristics. mitoses, score 1, giving a total score of 3 (grade 1)
I
of adenocarcinoma or adenocarcinoma with NST carcinoma associated with elevated levels

metaplastic spindle and squamous differentia- of serum human chorionic gonadotropin. Up to
tion. The tumors are typically of grade 3 with 60% of NST carcinomas have been found to
a high mitotic frequency and central necrosis. contain HCG-positive cells. Histological evi-
Carcinoma with osteoclast-like stromal giant dence of choriocarcinomatous differentiation,
cells. The 2012 WHO classification defines however, is exceptionally rare with only a few
these carcinomas by the presence of osteoclas- cases reported.
tic giant cells (OGCs) in the stroma. The giant Carcinoma with melanotic features. The 2012
cells are generally associated with an inflam- WHO classification defines this as an excep-
matory, fibroblastic, hypervascular stroma, tionally rare tumor which appears to represent
with extravasated erythrocytes, lymphocytes, combinations of NST carcinoma and malignant
and monocytes, along with mononucleated melanoma and in some of these cases exhibits
and binucleated histiocytes, some containing a transition from one cell type to the other.
hemosiderin. The giant cells vary in size and The mere presence of melanin in breast cancer
contain a variable number of non-atypical cells should not be construed as evidence of
nuclei. The carcinomatous part of the lesion is melanocytic differentiation, since pigmenta-
most frequently a well – to moderately differ- tion of carcinoma cells with melanin can
entiated infiltrating breast carcinoma NST occur when breast cancers invade the skin
but all the other histological types have been and involve the dermoepidermal junction.
observed particularly invasive cribriform car- In addition, care must be taken to distinguish
cinoma (▶ Invasive Cribriform Carcinoma), tumors showing melanocytic differentiation
and also tubular (▶ Tubular Carcinoma), from breast carcinomas with prominent cyto-
mucinous (▶ Invasive Mucinous Carcinoma), plasmic deposition of lipofuscin. It should also
papillary, lobular (▶ Invasive Lobular Carci- be noted that most melanotic tumors of the
noma), squamous, and other metaplastic breast represent metastases from malignant
(▶ Invasive Metaplastic Carcinoma) patterns melanomas originating in extra-mammary
and pleomorphic carcinoma. sites. Primary melanomas may arise anywhere
Carcinoma with choriocarcinomatous features. in the skin of the breast, but an origin in the
The 2012 WHO classification defines these as nipple-areola complex is extremely rare.
Additional Classification Systems Ellis 1991). The method has now been shown to
have good reproducibility in other centres and it
Histological Grade has been adopted for use in the pathological data
One of the most fundamental aspects of oncological set of the United Kingdom NHS BSP and in the
pathology, which has undoubtedly stood the test of USA and Europe (Rakha et al. 2010). Examples
time, has been the recognition that the detailed of grade 1, grade 2, and grade 3 carcinomas
morphological structure of tumors can be correlated are shown in Figs. 2a, b, 3, 4, and 5.
with their degree of malignancy. Greenhough in
1928, in Boston, USA, undertook the first formal Tumor Infiltrating Lymphocytes
study of the grading of breast cancer. Scarff and his It has been recognized that some types of breast
colleagues at the Middlesex Hospital in London cancer such as medullary like, NST, triple negative
re-examined Greenhough’s method and decided and HER2 positive, are associated with tumor-
that only three factors, tubule formation, nuclear infiltrating lymphocytes (TILs) (Fig. 6). Formal
pleomorphism, and hyperchromatism were of evaluation of TILs is gaining momentum as evi-
importance. Scarff’s method has formed the basis dence strengthens for the clinical relevance of phe-
of all subsequent grading systems. The perceived nomenon which is regarded as an immunological
poor reproducibility and consistency has been biomarker. The extent of lymphocytic infiltration in
largely resolved by use of semi objective scoring tumor tissue can be assessed as by evaluation of
systems and adherence to written criteria. These hematoxylin and eosin (H&E)-stained tumor sec-
studies have highlighted the need for grading to be tions and has been shown to provide prognostic
carried out by trained histopathologists who work to and potentially predictive value, particularly in the
an agreed protocol. triple-negative and HER 2 positive settings.
The Nottingham method, outlined in A standardized methodology for evaluating
Tables 1 and 2, is the most widely used method. TILs has been developed for visual assessment
Three characteristics of the tumor are evaluated on H&E sections (Salgado et al. 2015) by the
according to semi quantitative criteria, tubule International TILs Working Group. Their key rec-
formation as an expression of glandular differen- ommendations are:
tiation, nuclear pleomorphism and mitotic counts.
It has been validated through long term follow 1. TILs should be reported for the stromal com-
up of a large series of patients confirming partment (=% stromal TILs).
conclusively the highly significant relationship 2. TILs should be evaluated within the borders
between histological grade and prognosis; sur- of the invasive tumor.
vival worsens with increasing grade (Elston and 3. Exclude TILs outside of the tumor border and
around DCIS and normal lobules.
Invasive Carcinoma NST, Table 1 Semiquantitative
4. Exclude TILs in tumor zones with crush arti-
method for assessing histological grade in breast
carcinoma facts, necrosis, regressive hyalinization as
well as in the previous core biopsy site.
Feature Score
5. All mononuclear cells (including lymphocytes
Tubule formation
Majority of tumor (>75%) 1
and plasma cells) should be scored, but poly-
Moderate degree (10–75%) 2 morphonuclear leukocytes are excluded.
Little or none (<10%) 3 6. One section (4–5 mm, magnification
Nuclear pleomorphism 200–400) per patient is currently consid-
Small, regular uniform cells 1 ered to be sufficient.
Moderate increase in size and variability 2 7. Full sections are preferred over biopsies
Marked variation 3 whenever possible.
Mitotic counts 8. A full assessment of average TILs in the
Dependent on microscope field area 1–3 tumor area by the pathologist should be
(see Table 2) used. Do not focus on hotspots.
Invasive Carcinoma NST, Table 2 Assignment of points for mitotic counts according to the field area
Number of mitoses corresponding to
Field diameter in mm Score 1 Score 2 Score 3
0.40 Up to 4 5–8 9 or more
0.41 Up to 4 5–9 10 or more
0.42 Up to 4 5–9 10 or more
0.43 Up to 4 5–10 11 or more
0.44 Up to 5 6–10 11 or more
0.45 Up to 5 6–11 12 or more
0.46 Up to 5 6–11 12 or more
0.47 Up to 5 6–12 13 or more
0.48 Up to 6 7–12 13 or more
0.49 Up to 6 7–13 14 or more
0.50 Up to 6 7–13 14 or more
0.51 Up to 6 7–14 15 or more
0.52 Up to 7 8–14 15 or more
0.53 Up to 7 8–15 16 or more
0.54 Up to 7 8–16 17 or more I
0.55 Up to 8 9–16 17 or more
0.56 Up to 8 9–17 18 or more
0.57 Up to 8 9–17 18 or more
0.58 Up to 9 10–18 19 or more
0.59 Up to 9 10–19 20 or more
0.60 Up to 9 10–19 20 or more
0.61 Up to 9 10–20 21 or more
0.62 Up to 10 11–21 22 or more
0.63 Up to 10 11–21 22 or more
0.64 Up to 11 12–22 23 or more
0.65 Up to 11 12–23 24 or more
0.66 Up to 11 12–24 25 or more
0.67 Up to 12 13–25 26 or more
0.68 Up to 12 13–25 26 or more
0.69 Up to 12 13–26 27 or more
0.70 Up to 13 14–27 28 or more
9. TILs should be assessed as a continuous low molecular weight cytokeratin, including CK’s
parameter. 7, 8 and 18. All of the major gene expression
10. No formal recommendation for a clinically molecular classes (luminal, basal/triple negative
relevant TIL threshold(s) can be given at and HER2 positive) are represented in the NST
this stage. group with the luminal ER positive tumors
predominating, approximately 70–80% of NST
breast cancers are ER-positive (▶ Hormone
Immunophenotype Receptors in Breast Cancer). The basal/triple neg-
ative for ER, progesterone receptor (PR)
Being a heterogeneous form of breast and HER2 group occur at a lower frequency
cancer tumors of NST type have not distinct (10–20%), as does the HER2 positive/ER positive
immunephenotypic characteristics. The majority and negative subgroups, with 12–20% of cases
of NST tumors are positive for GCDFP-15 and being HER2 positive (▶ HER2 in Breast Cancer).
Invasive Carcinoma NST, Fig. 5 Example of a grade

Invasive Carcinoma NST, Fig. 3 Example of a grade 3 tumor. There is no evidence of tubule/gland formation,
1 carcinoma. The tumour shows prominent tubule/gland score 3, a high degree of nuclear pleomorphism and
formation (score 1), moderate to high nuclear pleomor- increase in nuclei size, score 3, assessment of 10 calibrated
phism (score 3) and no mitotic figures (score 1). Final high power fields showed a high frequency of mitosis,
garde score 5 indicating a grade 1 invasive carcinoma. score 3. The total grade score is 9 indicating a grade
The differential diagnosis would be with a pure tubular 3 tumor (H&E)
carcinoma but the degree of nuclear pleomorphism
exhibited preclude a diagnosis of pure tubular carcinoma
and classification as grade 1 NST carcinoma is appropriate
(H&E) single disease with variable histology and clin-
ical course. Recently high-throughput molecu-
lar biology analytical methods such as cDNA
microarray analysis when applied to breast
cancer as a whole and to the NST class
revealed unexpectedly large-scale molecular
differences between ER-positive cancers and
ER-negative cancers (Fig. 7) (Allison 2012;
Rakha and Green 2017). In addition these
molecular biology studies have shown specific
genetic lesions or regions of alteration associ-
ated with some histological special types or
grade, for example the low nuclear grade
tumors including invasive lobular (▶ Invasive
Lobular Carcinoma) and tubular carcinoma
(▶ Tubular Carcinoma) cluster in the luminal
Invasive Carcinoma NST, Fig. 4 Example of a grade A intrinsic class and have distinct similar
2 invasive carcinoma. There is over 10% tubule/gland alterations of chromosomes 1 and 16. In con-
formation, score 2, moderate nuclear pleomorphism, trast, the group of NST breast cancers harbors
score 2 and on assessment of 10 calibrated high power
all the molecular intrinsic classes and has
fields a mitotic frequency score of 2. Total grade score 6,
indicating a grade 2 tumor (H&E) genetic alterations across the genome. These
results imply that breast cancer overall and the
NST group appear to develop via multiple
Molecular Features different genetic evolutionary pathways. As a
consequence, NST breast cancer is viewed not
NST breast cancer shows high genetic varia- as a single disease but as a collection of sev-
tion comparable to breast cancer as a whole. eral biologically distinct neoplastic diseases
Historically breast cancer was regarded as a that arise from the breast epithelium.
Invasive Carcinoma NST,

Fig. 6 A high grade
invasive carcinoma with
some medullary like
features showing marked
stromal infiltration by
lymphocytes and plasma
cells (TILs) (H&E)
St Gallen 2017 division of subtypes

I
Clinical grouping Notesa
Triple negative Negative ER, PR and
HER2
Hormone receptor- International guidelines
negative and HER2-
positive
Hormone receptor-positive International guidelines
and HER2-positive
Hormone receptor-positive ER and/or PgR positive
and HER2-negative 1%
– a spectrum of ER+/
HER2-negative
High receptor, low Multi-parameter
Invasive Carcinoma NST, Fig. 7 An example of a triple proliferation, low grade molecular marker ‘good’
negative, for ER, PR and HER2, grade 3 invasive carci- (luminal A-like) if available.b High ER/PR
noma of NST type showing undifferentiated basal like and clearly low Ki-67 or
characteristics (H&E) grade.
Intermediate Multi-parameter
All four different molecular types of breast molecular marker
‘intermediate’ if available.
cancer can be observed in NST breast cancer:
Uncertainty persists about
degree of risk and
• Luminal A type – low proliferation responsiveness to
ER-positive endocrine and cytotoxic
therapies.
• Luminal B type – highly proliferative ER-
Low receptor, high Multi-parameter
positive, PR low or negative proliferation, high grade molecular marker ‘bad’
• Basal/triple negative – ER/PR-negative and (luminal B-like) if available. Lower ER/
HER-2-negative PR with clearly high
• HER-2 amplified breast cancer Ki-67, histological
grade 3.
a
Basal like breast cancer and HER2-enriched subtype can
However, for clinical purposes, these have
be defined by genomic assay only.
been further refined by the St Gallen consensus b
No role for gene testing in clinical pathologic low risk
conference (Curigliano et al. 2017): cases (pT1a, pT1b, G1, ER high, pN0).
Differential Diagnosis Mitchell, M. J., Ball, G. R., Haybittle, J. L., &

Elston, C. W. (2007). Survival of invasive breast cancer
according to the Nottingham Prognostic Index in cases
The principle differential diagnosis relates to dis- diagnosed in 1990–1999. European Journal of Cancer,
tinction from invasive mammary carcinomas of 43, 1548–1555.
recognized pure special types such as invasive Blamey, R. W., Hornmark-Stenstam, B., Ball, G., Blichert-
lobular carcinoma (▶ Invasive Lobular Carci- Toft, M., Cataliotti, L., Fourquet, A., Gee, J., Holli, K.,
Jakesz, R., Kerin, M., Mansel, R., Nicholson, R.,
noma), tubular (▶ Tubular Carcinoma)/invasive Pienkowski, T., Pinder, S., Sundquist, M.,
cribriform carcinoma (▶ Invasive Cribriform Car- van de Vijver, M., & Ellis, I. (2010). ONCOPOOL –
cinoma), mucinous carcinoma (▶ Invasive A European database for 16,944 cases of breast cancer.
Mucinous Carcinoma), medullary-like carcinoma European Journal of Cancer, 46, 56–71.
Carlson, R. W., Brown, E., Burstein, H. J., Gradishar, W. J.,
(▶ Invasive Carcinoma with Medullary Features), Hudis, C. A., Loprinzi, C., Mamounas, E. P.,
and other rarer special types. Such distinction Perez, E. A., Pritchard, K., Ravdin, P., Recht, A.,
requires knowledge and application of the defin- Somlo, G., Theriault, R. L., Winer, E. P., &
ing features of each type which are predominantly Wolff, A. C. (2006). NCCN Task Force report: Adju-
vant therapy for breast cancer. Journal of the National
morphological and detailed elsewhere in the rele- Comprehensive Cancer Network, 4(Suppl 1), S1–S26.
vant sections. However, a very high proportion of Curigliano, G., Burstein, H. J., Winer, E. P., Gnant, M.,
invasive lobular carcinomas (▶ Invasive Lobular Dubsky, P., Loibl, S., Colleoni, M., Regan, M. M.,
Carcinoma) have alterations in the E-Cadherin Piccart-Gebhart, M., Senn, H.-J., Thürlimann, B.,
André, F., Baselga, J., Bergh, J., Bonnefoi, H.,
gene with resultant loss of E-Cadherin protein Brucker, S. Y., Cardoso, F., Carey, L., Ciruelos, E.,
expression. Immunohistochemical staining for Cuzick, J., Denkert, C., Di Leo, A., Ejlertsen, B.,
E-Cadherin can therefore be a helpful supporting Francis, B., Galimberti, V., Garber, J., Gulluoglu, B.,
adjunct test to differentiate the lobular class from Goodwin, P., Harbeck, N., Hayes, D. F., Huang, C. S.,
Huober, J., Khaled, H., Jassem, J., Jiang, Z.,
the NST group of cancers. Karlsson, P., Morrow, M., Orecchia, R.,
The UK, EU, and WHO classification systems Osborne, K. C., Pagani, O., Partridge, A. H.,
highlight the need for >90% purity of special Pritchard, K., Ro, J., Rutgers, E. J. T., Sedlmayer, F.,
type characteristics to define most special types Semiglazov, V., Shao, Z., Smith, I., Toi, M., Tutt, A.,
Viale, G., Watanabe, T., Whelan, T. J., & Xu, B. (2017).
of cancer to ensure their prognostic characteristics De-escalating and escalating treatments for early-stage
will be manifest. Tumors exhibiting between breast cancer: The St. Gallen International Expert
50% and 90% special type characteristics are Consensus Conference on the Primary Therapy of
recommended to be designated as mixed special Early Breast Cancer 2017. Annals of Oncology, 28,
1700–1712.
and NST type (see above). Early Breast Cancer Trialists’ Collaborative Group
Tumors of unusual morphological appearance, (EBCTCG). (2018). Long-term outcomes for neo-
particularly if ER negative and lacking an accom- adjuvant versus adjuvant chemotherapy in early breast
panying in situ component such as DCIS, may cancer: Meta-analysis of individual patient data from
ten randomised trials. Lancet Oncology, 19, 27–39.
represent a metastatic tumor deposit in the breast Ellis, I. O., Al-Sam, S., Anderson, N., Carder, P., Deb, R.,
rather than a primary NST mammary carcinoma. Girling, A., Hales, S., Hanby, A., Ibrahim, M.,
Clinical information relating to past medical his- Lee, A. S. H., Liebmann, R., Mallon, E., Pinder, S. E.,
tory of a malignancy elsewhere, clinical investi- Provenzano, E., Quinn, C., Rakha, E., Rowlands, D.,
Stephenson, T., & Wells, C. A. (2016). Pathology
gation, and immunophenotype of the tumor can reporting of breast disease in surgical excision speci-
help distinguish a primary from a metastatic tumor mens incorporating the dataset for histological
(Lee 2007). reporting of breast cancer. The Royal College of Pathol-
ogists, London. file:https://www.rcpath.org/profession/
guidelines/cancer-datasets-and-tissue-pathways.html#
Elston, C. W., & Ellis, I. O. (1991). Pathological prognostic
factors in breast cancer. I. The value of histological
grade in breast cancer: Experience from a large
Allison, K. H. (2012). Molecular pathology of breast study with long-term follow-up. Histopathology, 19,
cancer: What a pathologist needs to know. American 403–410.
Journal of Clinical Pathology, 138, 770–780. Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., &
Blamey, R. W., Ellis, I. O., Pinder, S. E., Lee, A. H., van de Vijver, M. J. (2012). WHO classification of
Macmillan, R. D., Morgan, D. A., Robertson, J. F., tumours of the breast (4th ed.). Lyon: IARC Press.
Invasive Carcinoma with Medullary Features 195
Lee, A. H. (2007). The histological diagnosis of metastases Definition

to the breast from extramammary malignancies.
Perry, N., Broeders, M., de Wolf, C., Törnberg, S., The 2012 WHO Classification of Tumors of the
Holland, R., & von Karsa, L. (2006). European guide- Breast recommends the use of the collective term
lines for quality assurance in breast cancer screening “Carcinoma with Medullary Features” to encom-
and diagnosis (4th ed.). Luxembourg: Office for pass tumors previously diagnosed as classical
Official Publications of the European Communities.
Rakha, E. A., & Green, A. R. (2017). Molecular classifi- medullary carcinoma (classical MC), atypical
cation of breast cancer: What the pathologist needs to medullary carcinoma (atypical MC), and a sub-
know. Pathology, 49, 111–119. group of invasive breast carcinoma of no special
Rakha, E. A., Reis-Filho, J. S., Baehner, F., Dabbs, D. J., type (NST) with medullary characteristics
Decker, T., Eusebi, V., Fox, S. B., Ichihara, S.,
Jacquemier, J., Lakhani, S. R., Palacios, J., (Lakhani et al. 2012).
Richardson, A. L., Schnitt, S. J., Schmitt, F. C., These tumors are characterized by the follow-
Tan, P. H., Tse, G. M., Badve, S., & Ellis, I. O. ing histological features:
(2010). Breast cancer prognostic classification in the
molecular era: The role of histological grade. Breast
Cancer Research, 12, 207. 1. An expansile or pushing border
Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., 2. A syncytial growth pattern
Klauschen, F., Pruneri, G., Wienert, S., Van den 3. High cytonuclear grade
Eynden, G., Baehner, F. L., Penault-Llorca, F., I
4. A prominent lymphoplasmacytic infiltrate
Perez, E. A., Thompson, E. A., Symmans, W. F.,
Richardson, A. L., Brock, J., Criscitiello, C.,
Bailey, H., Ignatiadis, M., Floris, G., Sparano, J., These diagnostic criteria are less strict than the
Kos, Z., Nielsen, T., Rimm, D. L., Allison, K. H., original criteria proposed by Ridolfi et al. for a
Reis-Filho, J. S., Loibl, S., Sotiriou, C., Viale, G., diagnosis of classical MC which requires com-
Badve, S., Adams, S., Willard-Gallo, K., Loi, S., &
International TILs Working Group 2014. (2015). The plete circumscription, a syncytial growth pattern
evaluation of tumor-infiltrating lymphocytes (TILs) in at least 75% of the tumor, a moderate to marked
in breast cancer: Recommendations by an International mononuclear stromal infiltrate, high nuclear
TILs Working Group 2014. Annals of Oncology, 26, grade, no intraduct component, and no micro-
259–271.
glandular features (Ridolfi et al. 1977).
Atypical MC displays some but not all of
the features of classical MC and permits lack
of complete circumscription, a less prominent
Invasive Carcinoma with
lymphoid infiltrate, accompanying intraduct
Medullary Features carcinoma and focal glandular differentiation.
A well-circumscribed tumor with classical MC
Cecily Quinn1,2 and Clare D’Arcy1
1 morphology in 75% of the tumor and the remain-
Department of Histopathology, Irish National
der composed of invasive carcinoma NST also
Breast Screening Programme and St. Vincent’s
qualifies as atypical MC.
University Hospital, Dublin, Ireland
2 A subset of invasive carcinoma NST that dis-
School of Medicine, University College Dublin,
plays medullary characteristics, including circum-
Dublin, Ireland
scription, high nuclear grade, and a prominent
lymphoplasmacytic stromal infiltrate, has been
observed, particularly in women with inherited
Synonyms
BRCA1 gene mutations.
In view of the need to recognize the latter
Atypical medullary carcinoma (atypical MC);
tumor subgroup and the considerable lack of
Carcinoma with medullary features (CMF); Clas-
reproducibility in the diagnosis of classical and
sical medullary carcinoma (classical MC); Inva-
atypical MC, the WHO group has taken the prag-
sive carcinoma of no special type (NST) with
matic approach to combine these three groups
medullary characteristics
emphasizing their common characteristics and
196 Invasive Carcinoma with Medullary Features
propose the collective term, “Carcinoma with BRCA1 gene mutations are also at increased
Medullary Features,” abbreviated to CMF for the risk of developing breast cancer. BRCA2
remainder of this chapter (Lakhani et al. 2012). mutations confer a higher risk of breast cancer
in men than in women.
• Site and Presentation
Clinical Features Patients may present with a discrete palpable
breast mass or may be diagnosed through
• Incidence mammographic screening, population based
Classical MC, as defined by Ridolfi et al. in or high-risk surveillance programs. CMF is
1977, is generally considered to be a rare breast typically well circumscribed and may have a
tumor accounting for <1% of all breast cancers soft consistency due to the lack of a stromal
(Ridolfi et al. 1977). Rates of up to 7% have desmoplastic reaction. In view of these fea-
been reported and this is likely attributable to tures and the relatively young age at presen-
interobserver and inter-institutional variation tation, these tumors may mimic benign
in the application of the histological criteria lesions both clinically and on imaging studies.
used to make the diagnosis. The overlying skin may be red. Bilateral syn-
In reported series, MC is less common chronous MCs have been reported, more com-
than atypical MC but the incidence is monly in patients with a positive family
largely unknown due to variation in defi- history.
nition and lack of and/or inconsistent coding CMF may be associated with a rapid growth
documentation. rate and may also come to medical attention as
CMF has a broader, more inclusive, defini- an interval screening breast cancer.
tion and includes a subset of tumors with med- Axillary lymph node involvement may occur
ullary characteristics that would previously but is relatively less common in CMF compared
have been categorized as invasive carcinoma with invasive carcinoma NST (▶ Invasive Car-
NST. It is difficult to obtain precise figures on cinoma NST). Concomitant enlarged axillary
overall incidence, but it is estimated that CMF lymph nodes are more likely to be reactive than
accounts for between 10% and 20% of invasive involved by metastatic CMF and presentation as
breast tumors (Hicks and Lester 2017). axillary lymph node involvement is rare (Hicks
• Age and Lester 2017). Presentation as distant metas-
The age at diagnosis of women with CMF ranges tases is also rare.
from 21 to 95 years, with an average age at • Treatment Surgery
presentation of between 45 and 50 years. The The primary goal of treatment is complete sur-
latter is approximately 10 years younger than the gical excision with clear margins. Conservation
average age profile of women diagnosed with surgery is clearly desirable and is feasible in
other types of invasive breast carcinoma. One most cases due to the absence of ductal carci-
in four diagnoses of CMF occurs in women noma in situ (▶ Ductal Carcinoma In Situ).
under the age of 35 years. This is likely to be Mastectomy may be necessary to treat large
due to the association of CMF with inherited and some centrally located tumors.
Breast Cancer susceptibility gene 1 (BRCA1) A diagnosis of CMF, in some countries, will
germline mutation (Eisinger et al. 1998). lead to genetic testing in women who have not
• Sex been previously tested. The results of this
CMF is predominantly reported in females in may lead to consideration of additional breast
line with all other forms of breast carcinoma. and other prophylactic surgery. This requires
The literature is scarce on histological tumor careful evaluation by the patient in consulta-
type in men. Most breast tumors in men are tion with her/his clinical team.
luminal A or triple negative. MC has been • Chemotherapy
reported in male patients. Male patients with
CMF is typically triple negative although cases was associated with a significantly higher sur-
of hormone receptor positive MC have been vival rate at 10 years, estimated at 84% for
reported. In view of the more favorable prog- patients with classical MC compared with
nosis associated with CMF, it has been 63% for patients with non-medullary invasive
suggested that patients with lymph node nega- breast carcinoma (Ridolfi et al. 1977). This
tive disease may possibly avoid chemotherapy. also pertained to patients with
In general, this tumor type tends to occur in positive axillary lymph nodes when the
younger women and the constellation of mor- two groups were compared. In addition to
phological features is usually associated with 57 patients with classical MC, the study popu-
triple negative status. At the present time it is lation included 79 patients with AMC and
recommended that adjuvant or neoadjuvant 56 with non-medullary carcinoma (invasive
chemotherapy treatment recommendations for carcinoma NST, using modern terminology).
patients with CMF should take account of the Patients with AMC also had an improved prog-
clinical, pathological, and biological character- nosis with a 10-year survival rate of 74% over-
istics as for all invasive breast cancers. PARP all. Interestingly, AMC with a sparse lymphoid
inhibitors and platinum agents are reported to infiltrate was associated with a relatively poor
be more effective in the treatment of BRCA1- prognosis. Apart from this observation, the
I
related tumors. authors were unable to draw any firm conclu-
• Immunotherapy sions regarding the prognostic effect of the
Several clinical trials are in progress to investi- other morphological features of AMC.
gate the efficacy of immunotherapy agents in In a more recent study, Mateo et al.
the treatment of triple negative breast carci- reviewed the outcome of patients diagnosed
noma (TNBC) (Dua and Tan 2017). This relates with MC (n = 3,688) and AMC (n = 288)
to the discovery that approximately 25% of registered with the National US Cancer Data-
TNBCs express the T-cell inhibitory molecule base (NCDB) during the period 2004 to 2013
PD-L1 (programmed death ligand-1), particu- (Mateo et al. 2016). Cases are reported to
larly in tumors with a high lymphocyte count. the NCDB using codes from the International
PDL1 is expressed on cancer cells, tumor infil- classification of diseases for Oncology
trating lymphocytes (TILs), and immune cells (ICD-O-3). During the study period 918,870
(Tung et al. 2016). The binding of PD-L1 to the cases of non-medullary breast carcinoma
PD-1 (programmed death 1) checkpoint recep- were registered. Over 20% of tumors diag-
tor on T cells is one mechanism for tumor nosed as MC or AMC were recorded as hor-
evasion of the immune response. As detailed mone receptor positive. The study did not
in subsequent sections, CMF is characterized include a review of histopathological slides
by a prominent inflammatory cell infiltrate with and the number of AMC tumors was rela-
a high TIL count. CMF is also associated with a tively small. Notwithstanding these limita-
high level of genomic instability leading to tions the authors found no significant
increased production of neoantigens and greater difference between MC and AMC in terms
immunogenicity (Weigelt et al. 2010). These of clinicopathological characteristics and
features suggest that CMF is likely to be a can- clinical outcome.
didate tumor type for targeted immunotherapy. Subsequent studies from several institutions
Adjuvant Radiotherapy: Recommenda- have also reported a more favorable outcome in
tions for post-surgical radiotherapy should be patients with MC compared with grade matched
made in accordance with those for other pri- invasive carcinoma NST. In a compilation of
mary invasive breast carcinomas. data from 13 International Breast Cancer Study
• Outcome Group (IBCSG) trials, Huober et al. found that
In the original report from Ridolfi et al., clas- patients with MC diagnosed on morphology
sical MC, diagnosed using their strict criteria, alone had an improved prognosis in terms of
disease free and overall survival at 14 years Foci of hemorrhage and necrosis may be evi-
(Huober et al. 2012). Restricting the diagnosis dent but are not extensive.
to patients with hormone receptor negative dis- Ridolfi et al. observed an average tumor size of
ease was associated with an even more favor- 2.9 cm (Ridolfi et al. 1977). Some studies report
able outlook. an average tumor size of up to 4 cm but in
In the last decade, the role of TILs in medi- most studies the recorded median size is in the
ating response to chemotherapy and improving range of 2– 3 cm.
clinical outcomes in all subtypes of breast can- The imaging characteristics of CMF, including
cer has been recognized. TNBCs are associated those observed on mammography and ultrasound
with a greater degree of lymphoid infiltration examination, may resemble a fibroadenoma.
than luminal tumors and survival benefit Magnetic resonance imaging (MRI) does not
increases with each 10% increase in TILs differentiate between CMF and other breast
(Stanton and Disis 2016). The survival advan- tumor types.
tage associated with TILs appears to be more Calcification is rare in CMF due to the lack of
powerful in TNBCs than in HER2 positive stromal desmoplasia and to the absence or low
tumors that may also feature lymphoid infiltra- volume of accompanying DCIS.
tion. Considering that a prominent lymphoid
infiltrate is one of the key morphological
criteria for a diagnosis of CMF, it appears likely Microscopy
that the improved prognosis in CMF is related
to the host immune response, particularly in The original criteria for a diagnosis of classical
triple negative tumors. Gene expression profil- MC included complete tumor circumscription
ing studies (GEP) have also demonstrated that with a pushing border and no extension of tumor
the expression levels of immune response genes cells into adjacent stroma, a syncytial growth
are independent predictors of outcome in highly pattern in at least 75% of the tumor, a moderate
proliferative breast cancers. A high TIL count to marked mononuclear stromal infiltrate, high
also has implications for targeted immunother- nuclear grade, no glandular features and no
apy as discussed above. intraduct component (DCIS). The last criterion
In the context of prognosis and treatment, was shown to be less important with a DCIS
the decision by the WHO to broaden the defi- component having no impact on prognosis.
nition and to create the designation of CMF A tumor showing the majority of these features
(to include MC, AMC, and invasive carcinoma can be diagnosed as CMF. This approach should
NST with specific histological appearances) facilitate recognition and identification of CMF.
takes account of the compelling data regarding However, due to the inherent flexibility in the
the improved outcome associated with specific application of the diagnostic criteria (“some but
MC morphology and that reported in relation not all of the features of MC”), interobserver
to a high TIL count in TNBC. variability and reproducibility of diagnosis con-
tinue to be a challenge.
Despite these limitations, tumors categorized
Macroscopy as CMF share the following morphological
features:
CMF, by definition, is a well-circumscribed tumor Outline: CMF is a well-delineated tumor
with an expansile or pushing border and may with a predominant pushing or expansile margin
resemble a fibroadenoma on gross inspection. The (Figs. 1 and 2).
cut surface is fleshy and the consistency is soft, Syncytial growth pattern: This refers to the
attributed to the absence of a stromal desmoplastic arrangement of tumor cells in solid, broad anasto-
reaction. The color varies from tan to grey-white. mosing sheets with minimal intervening stroma.
In classical MC, this pattern is present in at least
Invasive Carcinoma with Medullary Features, Fig. 1 Invasive Carcinoma with Medullary Features, Fig. 3
(H&E 4) Low-power view of CMF showing the classical (H&E 20) Tumor cells of CMF show a syncytial growth
well-circumscribed outline with an expansile edge pattern, high nuclear grade and mitotic activity
Invasive Carcinoma with Medullary Features, Fig. 2 Invasive Carcinoma with Medullary Features, Fig. 4
(H&E 10) CMF at higher magnification showing the (H&E 10) CMF showing a prominent lymphoplas-
classical well-circumscribed outline with an expansile edge macytic infiltrate
75% of the tumor. Although the latter is not a Lymphoplasmacytic infiltrate: This is
requirement for diagnosis, CMF shows a predom- usually a prominent feature of CMF (Fig. 4). The
inant solid growth pattern with scant intervening infiltrate tends to be more marked at the periphery
stroma. The relative paucity of stroma and lack of of the tumor and comprises a mixed population of
a desmoplastic reaction confer a soft consistency CD3+ T lymphocytes, cytotoxic CD8+ T lympho-
on these tumors which, together with the typical cytes, and plasma cells.
pushing border, may give a false impression of a The presence of a prominent lympho-
benign lesion on gross examination. plasmacytic infiltrate is associated with an
High nuclear grade: CMF is composed of improved prognosis related to the host lymphocyte
cells with high nuclear grade and prominent response.
nucleoli that may be multiple. Tumor giant cells Gland formation: The complete absence of
are commonly seen. Mitotic figures, including gland formation is a strict requirement for a
atypical forms, are frequent (Fig. 3).
diagnosis of classical MC. Although CMF may more high-molecular-weight/basal cytokeratins

show some gland formation, this should be (CK5/6, CK14, and CK17) and (c) triple negative
minimal. (ER, PR, HER2 negative) immunophenotype
DCIS: Accompanying DCIS is usually absent combined with expression of CK5/6 and/or epi-
or low volume in CMF. dermal growth factor receptor (EGFR) (Badve
Lymphovascular invasion: This is uncom- et al. 2010).
mon in CMF. CMF is negative for ER, PR, and HER2 in the
Other features: Hemorrhage and necrosis may majority of cases. However, expression of these
be present within the tumor. Breast tissue in the biomarkers has been reported in small numbers of
vicinity of CMF may show lymphocytic lobulitis. CMF indicating that tumors with this light micro-
Histological grading: Opinion is divided scopic morphology are heterogeneous at cellular
regarding the role of histological tumor grading level (Matkovic et al. 2008; Mateo et al. 2016).
of CMF. Some authorities advise against grading Notwithstanding this if any of these biomarkers is
as the morphological characteristics of CMF will positive one should at least consider alternative
conform to a grade 3 carcinoma and not reflect the tumor types in the differential diagnosis.
improved prognosis of CMF relative to a grade In addition to triple negative status, CMF has
matched invasive carcinoma NST (▶ Invasive been shown to express basal type cytokeratins, in
Carcinoma NST). RCPath UK guidelines recom- particular CK5/6, with greater frequency than non
mend grading all special type carcinomas in addi- CMF breast tumors. Reported rates of CK5/6
tion to invasive carcinoma NST (Ellis et al. 2016). expression vary, attributed to variation in anti-
The reasons cited include the diagnostic difficulty bodies used and the inclusion of hormone receptor
that may be encountered in separating a special positive tumors with classical CMF/MC morphol-
type carcinoma from invasive carcinoma NST ogy in some studies. CK 14 expression has also
where knowledge of histological grade may been reported but appears to be less commonly
inform further treatment planning. expressed than CK5/6. Up to 70% of CMF tumors
have been shown to express EGFR.
Expression of other immunomarkers associ-
Immunophenotype ated with basal-like tumors has been documented
in CMF including P-cadherin, p63, smooth mus-
At the present time, CMF is defined based on the cle actin, S100, and caveolin.
constellation of morphological characteristics The majority of CMF tumors are immunohis-
outlined above. While CMF is associated with a tochemically p53 positive due to the high rate of
classical immunohistochemical profile, these are TP53 mutation (see Molecular Features) (Silwal-
not the defining properties of this tumor type and Pandit et al. 2014).
some variation in the expression of the following In keeping with the morphology, CMF is a
proteins will occur. highly proliferative tumor with a high Ki67 index.
CMF is one of the morphological subtypes TILs are now known to play a key role
of invasive breast carcinoma with an immuno- in mediating response to chemotherapy and
phenotype that correlates with the specific improving clinical outcomes in invasive breast
so-called basal-like tumor gene expression profile carcinoma, particularly in TNBC. The dense lym-
(Flucke et al. 2010; Jacquemier et al. 2005; Rakha phoid infiltrate that is a key criterion for the diag-
and Green 2017). There is no internationally nosis of CMF typically contains a high proportion
accepted definition of a basal-like tumor. of CD8+ cytotoxic T lymphocytes that likely
Immunohistochemical marker expression profiles accounts for the improved prognosis associated
that have been proposed to define basal-like with this morphological variant of breast cancer.
breast cancers include (a) triple negative for estro- Although CMF shows morphological similar-
gen (ER) and progesterone (PR) receptors ities to Epstein Barr Virus (EBV) associated
and HER2 expression, (b) expression of one or
lymphoepithelioma-like carcinoma of the breast, that approximately 20% of patients with CMF
expression of EBV protein is rare. test positive for BRCA1 mutation. CMF is
uncommon in patients with BRCA2 mutations.
Somatic BRCA1 mutations and BRCA1 pro-
Molecular Features moter hypermethylation have also been reported
in CMF. Promoter hypermethylation may lead to
Molecular Classification inactivation of the BRCA1 gene and contribute to
Gene expression profiling (GEP) studies, using breast carcinogenesis.
unsupervised cluster analysis, has led to the classi- The most common somatic mutation in CMF is
fication of breast cancer based on molecular char- TP53, which occurs at a higher rate than in non
acteristics (Perou et al. 2000). The vast majority of CMF tumors. TP53 mutations are common in all
CMF tumors segregate as basal-type, which are forms of breast cancer and overall are associated
typically characterized by lack of expression of with a worse prognosis. However, the prognostic
ER, PR, and HER2 and by positive expression of impact appears to vary with molecular subtype
genes that are expressed in the basal-like cells of the and may be limited to ER positive tumors.
normal breast and those associated with high pro- In keeping with the high rate of TP53 mutations
liferative activity. Further transcriptional analysis in CMF, high-density array comparative genomic
I
of the basal-like TNBC group has led to the recog- hybridization (CGH) studies have demonstrated a
nition of heterogeneity within this group of tumors high level of genomic instability in these tumors.
and the identification of basal-like TNBC molecu- Gains of 1q and 8q are common to all basal-like
lar subtypes (Lehmann and Pietenpol 2013). carcinomas and are observed in CMF. CMF
CMF tumors display a unique gene expression tumors also show a specific pattern of genetic
profile (Bertucci et al. 2006). CMF tumors are alteration including recurrent gains at 3p, 9p,10p,
characterized by upregulation of genes involved and 16q and losses at 4p and amplicons of 1q, 8p,
in the immune response including those that con- and 10p (Vincent-Salomon et al. 2007).
trol interleukin, interferon, and cytokine produc-
tion. Genes involved in activation of the apoptosis
pathway are also over-expressed compared with Differential Diagnosis
non-CMF basal-like tumors. In contrast, genes
that are involved in remodeling of the cytoskeleton When confronted with a well-circumscribed inva-
and those that control cell invasiveness are under- sive breast tumor with no associated DCIS and
expressed in CMF (Weigelt et al. 2010). This pro- triple negative for ER, PR, and HER2, it is always
file correlates with the immunomodulatory subtype wise to maintain a broad differential diagnosis.
of TNBC tumors, associated with an improved Recognition of CMF is important due to its
response to chemotherapy, a more favorable prog- association with the BRCA1 germline mutation.
nosis and potential for treatment with A diagnosis of CMF, particularly in a younger
immunotherapy. patient, will lead to consideration of genetic test-
ing for the patient and her/his family. CMF also
Genetic Alterations has a more favorable prognosis than a grade
BRCA1, located at chromosome 17q12–21, is a 3 invasive carcinoma NST. These characteristics
tumor suppressor gene. Germline mutations of emphasize the importance and value of careful
BRCA1 account for 30–40% of hereditary breast assessment of breast tumor morphology, even in
carcinomas. Most breast tumors that develop in this era of sophisticated genetic methodologies.
patients with BRCA1 germline mutations are of The main alternative diagnosis is invasive car-
CMF type. A diagnosis of CMF may, therefore, cinoma NST (▶ Invasive Carcinoma NST). To
signify a BRCA1 mutation and consideration of date there has been considerable interobserver var-
genetic testing. However, not all patients with iation in the diagnosis of MC and AMC. Applica-
CMF have a BRCA1 mutation. It is estimated tion of the more relaxed histological criteria
proposed by the WHO and outlined above should Dua, I., & Tan, A. R. (2017). Immunotherapy for triple-
improve observer agreement in recognizing CMF negative breast cancer: A focus on immune checkpoint
inhibitors. American Journal of Haematology and
and distinguishing it from NST. In view of the Oncology, 13, 20–27.
clinical relevance, it is more important to entertain Eisinger, F., Noguès, C., Birnbaum, D., Jacquemier, J., &
the diagnosis than to assign these tumors to the Sobol, H. (1998). BRCA1 and medullary breast cancer.
NST category. The preferential expression of basal Journal of the American Medical Association, 280,
1227–1228.
type immunohistochemical markers may be help- Ellis, I. O., Al-Sam, S., Anderson, N., Carder, P., Deb, R.,
ful in making a diagnosis of CMF. Girling, A., et al. (2016). Pathology reporting of breast
The possibility of a metastasis from an alternative disease in surgical excision specimens incorporating
primary site or an intramammary lymph node the dataset for histological reporting of breast cancer.
(2016). Rcpath.org. Available from: http://www.rcpath.
replaced by metastatic tumor should be borne in org. Accessed Sept 2017.
mind. This is less likely when dealing with a single Flucke, U., Flucke, M., Hoy, L., Breuer, E., Goebbels, R.,
tumor. Tumors that metastasize to the breast include Rhiem, K., et al. (2010). Distinguishing medullary car-
melanoma, which may be pigmented, ovarian carci- cinoma of the breast from high-grade hormone receptor-
negative invasive ductal carcinoma: An immunohisto-
noma, lung carcinoma, sarcomatoid carcinoma, and chemical approach. Histopathology, 56, 852–859.
sarcoma and primary sarcoma. Thorough evaluation Hicks, D. G., & Lester, S. C. (2017). Carcinoma with
of tumor morphology and consideration of the clin- medullary features. Available from: https://app.
ical history and radiological findings are key to expertpath.com. Accessed Sept 2014.
Huober, J., Gelber, S., Coates, A. S., Viale, G.,
reaching a correct diagnosis. In the case of an Ohlschlegel, C., et al. (2012). Prognosis of medullary
intramammary lymph node replaced by tumor, a breast cancer: Analyses of 13 international breast can-
search for lymph node capsule and any residual cer study group (IBCSG) trials. Journal of Clinical
normal lymph node architecture should assist the Oncology, 11, 2843–2851.
Jacquemier, J., Padovani, L., Rabayrol, L., Lakhani, S.,
diagnosis. Comparison with previous histology Penault-Llorca, F., Denoux, Y., et al. (2005). Typical
and the use of immunohistochemistry will also assist medullary breast carcinomas have a basal/myo-
accurate diagnosis of an intramammary metastasis. epithelial phenotype. The Journal of Pathology, 207,
Lymphoma of the breast is a rare condition that 260–268.
Lakhani, S., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van de
should also be considered in the differential diag- Vijver, M. J. (2012). WHO classification of tumours of
nosis. Breast lymphoma (mostly diffuse large the breast (pp. 46–47). Lyon: International Agency for
B-cell lymphoma) may occur as a primary process Research on Cancer.
or represent breast involvement by known sys- Lehmann, B., & Pietenpol, J. (2013). Identification and use
of biomarkers in treatment strategies for triple-negative
temic lymphoma. It usually forms a solid mass breast cancer subtypes. The Journal of Pathology, 232,
and may mimic carcinoma both radiologically 142–150.
and histologically. On close inspection, it lacks Mateo, A., Pezzi, T., Sundermeyer, M., Kelley, C.,
the syncytial growth pattern observed in CMF. Klimberg, V., & Pezzi, C. (2016). Chemotherapy
significantly improves survival for patients with
Consideration of the diagnosis and the use of T1c-T2N0M0 medullary breast cancer: 3739 cases
immunohistochemistry will clarify the diagnosis. from the National Cancer Data Base. Annals of Surgi-
cal Oncology, 24, 1050–1056.
Matkovic, B., Juretic, A., Separovic, V., Novosel, I.,
Separovic, R., Gamulin, M., et al. (2008). Immunohis-
References and Further Reading tochemical analysis of ER, PR, HER-2, CK 5/6,
p 63 and EGFR antigen expression in medullary breast
Badve, S., Dabbs, D., Schnitt, S., Baehner, F., Decker, T., cancer. Tumori, 94, 838–844.
Eusebi, V., et al. (2010). Basal-like and triple-negative Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M.,
breast cancers: A critical review with an emphasis Jeffrey, S. S., Rees, C. A., et al. (2000). Molecular
on the implications for pathologists and oncologists. portraits of human breast tumors. Nature, 406,
Modern Pathology, 24, 157–167. 474–452.
Bertucci, F., Finetti, P., Cervera, N., Charafe-Jauffret, E., Rakha, E., & Green, A. (2017). Molecular classification of
Mamessier, E., Adélaïde, J., et al. (2006). Gene expres- breast cancer: What the pathologist needs to know.
sion profiling shows medullary breast cancer is a sub- Pathology, 49, 111–119.
group of basal breast cancers. Cancer Research, 66, Ridolfi, R., Rosen, P., Port, A., Kinne, D., & Miké, V.
4636–4644. (1977). Medullary carcinoma of the breast.
Invasive Carcinoma with Neuroendocrine Differentiation 203
A clinicopathologic study with 10 year follow-up. carcinomas/small cell carcinomas, and invasive
Cancer, 40, 1365–1385. carcinomas with NE differentiation.
Silwal-Pandit, L., Vollan, H., Chin, S., Rueda, O.,
McKinney, S., Osako, T., et al. (2014). TP53 mutation
Spectrum in breast cancer is subtype specific and has
distinct prognostic relevance. Clinical Cancer Clinical Features
Research, 20, 3569–3580.
Stanton, S., & Disis, M. (2016). Clinical significance
of tumor-infiltrating lymphocytes in breast cancer. • Incidence
Journal for Immunotherapy of Cancer, 4, 59. Invasive breast carcinomas with NE features
Tung, N., Garber, J., Hacker, M., Torous, V., Freeman, G., are rare and represent less than 5% of breast
Poles, E., et al. (2016). Prevalence and predictors of cancers (Wang et al. 2014).
androgen receptor and programmed death-ligand 1 in
BRCA1-associated and sporadic triple-negative breast • Age
cancer. Breast Cancer, 2, 16002. Most patients are in the sixth or seventh
Vincent-Salomon, A., Gruel, N., Lucchesi, C., decades of life.
MacGrogan, G., Dendale, R., Sigal-Zafrani, B., et al. • Sex
(2007). Identification of typical medullary breast carci-
noma as a genomic sub-group of basal-like carcinomas, There is a female predilection. Single case
a heterogeneous new molecular entity. Breast Cancer reports of invasive breast carcinomas with
Research, 9, R24. NE features in male patients were occasionally
Weigelt, B., Geyer, F., & Reis-Filho, J. (2010). Histological I
described.
types of breast cancer: How special are they?
Molecular Oncology, 4, 192–208. • Site
Usually, invasive breast carcinomas with NE
differentiation present unilaterally, neverthe-
less a single case report with bilateral primary
breast NE carcinoma in a young woman has
Invasive Carcinoma with been described (Zhang and Chen 2011). The
Neuroendocrine central and subareolar region of the breast or
Differentiation the upper outer quadrant are the most frequent
locations where this type of carcinoma arises.
Ewa Chmielik Rarely, multicentric forms were reported.
Tumor Pathology Department, Maria • Treatment
Sklodowska-Curie Memorial Cancer Center and Surgery is the standard initial treatment for early
Institute of Oncology, Gliwice, Poland invasive carcinomas with NE features. Patients
with locally advanced cases or with inoperable
carcinomas are treated with neoadjuvant ther-
Synonyms apy. Patients with luminal A or B carcinomas
are candidates for adjuvant endocrine therapy. In
Carcinoid tumor of the breast; Endocrine hormone receptor positive cases with high
carcinoma Ki-67 proliferation index, adjuvant chemother-
apy in addition to endocrine therapy may be
beneficial. Anti-HER2 therapy is an option for
Definition patients with HER2-positive carcinomas with
NE features, which is a quite rare event. Peptide
Invasive carcinoma with neuroendocrine receptor radionuclide therapy (PPRT) has been
(NE) differentiation presents microscopic features reported in patients with carcinomas expressing
similar to NE neoplasms of other organs. somatostatin receptors (Inno et al. 2016).
Bussolati and Badve (2012) classifies Breast NE carcinomas can metastasize to
invasive carcinomas with NE differentiation multiple organs even years after treatment of
into three subtypes: well-differentiated NE the primary tumor, and therefore long-term
tumors, poorly differentiated neuroendocrine follow-up is advisable (Inno et al. 2016).
204 Invasive Carcinoma with Neuroendocrine Differentiation
• Outcome
Well-differentiated NE tumors have a favorable
prognosis and have significantly less frequent
lymph node metastases compared with those with
partial NE differentiation (Sapino et al. 2001a).
Mucinous differentiation, estrogen receptor
(ER) expression, and progesterone receptor
(PR) expression are important parameters for
favorable prognosis in invasive carcinomas
with NE features (Sapino et al. 2001a).
However, as a group, patients with breast car-
cinomas showing NE differentiation have worse
overall survival (OS) and disease-free survival
(DFS) than those without (Kwon et al. 2014).
In particular, poorly differentiated/small cell
carcinomas are aggressive with poor prognosis
(Sapino et al. 2001a). The most frequent meta-
static sites of breast NE carcinomas are bone,
lungs, bone marrow, liver, pleura, skin, adrenal
gland, and pancreas (Lavigne et al. 2017) and
less frequently in other organs.
Invasive Carcinoma with Neuroendocrine Differenti-
ation, Fig. 1 Mammography shows a stellate lesion
Macroscopy which was histologically a well-differentiated NE breast
tumor with microcalcifications, BI-RADS 5, ACR 2
Invasive breast carcinomas with NE differentia-
tion may be grossly well circumscribed or with
infiltrative border (Fig. 1 radiogram of invasive
breast carcinoma with NE differentiation).
Microscopy
Like NE tumors of other organs, well-differentiated

NE tumors of the breast are composed by polygo-
nal, plasmacytoid, or spindle cells with eosino-
philic granular cytoplasm. Nuclei show low
pleomorphism varying from ovoid to round, they
may be centrally or eccentrically located, and chro-
matin is finely punctuated. Nucleoli are inconspic- Invasive Carcinoma with Neuroendocrine Differenti-
uous. The number of mitoses is very low. ation, Fig. 2 Carcinoid-like pattern with rosettes (H&E,
The following growth patterns have been 20)
described: solid cohesive, solid papillary, alveo-
lar, and cellular mucinous (Sapino et al. 2000).
In solid cohesive or carcinoid-like patterns, The solid papillary (▶ Solid Papillary Carci-
neoplastic cells are organized in glandular or noma) growth pattern shows plasmacytoid, spin-
rosette-like structures (Figs. 2 and 3 H&E) and dle, or signet-ring cells. Intracellular (signet ring)
form peripheral palisading similar to typical or extracellular mucin is a common finding. For
carcinoid tumors. this reason, it has been postulated that this variant
Invasive Carcinoma with Neuroendocrine Differentiation 205
Invasive Carcinoma with Neuroendocrine Differenti- Invasive Carcinoma with Neuroendocrine Differenti-
ation, Fig. 3 Carcinoid-like pattern with rosettes (H&E, ation, Fig. 4 Strongly and diffusely positive
40) immunostaining for synaptophysin (10)
I
is the preinvasive counterpart of mucinous carci-
noma with NE differentiation.
The mucinous variant of NE carcinoma shows
lakes of mucin populated by large clusters of cells
unlike non-NE mucinous carcinoma (▶ Invasive
Mucinous Carcinoma).
In alveolar growth pattern, large clear cells are
separated by scanty dense stroma. The number of
mitoses can be higher than in the other
histotypes.
Within poorly differentiated NE carcinomas
of the breast, the small cell variant is character-
ized by high nuclear/cytoplasmic ratio, dark Invasive Carcinoma with Neuroendocrine Differenti-
chromatin, inconspicuous nucleoli, and scant ation, Fig. 5 Carcinoma in situ component of NE breast
eosinophilic cytoplasm. The mitotic activity is carcinoma positive for Chromogranin A (40)
brisk (approximately 10 mitoses/10HPF). Zones
of necrosis or hemorrhage are often encountered.
The presence of an intraductal component of differentiation detected only by immunohistochem-
small cell carcinoma supports the breast origin. istry occurs in up to 30% of invasive carcinomas
NST (▶ Invasive Carcinoma NST) or other special
types. CD56 immunostaining and TTF-1 (20% of
Immunophenotype cases) have been documented in primary breast
small cell carcinoma.
All invasive carcinomas with NE differentiation ER are expressed in all of well-differentiated NE
express NE markers. Synaptophysin (Fig. 4) and tumors (Lavigne et al. 2017) or nearly in all (95%)
chromogranin A (Fig. 5) are considered as the cases (Bogina et al. 2016). The vast majority of
most sensitive and specific NE markers. cases (89%) express PR (Lavigne et al. 2017).
Seventy percent of NE carcinomas express Only few cases show immunophenotype
chromogranin A, 96% express synaptophysin, and ER+/HER2+, ER /HER2+, or lack ER and
66% express both markers (Lavigne et al. 2017). NE HER2 expression (Bogina et al. 2016).
206 Invasive Carcinoma with Neuroendocrine Differentiation
According to molecular classification, carcino- acquisition of the genetic/epigenetic features typical

mas with NE differentiation belong to luminal of these histotypes.
A or luminal B subtypes.
Androgen receptors are positive in 45%
of carcinomas with NE differentiation and up to Differential Diagnosis
35% of carcinomas express somatostatin recep-
tors (Righi et al. 2010). Well-differentiated NE Differential diagnosis includes alveolar variant of
carcinoma may co-express NE and apocrine infiltrating lobular carcinoma (▶ Invasive Lobular
(GCDFP-15) markers and androgen receptors Carcinoma), solid variant of mammary adenoid
together with ER and PR (Sapino et al. 2001b). cystic carcinoma (▶ Adenoid Cystic Carcinoma),
Nearly all (96–98%) NE breast carcinomas and metastatic neuroendocrine tumor.
express FOXA1, GATA3, and CK8/18 (Lavigne Alveolar variant of infiltrating lobular carci-
et al. 2017). noma consists of groups of monotonous cells sep-
arated by bands of fibrous stroma. Coexistence of
lobular neoplasia and infiltrating lobular carci-
Molecular Features noma, classical variant, is typical. Chromogranin
positivity can be focal and weak. As for all vari-
Cytogenetics ants of lobular carcinomas, ER is generally posi-
NE breast carcinomas are characterized by chromo- tive and E-cadherin is negative.
somal numerical aberrations and/or structural aber- Solid variant of mammary adenoid cystic carci-
rations. Numerical aberrations like trisomy 7 and nomas usually presents as a discrete, palpable, lob-
12 recently detected in NE breast carcinomas are ulated mass located in the sub-/periareolar region in
known as cytogenetic abnormalities of carcinoid approximately 50% of cases. Adenoid cystic carci-
tumors of the lung and gastrointestinal tract. Clonal nomas are composed of epithelial and myoepithelial
structural chromosomal aberrations involved chro- cells. On higher power view, adenoid cystic carci-
mosomes 1, 3, 6q, and 17q. Complex karyotypes nomas show moderate to marked nuclear atypia and
including both numerical and structural aberrations high mitotic rate. Pseudoglandular structures can
per cell were identified in 57.1% of intermediate- occasionally be seen within the tumor nests. Ade-
and high-grade NE breast carcinomas. noid cystic carcinomas are negative for NE markers
Chromothripsis (chromosomal shattering) of chro- and frequently positive for c-kit.
mosome 8 was rarely observed (Xiang et al. 2014). Metastatic NE tumors in the breast show the
typical architectural patterns (trabecular, acinar,
Molecular Genetics etc.) and cytologic features (“salt-and-pepper”
Breast carcinomas with NE differentiation harbor chromatin) (Fig. 6 H&E). The neoplastic cells
similar number of somatic mutations as luminal are obviously positive for NE markers; however,
B breast carcinomas but significantly higher than markers such as CDX2 (gastrointestinal) and thy-
that of luminal A breast carcinomas. GATA3, roglobulin (thyroid) can help in defining the pri-
FOXA1, TBX3, and ARID1A are mutated in 17% mary site of origin. NE carcinomas of small
of cases (Marchiò et al. 2017). PIK3CA mutations bowel, lung, and ovary are those most frequently
were less frequent than in luminal A carcinomas and spreading to the breast. Sometimes a breast mass
invasive lobular carcinomas (▶ Invasive Lobular can be the first manifestation of the disease
Carcinoma). Similarly to NE neoplasms of lung because the primary tumor, e.g., in gastrointesti-
and colon, breast NE carcinomas are characterized nal tract, may be very small and undetected. ER
by lack of TP53 mutations. Comparative study and PR are usually negative in metastatic NE
performed by Marchiò et al. (2017) suggested that cancer. The most important feature of metastases
NE differentiation in invasive mucinous carcinomas to the breast is the absence of an in situ compo-
(▶ Invasive Mucinous Carcinoma) and invasive nent. It is important to differentiate primary NE
lobular carcinomas may develop after the breast carcinoma from metastatic NE carcinoma
Invasive Carcinoma with Signet Ring Cell Differentiation 207
Marchiò, C., Geyer, F. C., Ng, C. K., Piscuoglio, S., De

Filippo, M. R., Cupo, M., Schultheis, A. M., Lim, R. S.,
Burke, K. A., Guerini-Rocco, E., Papotti, M., Norton, L.,
Sapino, A., Weigelt, B., & Reis-Filho, J. S. (2017). The
genetic landscape of breast carcinomas with neuroendo-
crine differentiation. The Journal of Pathology, 241,
405–419.
Righi, L., Sapino, A., Marchiò, C., Papotti, M., &
Bussolati, G. (2010). Neuroendocrine differentiation
in cancer: Established facts and unresolved problems.
Seminars in Diagnostic Pathology, 27, 69–76.
Sapino, A., Righi, L., Cassoni, P., Papotti, M., Pietribiasi, F.,
& Bussolati, G. (2000). Expression of the neuroendo-
crine phenotype in carcinomas of the breast. Seminars in
Diagnostic Pathology, 17, 127–137.
Sapino, A., Papotti, M., Righi, L., Cassoni, P., Chiusa, L.,
Invasive Carcinoma with Neuroendocrine Differenti- & Bussolati, G. (2001a). Clinical significance of
ation, Fig. 6 Metastatic neuroendocrine tumor to the neuroendocrine carcinoma of the breast. Annals of
breast from gastrointestinal tract (H&E) Oncology, 12(Suppl 2), S115–S117.
Sapino, A., Righi, L., Cassoni, P., Papotti, M., Gugliotta, P.,
& Bussolati, G. (2001b). Expression of apocrine differ-
to the breast due to the differences in management entiation markers in neuroendocrine breast carcinomas I
and prognosis. Patients with single metastatic NE of aged women. Modern Pathology, 14, 768–776.
Wang, J., Wei, B., Albarracin, C. T., Hu, J., Abraham, S. C.,
tumor to the breast should undergo wide local & Wu, Y. (2014). Invasive neuroendocrine carcinoma
excision alone without axillary dissection. of the breast: A population-based study from the sur-
veillance, epidemiology and end results (SEER) data-
base. BMC Cancer, 4(14), 147–156.
Xiang, D. B., Wei, B., Abraham, S. C., Huo, L.,
References and Further Reading Albarracin, C. T., Zhang, H., Babiera, G.,
Caudle, A. S., Akay, C. L., Rao, P., Zhao, Y. J., Lu,
Bogina, G., Munari, E., Brunelli, M., Bortesi, L., X., & Wu, Y. (2014). Molecular cytogenetic character-
Marconi, M., Sommaggio, M., Lunardi, G., Gori, S., ization of mammary neuroendocrine carcinoma.
Massocco, A., Pegoraro, M. C., & Zamboni, G. (2016). Human Pathology, 45, 1951–1956.
Neuroendocrine differentiation in breast carcinoma: Zhang, J.-Y., & Chen, W.-J. (2011). Bilateral primary
Clinicopathological features and outcome. breast neuroendocrine carcinoma in a young woman:
Histopathology, 68, 422–432. Report a case. Surgery Today, 41, 1575–1578.
Bussolati, G., & Badve, S. (2012). Carcinoma with neuro-
endocrine features. In S.R. Lakhani, I.O. Ellis, S. J.
Schnitt, P. H. Tan, M. J. van de Vijver (Eds). WHO
Classification of Tumours of the Breast (pp 62–63) Invasive Carcinoma with
Lyon: IARC Signet Ring Cell
Inno, A., Bogina, G., Turazza, M., Bortesi, L., Duranti, S.,
Massocco, A., Zamboni, G., Carbognin, G., Alongi, F., Differentiation
Salgarello, M., & Gori, S. (2016). Neuroendocrine
carcinoma of the breast: Current evidence and future Ian Ellis
perspectives. The Oncologist, 21, 28–32. Department of Histopathology, City Hospital
Kwon, S. Y., Bae, Y. K., Gu, M. J., Choi, J. E., Kang, S. H.,
Lee, S. J., Kim, A., Jung, H. R., Kang, S. H., Oh, H. K., Campus, Nottingham University Hospitals,
& Park, J. Y. (2014). Neuroendocrine differentiation Nottingham City Hospital, Nottingham, UK
correlates with hormone receptor expression and
decreased survival in patients with invasive breast
carcinoma. Histopathology, 64, 647–659.
Lavigne, M., Menet, E., Tille, J. C., Lae, M., Fuhrmann, L., Synonyms
Bonneau, C., Deniziaut, G., Melaabi, S., Ng, C. C. K.,
Marchiò, C., Rouzier, R., Bièche, I., & Vincent- Mucinous carcinoma; Signet ring cell carcinoma;
Salomon, A. (2017). Comprehensive clinical and Signet ring cell carcinoma arising in invasive no
molecular analyses of neuroendocrine carcinomas of
the breast. Modern Pathology. https://doi.org/10.1038/ special type (ductal) carcinoma; Signet ring cell
modpathol.2017.107. [Epub ahead of print]. variant of invasive lobular carcinoma
208 Invasive Carcinoma with Signet Ring Cell Differentiation
Definition • Treatment
These tumors are generally recognized to have
The definition of primary mammary invasive signet an aggressive behavior with higher frequency
ring cell carcinoma (SRCC) varies in the limited of vascular invasion and lymph node involve-
number of published series to date. Some restrict ment. Treatment will be governed but the char-
the definition to lobular carcinoma (Merino and acteristics of the individual patient and based
Livolsi 1981), with a population of signet ring on tumor size, grade, lymph node stage, hor-
cells present and exclude signet ring cell variant mone receptor (▶ Hormone Receptors in
of invasive ductal/NST carcinoma or vica versa. Breast Cancer), and HER2 (▶ HER2 in Breast
Others recognize signet ring cell tumor cell mor- Cancer) status.
phology in invasive ductal, lobular, and mucinous • Outcome
carcinoma, and one recent study has shown no Most but not all of the published series recog-
difference between these variants (Ohashi et al. nize SRC to be more aggressive than mucinous
2016). The current 2012 WHO classification of carcinoma (▶ Invasive Mucinous Carcinoma),
breast tumors (Lakhani et al. 2012) includes invasive ductal carcinoma of no special type
SRCC as a subcategory of invasive mucinous car- (▶ Invasive Carcinoma NST), and classic
cinoma (▶ Invasive Mucinous Carcinoma) and invasive lobular carcinoma (▶ Invasive Lobu-
uses the following definition, “Carcinomas with lar Carcinoma) of the breast, with frequent
signet-ring-cell differentiation are characterized by metastasis to regional lymph nodes and distant
abundant intracellular mucin that pushes the metastasis to the lung, liver, and bone but also
nucleus to one side, creating the characteristic with unusual sites of metastasis including the
signet-ring-cell morphology.” The published series stomach, endometrium, cervix, serosa, gastro-
differ on the number of signet cells that must be intestinal tract, urinary tract, and spleen.
present to label a carcinoma as SRCC, but generally
require >10–20% signet ring cells as a minimum
Macroscopy
requirement.
There are no specific macroscopic features.
Clinical Features
• Incidence Microscopy
Primary SRCC carcinoma of the breast is a
very rare tumor subtype with few series SRCC has been defined as a lesion with diffuse
published to date. It is exceptionally rare as a infiltration of the stroma by mucin containing signet
pure form but presence of SRCC cells have ring cells where mucin fills the cytoplasm and dis-
been reported to occur in between 1% and 4% places nucleus. Prominent signet-ring-cell differen-
of primary breast carcinomas; however, there tiation is most common in invasive lobular
are no detailed epidemiological or comparative carcinomas but may also be seen in invasive carci-
studies available. noma NST and other special type cancers, particu-
• Age larly mucinous carcinoma. Pure SRCC is
No large series exist but the average age at exceptionally rare, and it has been argued that car-
presentation appears to be older than that for cinomas with signet-ring-cell differentiation do not
breast cancer as a whole. represent a distinct entity. The current 2012 WHO
• Sex classification of breast tumors (Bussolati and
Marked female predominance. Sapino 2012) describes two cytological types of
• Site carcinomas with signet-ring-cell differentiation.
Breast but exclusion of metastatic SRCC from One type characterized by large intracytoplasmic
distant sites particularly GI tract needs to be vacuoles, with a “target” appearance owing to the
excluded. presence of large intracytoplasmic lumina
Invasive Carcinoma with Signet Ring Cell Differentiation 209
Invasive Carcinoma with

Signet Ring Cell
Differentiation,
Fig. 1 Signet ring cell
carcinoma of the breast
showing the characteristic
appearance of the tumor
cells with pushed aside
nuclei and mucin filled
cytoplasm (H&E high
power)
I
containing a periodic acid Schiff (PAS)/Alcian blue Differential Diagnosis
and HMFG2-positive central globule. This cytolog-
ical pattern is typically observed in lobular neopla- The differential diagnosis includes mucinous
sia, in classic ▶ invasive lobular carcinoma, and it carcinomas and clear cell carcinomas and metas-
has also been associated with the pleomorphic var- tasis from other sites. It is important to differen-
iant of lobular carcinoma (▶ Pleomorphic Lobular tiate from these carcinomas as the treatment
Carcinoma). The other cytological type is similar to options and the outcome varies considerably.
the cells of diffuse gastric carcinoma (Fig. 1) and is Metastases will lack an accompanying in situ
characterized by acidic muco-substances that dif- carcinoma (DCIS or LCIS) component.
fusely fill the cytoplasm and dislodge the nucleus to A variety of immunohistochemical markers
one pole of the cell. This type of signet-ring cell has have been applied to distinguish SRCC from
also been described as a variant of DCIS. metastasis from different organs. SRCCs of the
breast are generally immunohistochemically
positive for GCDFP-15, whereas SRCCs of the
Immunophenotype gastrointestinal tract are negative. ER is very
often positive in primary SRCC of the breast,
Primary breast SRCC are usually GCDFP-15 pos- but commonly negative in gastric and colonic
itive and approximately 80% are positive for SRCC. Adenocarcinomas of the breast, stomach,
estrogen receptor. HER2 status frequency is not and colon also show different CK7 and CK20
well described but HER2 positive cases occur but expression patterns (Tot 2000). While primary
at a lower frequency than breast cancer as a whole. SRCC of the breast is typically positive for
These tumors typically have a luminal type CK7 but negative for CK20, the gastrointestinal
cytokeratin profile being low molecular weight SRCCs are commonly positive for CK20 but
cytokeratin CK8/18 and CK7 positive. Lobular usually negative for CK7. In combination with
variants are usually E-Cadherin negative. ER staining, CK7 and CK20 expression patterns
can be used to distinguish gastrointestinal SRCC
from SRCC of the breast but it should be borne in
Molecular Features mind that approximately 20% of SRCCs of the
breast are negative for ER (Tot 2000). Mucin
There are no known specific genetic or molecular secretion type may also be helpful (Chu and
features. Weiss 2004). Adenocarcinomas of the breast
210 Invasive Cribriform Carcinoma
usually express MUC1 but not MUC2, whereas

gastrointestinal adenocarcinomas frequently Invasive Cribriform
express MUC2 but less frequently express Carcinoma
MUC1. The combination of immunomarkers
can substantially increase the sensitivity and Emad Rakha
specificity for diagnosing SRCCs of these Department of Histopathology, Division of
organs. SRCC of the breast can be distinguished Cancer and Stem Cells, University of
from gastrointestinal SRCC, if ER and MUC1 Nottingham, Nottingham, UK
are used as markers for SRCC of the breast, and
MUC2 and CDX2 can be used as markers for
gastric and colon SRCCs. To distinguish SRCCs Synonyms
of gastric versus colonic origin, Hep Par1 and
CDX2 strongly favor a gastric primary site, Invasive cribriform carcinoma; Pure invasive
whereas Hep Par1 negativity and MUC2 positiv- cribriform carcinoma
ity strongly favor a colonic primary site (Fan
et al. 2003). E-Cadherin is less useful and lacks
sensitivity. Definition
A special type of invasive carcinoma with an

References and Further Reading excellent prognosis that grows in a pattern similar
to that seen in intraductal cribriform carcinoma.
Bussolati, G., & Sapino, A. (2012). Carcinomas with sig-
net ring cell differentiation. In S. R. Lakhani, I. O. Ellis,
S. J. Schnitt, P. H. Tan, & M. J. van de Vijver (Eds.),
WHO classification of tumours of the breast (4th ed.,
Clinical Features
p. 61). Lyon: IARC Press.
Chu, P. G., & Weiss, L. M. (2004). Immunohistochemical • Incidence
characterization of signet-ring cell carcinomas of the Invasive cribriform carcinoma accounts for
stomach, breast, and colon. American Journal of Clin-
ical Pathology, 11, 884–892.
0.3–0.8% of breast carcinomas (Venable et al.
Fan, Z., van de Rijn, M., Montgomery, K., & Rouse, 1990; Li et al. 2005; Louwman et al. 2007);
R. V. (2003). Hep par 1 antibody stain for the differ- however, a frequency of up to 4% has been
ential diagnosis of hepatocellular carcinoma: reported in some series (Page et al. 1983;
676 tumors tested using tissue microarrays and con-
Venable et al. 1990).
ventional tissue sections. Modern Pathology, 16,
137–144. • Age
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van Mean patient age is 53–58 years (Venable
de Vijver, M. J. (2012). WHO classification of tumours et al. 1990).
of the breast (4th ed.). Lyon: IARC Press.
• Sex
Merino, M. J., & Livolsi, V. A. (1981). Signet ring carci-
noma of the female breast: A clinicopathologic analysis Female; rare in male as for other forms of
of 24 cases. Cancer, 48, 830–837. breast cancer.
Ohashi, R., Hayama, A., Yanagihara, K., Yamashita, K., • Site
Sakatani, T., Takei, H., & Naito, Z. (2016). Prognostic
Anywhere in the breast but most frequent in the
significance of mucin expression profiles in breast car-
cinoma with signet ring cells: A clinicopathological upper outer quadrant like other types of breast
study. Diagnostic Pathology, 11, 131. cancer.
Tot, T. (2000). The role of cytokeratins 20 and 7 and • Treatment
estrogen receptor analysis in separation of metastatic
Local control and hormone therapy are the
lobular carcinoma of the breast and metastatic signet
ring cell carcinoma of the gastrointestinal tract. APMIS, main treatment options. Even when patients
11, 467–472. have axillary metastases from pure invasive
Invasive Cribriform Carcinoma 211
cribriform carcinoma, the prognosis is good. DCIS, generally of cribriform architecture, is

The use of systemic adjuvant chemotherapy is frequent (80%) (Page et al. 1983). If axillary
typically not needed in pure early-stage inva- metastasis develops, the cribriform pattern is typ-
sive cribriform carcinomas. ically retained. Invasive cribriform carcinoma can
• Outcome show prominent tubular component similar to that
Invasive cribriform carcinoma, like tubular car- of ▶ tubular carcinoma in up to 50% of the tumor
cinoma (▶ Tubular Carcinoma), has a favorable (Page et al. 1983). Cases with a 10–40% compo-
outcome with 10-year overall survival of 90% nent of another morphological type (other than
(Ellis et al. 1992) to 100% (Page et al. 1983; tubular carcinoma) are regarded as mixed type
Louwman et al. 2007). The outcome of mixed (Page et al. 1983; Venable et al. 1990).
invasive cribriform carcinoma is less favorable
than that of the pure form but better than that of Immunophenotype
no special type ▶ (NST) carcinoma (Page et al.
1983). Axillary node metastases occur in 14% Invasive cribriform carcinoma typically displays a
of cases (Page et al. 1983) and rarely involve luminal A phenotype with high expression of
more than one or two axillary lymph nodes. hormone receptors, luminal cytokeratins, and
E-cadherin. Pure invasive cribriform carcinoma I
Macroscopy does not express basal cytokeratins and lacks
HER2 gene amplification and p53 expression.
There is no specific macroscopic feature that dis-
tinguishes invasive cribriform carcinoma from no
Molecular Features
special type (NST) or mixed types. Mean tumor
size is 3 cm (Page et al. 1983). The consistency is
Invasive cribriform carcinoma and tubular carci-
generally hard, but foci of hemorrhage may be
noma have similar genomic and transcriptomic
seen. Necrosis is not a feature of cribriform carci-
features.
noma. Calcification is common and may be the
presenting sign on mammography.
Microscopy Invasive cribriform carcinoma should be differenti-

ated from cribriform DCIS (▶ Ductal Carcinoma In
Pure invasive cribriform carcinoma consists of an Situ), ▶ adenoid cystic carcinoma, and other types of
invasive cribriform pattern in more than 90% of breast carcinoma with cribriform areas. Invasive
the lesion (Fig. 1). The tumor is arranged as, often cribriform carcinoma is distinguished from cribri-
angulated, invasive islands, in which well-defined form DCIS by the lack of a myoepithelial cell layer
cribriform spaces are formed by arches of cells around its invasive islands and its haphazard distri-
(sieve-like pattern). Apical snouts are common. bution and irregular configuration. Adenoid cystic
Mucin-positive secretion bearing micro- carcinoma (▶ Adenoid Cystic Carcinoma) has a sec-
calcifications can be present within the lumina ond population of cells as well as intracystic secre-
(Page et al. 1983; Wells and Ferguson 1988). tory and basement membrane-like (e.g., laminin
Tumor cells are small to moderate in size with positive) material (Wells and Ferguson 1988). The
mild or moderate degree of pleomorphism. Mito- presence of osteoclast-like giant cells in the stroma is
ses are rare. A prominent fibroblastic stroma is mostly seen in ICC, but such giant cells may be seen
common; in occasional cases, osteoclast-like in other types of invasive mammary carcinoma and
giant cells of histiocytic origin are found. are not diagnostic of invasive cribriform carcinoma.
212 Invasive Lobular Carcinoma
Invasive Cribriform Carcinoma, Fig. 1 (H&E) a) A arranged in cribriform pattern and desmoplastic stroma.
case of invasive cribriform carcinoma showing irregular Higher-power view is shown in Fig. 1b
infiltrating islands of low-nuclear-grade malignant cells
References Definition
Ellis, I. O., Galea, M., Broughton, N., Locker, A., Invasive lobular carcinoma (ILC) is characterized
Blamey, R. W., & Elston, C. W. (1992). Pathological
by noncohesive cells, usually E-cadherin negative,
prognostic factors in breast cancer. II. Histological
type. Relationship with survival in a large study with that are dispersed or arranged in single-file linear
long-term follow-up. Histopathology, 20, 479–489. pattern, but can show several additional architec-
Li, C. I., Uribe, D. J., & Daling, J. R. (2005). Clinical tural patterns (Tavassoli and Eusebi 2009; Lakhani
characteristics of different histologic types of breast
cancer. British Journal of Cancer, 93, 1046–1052.
et al. 2012). ILC is frequently associated with
Louwman, M. W., Vriezen, M., van Beek, M. W., lobular carcinoma in situ (LCIS).
Nolthenius-Puylaert, M. C., van der Sangen, M. J.,
Roumen, R. M., Kiemeney, L. A., & Coebergh, J. W.
(2007). Uncommon breast tumors in perspective: Inci-
dence, treatment and survival in the Netherlands. Inter-
Clinical Features
national Journal of Cancer, 121, 127–135.
Page, D. L., Dixon, J. M., Anderson, T. J., Lee, D., & • Incidence
Stewart, H. J. (1983). Invasive cribriform carcinoma ILC is the second most common type of breast
of the breast. Histopathology, 7, 525–536.
cancer and constitutes 5–15% of all invasive
Venable, J. G., Schwartz, A. M., & Silverberg, S. G. (1990).
Infiltrating cribriform carcinoma of the breast: breast tumors (Lakhani et al. 2012), although
A distinctive clinicopathologic entity. Human Pathology, incidence varies according to the criteria
21, 333–338. applied for diagnosis. The incidence of ILC is
Wells, C. A., & Ferguson, D. J. (1988). Ultrastructural and
immunocytochemical study of a case of invasive crib-
increasing, especially among postmenopausal
riform breast carcinoma. Journal of Clinical Pathology, women, probably as consequence of hormonal
41, 17–20. replacement therapy and alcohol abuse (Rakha
and Ellis 2010).
• Age
ILC usually affects peri and postmenopausal
Invasive Lobular Carcinoma women aged 50 or more but it can be seen in a
wide age range of patients, from young, in their
Maria P. Foschini and Luca Morandi third decade of life, to elderly women, aged more
Department of Biomedical and Neuromotor than 80 years (Tavassoli and Eusebi 2009).
Sciences (DIBINEM), Unit of Anatomic • Sex
Pathology at Bellaria Hospital, University of ILC affects more frequently female patients
Bologna, Bologna, Italy and it is rare in men.
Invasive Lobular Carcinoma 213
• Site ILC can show a great variety of morpholog-

ILC arises in the breast parenchyma, affecting ical variants, whose prognostic impact has
any of the breast quadrants. Bilaterality and been poorly studied. According to the data
multifocality are seen in ILC more frequently obtained by Orvieto et al. (2008), the classical
than in other breast cancers (Rakha and Ellis variant shows a better prognosis than other
2010). Paget’s disease (▶ Paget Disease of the morphological variants of ILC, due to a lower
Nipple) is not associated with ILC. number of recurrences and metastases.
ILC may present as a palpable breast mass Histological grade is related to ILC progno-
of variable size. Mammographic features are sis (Rakha and Ellis 2010). ILC grade 3 shows
often difficult to interpret, and this may impair more frequent aggressive prognostic parame-
early diagnosis. ILC is the most common ters as advanced T stage, vascular invasion,
type of cancer among mammographically lymph-node metastases at presentation. As
undetected cancers (Tavassoli and Eusebi expected, these features are related to poorer
2009). Furthermore, Magnetic Resonance outcome, when compared with ILC grade 2.
Imaging (MRI) is more effective to estimate
both the size and the bilaterality of ILC than
Macroscopy
mammography. Preoperative diagnosis, when
I
based on fine needle aspiration cytology can
Macroscopic features vary according to mam-
lead to inadequate results, as a consequence
mography and clinical presentation. About half
of low cellularity of ILC.
of the cases present as an ill-defined, firm mass.
• Treatment
In addition, ILC can present as multiple minute
Surgery associated with endocrine therapy
nodules. Due to the diffuse growth pattern in
constitutes the treatment of choice in operable
about 30% of the cases, it is very difficult to detect
cases; however, adjuvant chemotherapy can
any nodule, the breast parenchyma being fibrous
be useful in advanced cases.
and firm (Tavassoli and Eusebi 2009).
• Outcome
ILC usually shows favorable prognostic pro-
file (low or intermediate nuclear grade, high
expression of estrogen (ER) and progesterone Microscopy
receptors (PR), low proliferative index). On
the other side, ILC presents at a more ILC shows a wide spectrum of different architec-
advanced stage than other types of carcinoma. tural and histological features (Tavassoli and
Studies focused on ILC prognosis led to Eusebi 2009) that should be recognized in order
conflicting results, failing to demonstrate a to achieve a correct diagnosis.
better prognosis when ILC is compared to
invasive carcinoma of no special type (NST) Architectural Variants
(▶ Invasive Carcinoma NST). Distant metas- Architectural histological variants are often
tases can occur after many years suggesting a intermingled one to the other and the predominant
worse long-term prognosis of ILC than of pattern (over 80% of tumor structure) determines
breast carcinoma NST (Rakha and Ellis the specific tumor type (Tavassoli and Eusebi
2010; Lakhani et al. 2012). ILC metastatic 2009).
pattern shows a greater tendency toward ILC Classical variant (ILC-C) has been recog-
abdominal dissemination (comprising metas- nized for long time and is characterized by a
tases to gastro-intestinal tract, uterus, and diffuse growth pattern with occasional nodules.
ovary) at presentation. In addition, brain, The cells are sparse and dissociated and invade the
meninges, bone, pleural and peritoneal sero- stroma in a single cell file (Fig. 1a, H&E) and may
sal membranes may be involved (Tavassoli surround the residual ducts and lobules in a
and Eusebi 2009; Lakhani et al. 2012). targetoid fashion (Fig. 1b, cytokeratin
Invasive Lobular Carcinoma, Fig. 1 A: ILC-C is char- stained with low molecular weight cytokeratin antibody)
acterized by a diffuse growth of neoplastic cells infiltrat- are arranged around a ductule in a targetoid fashion
ing the mammary tissue (H&E). B: Neoplastic cell, (here
Invasive Lobular Carcinoma, Fig. 2 ILC-C sometimes a solid architecture can be seen (A) (H&E). Negative
immunohistochemistry for E-cadherin helps in the differential diagnosis with invasive carcinoma of no special type (B)
immunohistochemistry (IHC)) due to invasion of prognosis. Mitotic count is low and necrosis is
the prelymphatic channels of Hartveit (Tavassoli rarely seen in this variant.
and Eusebi 2009). No inflammatory reaction of ILC with solid architecture (ILC-S) can present
the stroma is seen. Neoplastic cells have monoto- as a solid mass, of varying size, usually >2
nous morphology, roundish central nucleus, with cm. ILC-S is composed of neoplastic cells similar
delicate chromatin, and scarce cytoplasm. to those of the ILC-C, but often showing higher
Intracytoplasmic vacuoles are not infrequent and nuclear grade (Fig. 2a, H&E). Atypical mitotic
can be highlighted by Alcian blue pH2.5/PAS figures and necrotic areas are frequent findings in
after diastase staining. On electron microscopy, ILC-S. Negative immunohistochemistry for
the intracytoplasmic lumina are lined by E-cadherin helps in the differential diagnosis with
microvilli (Tavassoli and Eusebi 2009). invasive carcinoma of no special type (▶ Invasive
ILC-C neoplastic cells can invade diffusely the Carcinoma NST) (Fig. 2b, (IHC) E-cadherin high-
mammary gland, in a “spider–web” fashion (Tot lights the epithelial cells of a residual duct. ILC
2016). This type of growth indicates poor nests are negative).
Invasive Lobular Carcinoma, Fig. 3 ILC-LA shows

neoplastic cells arranged in alveolar structures, separated
by fibrous septa (H&E)
Invasive Lobular Carcinoma, Fig. 4 ILC-H: is com-
posed of neoplastic cells with foamy cytoplasm and mild
Mucinous variant (ILC-Muc) is a rare variant nuclear atypia (H&E)
of ILC that shows abundant extracellular mucin
deposition (Cserni et al. 2017). Mucin deposition
I
can be focal or diffuse. ILC-Muc neoplastic cells
are similar to those seen in ILC-C.
Loose alveolar variant (ILC-LA) is character-
ized by neoplastic cells arranged in alveolar struc-
tures, separated by fibrous septa (Fig. 3, H&E).
The neoplastic cells show the same morphological
features of ILC-C.
Tubulo-lobular variant (ILC-TL) is character-
ized by a mixture of tubular carcinoma and ILC
(Tavassoli and Eusebi 2009).
Cytologic Variants
All these features may manifest within each his-
tologic variants. Invasive Lobular Carcinoma, Fig. 5 ILC-SR shows
Histiocytoid variant (ILC-H) (Tan et al. 2011) numerous cells with intracytoplasmic vacuole (H&E)
is composed of neoplastic cells that resemble his-
tiocytes having a clear and finely foamy cyto-
plasm (Fig. 4, H&E). On electron microscopy, two types of signet ring cells can be encountered
the neoplastic histiocytoid cells show large clear (Tavassoli and Eusebi 2009). The first and more
vesicles, typical of apocrine cells. The apocrine common type is characterized by intracytoplasmic
nature of these neoplastic cells can be demon- mucin-filled vacuoles, with microvilli seen on elec-
strated with positive immunohistochemical reac- tron microscopy. The second type shows dilated
tion for the apocrine marker Gross Cystic Disease cisternae of the endoplasmic reticulum filled with
Fluid Protein 15 (GCDFP-15). PAS or Alcian blue positive mucin similar to the SR
Apocrine variant (ILC-A): the neoplastic cells cells of the stomach.
show eosinophilic and granular cytoplasm, central Myoepithelial cell variant (ILC-M): rare
nucleus with evident nucleolus. Diffuse positivity cases showing evidence of myoepithelial cell dif-
for GCDFP-15 is usually encountered. ILC-A may ferentiation are on record (Del Vecchio et al. 2005;
be associated with LCIS with apocrine features. Tavassoli and Eusebi 2009). The cases described
Signet ring cell variant (ILC-SR): cells with a by Del Vecchio et al. (2005) were composed of
signet ring appearance are the predominant cells having features intermediate between
neoplastic population (Fig. 5, H&E). In ILC-SR, epithelial-secretory and myoepithelial (therefore
the name of “myosecretory” was applied) (Del

Vecchio et al. 2005). The myosecretory features
were present both in the invasive and in situ
components.
Pleomorphic variant (ILC-P): this variant is
described in a dedicated chapter (▶ Pleomorphic
Lobular Carcinoma).
All ILC variants are frequently associated with
in situ lobular carcinoma (LCIS) (▶ Lobular In
Situ Neoplasia) or to in situ duct carcinoma
(▶ Ductal Carcinoma In Situ) (DCIS) of low
nuclear grade. LCIS is frequently multifocal and
can be localized within the invasive component or Invasive Lobular Carcinoma, Fig. 6 Lymph-node
metastasis of ILC-C is characterized by single or small
in the surrounding parenchyma, as well as in other groups of neoplastic cells, and sometimes it is difficult to
quadrants or in the contralateral breast (Foschini define the size of the metastatic deposit (cytokeratin IHC
et al. 2006). reaction)
ILC grading: ILC is usually graded following
the Nottingham grading system applied in all the European Working Group on Breast Screening
breast carcinomas (Rakha and Ellis 2010). ILC Pathology (EWGBSP) is the most accurate in
grade can be difficult to assess due to the lack of defining patients with high or low risk of further
tubule formation and low mitotic index. The vast axillary metastatic load.
majority of ILC are grade 2. Grade 3 ILC are more Frozen section interpretation of sentinel node
frequently encountered among the special vari- metastases from ILC is difficult, as single neoplas-
ants, as ILC-S and ILC-P. tic cells intermingled with lymphocytes can be
Nevertheless, studies based on large cohort of missed on a quick intra-operative evaluation. To
patients, with long-term follow-up information, this purpose, the application of rapid cytokeratin
demonstrate that ILC grading might predict immunohistochemical staining can be of help to
prognosis. highlight the neoplastic cells.
Tumor infiltrating lymphocytes (TIL) are
scanty in ILC. Prominent TIL can be observed in
those variants showing more aggressive features, Immunophenotype
as ILC-P, ILC-S, and in ILC grade 3 cases. On
very rare occasions TIL can be so prominent that Loss of E-cadherin expression is the most typical
ILC acquire the features of lymphoepithelioma- immunohistochemical feature of ILC neoplastic
like carcinoma (Cristina et al. 2000). cells (Dabbs et al. 2013) as to be used in the
The architectural pattern of ILC is reflected in differential diagnosis between ILC and other
lymph node metastases, which are composed of breast carcinoma histotypes. In ILC-C,
neoplastic cells dispersed among the lymph- E-cadherin loss is almost complete; no staining
node parenchyma or disposed in linear files and is visible along the cell membrane of the neoplas-
small clusters (Fig. 6, (IHC) cytokeratin tic cells. In some ILC variants, E-cadherin loss
immunostaining of ILC metastasis in lymph can be partial and the neoplastic cells can show a
node). Specifically, the differential diagnosis residual, partial positivity along the cell mem-
between isolated tumor cells (ITC), micro- and brane (Canas-Marques and Schnitt 2016).
macrometastases, can be a matter of subjective ILC, in addition to loss of E-cadherin expres-
interpretation. In order to achieve a reliable inter- sion, is characterized by altered P120 catenin
pretation that can give accurate information on the expression within the cytoplasm instead of the
risk of further axillary metastases, several membrane (Canas-Marques and Schnitt 2016).
methods have been proposed. Van Deurzen et al. Combined immunohistochemical reactions,
(2010) demonstrated that the method proposed by showing E-cadherin loss and P120 cytoplasmic
A wide spectrum of genetic or epigenetic alter-

ations can affect the CDH1 gene, as deletions,
mutations, and methylation. The most frequent
alterations, detected in ILC, are 16q loss and
gains of 1q and 16p. In addition, several other
genetic aberrations have been found, as 8q gain
and losses at 8p23-p21, 11q14.1q25, 13q, Xq
(Rakha and Ellis 2010).
The E-cadherin transcriptional regulation can
be altered by numerous different transcription fac-
tors as activation of the TGFb pathway, SNAIL
and SLUG upregulation, and ZEB1 expression
Invasive Lobular Carcinoma, Fig. 7 Most of the ILC (Dabbs et al. 2013).
neoplastic cells are ER positive (IHC, ER in red)
The different genetic mechanisms leading to
E-cadherin inactivation and\or protein loss are
expression, can be of help in the correct ILC reflected by the different patterns of E-cadherin
diagnosis. expression detected on immunohistochemistry
ILC cells in addition express low-molecular
I
(Dabbs et al. 2013; Canas-Marques and Schnitt
weight cytokeratins, cytokeratin 34BetaE12, 2016).
GATA3, mammaglobin, GCDFP-15, Epithelial CDH1 mutations were enriched in multifocal
membrane antigen (EMA), cathepsin D, and cyclin rather than unifocal tumors, suggesting that these
D1 (Rakha and Ellis 2010). Myoepithelial cell aberrations might be implicated in ILC spreading
markers are usually negative with the exception within the breast stroma. They may be probably
of the “hybrid” variant (Del Vecchio et al. 2005). related even to the peculiar pattern of metastatic
ER (Fig. 7, (IHC) ER positive nuclei in red) and dissemination to organs such as the GI tract, ova-
PR are highly expressed in the vast majority of ILC ries, and peritoneum due to critical role of
and in most of the neoplastic cells (>80%), while cadherin in cell adhesion.
the intensity and the percentage of positive cells Other four key genes have been reported to
can decrease in the ILC variants, especially in the be frequently mutated in ILC: PIK3CA (~45%),
aggressive variants. Androgen receptor (AR) is PTEN (usually LOH or mutations in ~13% of
highly expressed in most ILCs (Riva et al. 2005). cases), AKT1 (~13%), and HER2 (~5.1%)
HER2 overexpression or amplification is an (Desmedt et al. 2016).
extremely rare event in ILC and is almost exclu- The transcriptomic characterization of
sively seen in the pleomorphic variant of ILC 141 cases of ILC based on a standardized molec-
(▶ Pleomorphic Lobular Carcinoma). ular assay revealed that 84% of samples were
Proliferative activity, evaluated immunohisto- classified as luminal A or luminal B (Ciriello
chemically with Ki67 antibody, is lower in ILC et al. 2015). A more recent study using immuno-
than in invasive breast carcinoma NST (▶ Inva- histochemistry surrogates evaluating 981 primary
sive Carcinoma NST). High proliferative index is ILC (Iorfida et al. 2012) confirmed those data,
seen in ILC grade 3 or in the special variants with where 41% and 57% of the ILC samples pertained
aggressive behavior. to the luminal A and B subtype, respectively.
Genetic studies based on clonal analyses dem-
onstrate a relation between LCIS and ILC
Molecular Features (Morandi et al. 2006). These data have been con-
firmed recently by an independent study (Sakr
The key molecular alterations detected in ILC are et al. 2016), indicating that LCIS and ILC have a
those affecting the CDH1 gene, mapped on similar repertoire of somatic mutations, with
16q22.1, whose protein product is E-cadherin PIK3CA and CDH1 being the most frequently
(Dabbs et al. 2013). mutated genes.
Differential Diagnosis carcinoma in situ; on permanent sections, granular

cell tumor has a specific immunoprofile (S100
The spectrum of differential diagnoses to be con- positivity) and lacks cytokeratin positivity.
sidered in cases of ILC varies according to ILC ILC-H and ILC-A should be differentiated from
variant. invasive carcinoma with apocrine changes
Differential diagnosis is more frequently car- (▶ Apocrine Carcinoma). To this purpose, the
ried out with invasive carcinoma NST (▶ Invasive absence or decreased expression of E-cadherin
Carcinoma NST), especially in cases of ILC-S. To together with cytoplasmic P120 are the main hall-
this purpose, in addition to the morphological marks of ILC.
features described above, absence or reduced ILC-SR can be difficult to differentiate from sig-
E-cadherin expression is of help. In more difficult net ring cell carcinomas arising in different organs
cases, cytoplasmic P120 expression can be added. especially in cases of ILC-SR presenting with gastric
Differential diagnosis between ILC-C and of gastro-intestinal metastases. Breast ILC-SR
polymorphous (low-grade) adenocarcinoma lesions show strong positivity for ER, PR, and AR,
(PLGA) is described in a specific chapter and GATA3, a feature usually lacking in similar
(▶ Polymorphous Carcinoma). Shortly, when carcinomas arising in organs different from breast.
morphology is difficult to interpret, E-cadherin ILC-Muc is differentiated from mucoid carci-
fragmented expression and reduced CK7 noma (▶ Invasive Mucinous Carcinoma) for
expression as observed in PLGA can help in the E-cadherin loss and cytoplasmic P120 (Cserni
differential diagnosis. In addition, BCL2 et al. 2017).
positivity and ER\AR negativity are frequently ILC-M is a rare variant that should be differenti-
seen in PLGA. Epithelioid Myofibroblastoma ated mainly from invasive carcinoma NST
(▶ Mammary Myofibroblastoma) is extremely (▶ Invasive Carcinoma NST). It has a bland cytol-
rare, but may mimic ILC-C, since the epithelioid ogy similar to ILC-C, partial loss of E-Cadherin and
cells are variously arranged in single cells, single a concurring expression of epithelial and
files or nests. These cells are positive for ER and myoepithelial cell markers (Del Vecchio et al. 2005).
PR and unlike ILC-C are variably positive also for ILC-P is discussed in detail in the dedicated
vimentin, desmin, alpha-smooth muscle actin, chapter (▶ Pleomorphic Lobular Carcinoma).
CD34, CD99, and CD10.
ILC-H should be differentiated from several
reactive and neoplastic conditions (Eusebi et al. References
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Bottiglieri, L., Rotmensz, N., Montagna, E., Guillaume Bataillon3 and
Dellapasqua, S., Veronesi, P., Galimberti, V., Luini, A., Anne Vincent-Salomon3
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Unit of Pathology, Candiolo Cancer Institute
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Cancer Res Treat, 133(2), 713–723. FPO-IRCCS, Candiolo, Italy
2
Lakhani, S. R., Rakha, E. A., & Simpson, P. T. (2012). Department of Medical Sciences, University of
Invasive lobular carcinoma. In S. R. Lakhani, I. O. Turin, Turin, Italy
Ellis, S. J. Schnitt, P. H. Tan, & M. van de Vijver 3
Institut Curie, Paris, France
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Orvieto, E., Maiorano, E., Bottiglieri, L., Maisonneuve, P., Carcinosarcoma; Matrix-producing carcinoma;
Rotmensz, N., Galimberti, V., Luini, A., Brenelli, F., Sarcomatoid carcinoma; Spindle cell metaplastic
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Immunohistochemical study of androgen receptors in cally heterogeneous group of invasive breast
220 Invasive Metaplastic Carcinoma
cancers in which a variable proportion of the compared to conventional types of triple-

tumor shows squamous and/or mesenchymal dif- negative breast cancer (TNBC) (Jung et al.
ferentiation featuring, for instance, spindle, 2010). A recent study has demonstrated that
chondroid, osseous, or rhabdoid cells (Lakhani patients affected by a metaplastic breast carci-
et al. 2012). noma and treated with chemotherapy in the neo-
adjuvant setting were more likely to have a
clinically progressive disease during neoadjuvant
Clinical Features therapy compared to other types of TNBC and
also showed a poorer disease-free survival
• Incidence (Tanabe et al. 2017). There seems to be a differ-
Metaplastic carcinomas represent an uncom- ence in response to chemotherapy across distinct
mon histologic type of breast cancer account- transcriptomic subtypes (see section Molecular
ing for 0.2–5% of all breast carcinomas Features): those cases classified as mesenchymal,
(Lakhani et al. 2012). basal-like2, and luminal androgen receptor show
• Age a lesser degree of response to neoadjuvant che-
Although the range of age at presentation is motherapy compared to basal-like1 cases
similar to that of invasive carcinomas of (Lehmann et al. 2016).
no special type (IC-NST) (▶ Invasive Carci- • Outcome
noma NST), two studies have reported an older Unlike conventional forms of TNBC, metaplas-
mean age at presentation in metaplastic carci- tic carcinomas have been reported to be resistant
nomas compared to that of patients affected by to chemotherapy and to have a worse outcome
IC-NSTs (Lai et al. 2013; Pezzi et al. 2007). (Jung et al. 2010). Although metaplastic carci-
• Sex nomas are mostly high grade and display an
Most of the cases have been described in aggressive behavior, it should be acknowl-
female patients; however there are reports of edged that there are two low-grade forms of
metaplastic carcinomas diagnosed in male metaplastic carcinoma, i.e., fibromatosis-like
patients. metaplastic carcinoma and low-grade
• Site adenosquamous carcinoma (Marchiò et al.
The location in the breast in which metaplastic 2016). Fibromatosis-like metaplastic carci-
carcinomas arise is not dissimilar to that of any noma still has a long-term metastatic potential,
IC-NSTs. although less than high-grade metaplastic car-
• Treatment cinomas, and must be surgically treated as
The treatment is based on a surgical approach carcinomas (Gobbi et al. 2003; Sneige et al.
with sentinel node biopsy. It should be noted 2001). ▶ Low Grade Adenosquamous Carci-
that mastectomy is more common than breast- noma tends to recur locally; nevertheless its
conserving surgery in these patients, most metastatic potential is minimal, and therefore
likely because of the large tumor size at pre- chemotherapy should be avoided (Marchiò
sentation. In addition, axillary involvement is et al. 2016).
less frequent than in IC-NSTs. Nevertheless,
axillary sentinel lymph node biopsy is a
recommended good practice. Surgery is Macroscopy
followed by adjuvant chemotherapy-based
regimens and radiotherapy, depending on clin- The gross appearance of these tumors is not
icopathological parameters. distinctive: similarly to other types of breast can-
When considering a therapeutic approach cer, they can show either well-circumscribed or
with neoadjuvant chemotherapy, it should be indistinct, irregular borders (Collins and Schnitt
kept in mind that these carcinomas usually 2013). It should be noted however that they can
show a poor response to chemotherapy occasionally present as a cystic lesion, and this is
particularly the case for squamous cell carcino- organs such as the skin and, when dealing with
mas; in addition, when heterologous elements male patients or whenever a patient has a history
are abundant and predominant, the macroscopic of lung cancer or is heavy smoker, the lung (see
appearance may be more distinctive. For below for section “Differential Diagnosis”).
instance, on cut surface, squamous or chondroid Squamous cell carcinomas of the breast
areas may appear as pearly white to gray glisten- typically present as a cystic lesion where the cav-
ing areas. ity is lined by a squamous epithelium with vari-
Finally, at the time of diagnosis, they tend to be able nuclear atypia, and there is evidence of
larger than IC-NSTs (▶ Invasive Carcinoma neoplastic infiltration in the adjacent stroma that
NST), with a reported mean size of 3.9 cm usually displays a marked inflammatory infiltrate
(Collins and Schnitt 2013). (Lakhani et al. 2012).
The squamous differentiation of the neoplastic
cells can show well to poorly differentiated fea-
Microscopy tures (Fig. 1a and b, H&E), and a spindle cell
morphology can also be appreciated, typically at
Histologically these tumors are most often of high the infiltrative border of the tumor (Lakhani
grade, with conspicuous nuclear pleomorphism et al. 2012).
I
and mitotic activity; however they constitute a An acantholytic variant of squamous cell car-
heterogeneous group of lesions encompassing cinoma has also been described, featuring irregu-
several entities (Fig. 1). The 2012 WHO classifi- lar spaces lined by squamous cells. These spaces
cation has adopted a descriptive classification can be misinterpreted as vascular spaces and lead
including: to a wrong diagnosis of angiosarcoma (Lakhani
et al. 2012; Collins and Schnitt 2013).
– Squamous cell carcinoma
– Metaplastic carcinoma with mesenchymal Metaplastic Carcinoma with Mesenchymal
differentiation Differentiation
– Spindle cell carcinoma These lesions are defined by the presence of a
– Fibromatosis-like metaplastic carcinoma varying degree of heterologous differentiation of
– Low-grade adenosquamous carcinoma mesenchymal origin (Collins and Schnitt 2013)
and can also be called “matrix-producing carcino-
When diagnosing a metaplastic breast cancer, mas.” The most frequent heterologous differen-
one should clearly describe the distinct morpho- tiation encountered in metaplastic carcinomas
logical components present as this may have clin- of the breast is either osseous or cartilaginous
ical implications. (Fig. 1e and f, H&E) (Collins and Schnitt 2013).
As a general rule, the heterologous compo-
Squamous Cell Carcinoma nents may appear either benign or malignant, in
Metaplastic squamous cell carcinomas can be the latter case resembling/mimicking a sarcoma-
pure or admixed with an IC-NST (Lakhani et al. tous component. Based on this, whenever the
2012; Collins and Schnitt 2013). Pure squamous mesenchymal component is predominant a differ-
cell carcinomas of the breast are rare. It is impor- ential diagnosis with (i) a malignant phyllodes
tant to keep in mind that some degree of squamous tumor (▶ Phyllodes Tumor) with heterologous
differentiation can be observed in invasive carci- differentiation or (ii) a sarcoma (primary or meta-
nomas of no special type (▶ Invasive Carcinoma static) has to be taken into account (Collins and
NST) and is more commonly seen in carcinomas Schnitt 2013; Rakha et al. 2016).
with medullary features (▶ Invasive Carcinoma In these cases, an extensive sampling of the
with Medullary Features) (Lakhani et al. 2012; lesion is often required to look for unequivocal
Collins and Schnitt 2013). It is good practice to epithelial elements or foci of ductal carcinoma in
rule out the possibility of a metastasis from other situ (▶ Ductal Carcinoma In Situ) (Collins and
Invasive Metaplastic Carcinoma, Fig. 1 H&E. Repre- carcinoma. (d) Fibromatosis-like metaplastic carcinoma. (e,
sentative microphotographs of the heterogeneity of metaplas- f) Two examples of a metaplastic carcinoma with mesenchy-
tic carcinomas. (a) squamous cell carcinoma. (b) A higher mal differentiation, one featuring chondroid differentiation
magnification of a metaplastic carcinoma with epidermoid (e) and the other showing bone tissue formation (f)
features showing high mitotic count. (c) Spindle cell
Schnitt 2013; Rakha et al. 2016). As discussed in is employed to demonstrate even a focal expres-
the differential diagnosis paragraph, this is the sion. It has to be stressed that not all metaplastic
typical scenario in which a panel of cytokeratins carcinomas express cytokeratins and that focal
cytokeratin expression can also be observed in carcinoma with spindle-like features. The authors
phyllodes tumors (▶ Phyllodes Tumor), thus originally described this lesion by using the term
making the differential diagnosis particularly “tumor” to avoid the word “carcinoma” because
challenging and, in some cases, not possible neither the phenotype nor the behavior seemed to
(Collins and Schnitt 2013). be that of a carcinoma (Gobbi et al. 1999); how-
ever this entity was labeled as “carcinoma” in the
Spindle Cell Carcinoma 2012 WHO classification.
Metaplastic carcinomas can present as a prolifer- The microscopic growth pattern is typically
ation of atypical spindle cells (Lakhani et al. infiltrative, with finger-like projections extending
2012), thus posing important differential diagno- into adjacent mammary structures and fat tissue;
sis issues with other spindle cell lesions of the however lesions with ill-defined border or nodular
breast. The neoplastic spindle cells show a wide appearance have also been described (Gobbi et al.
morphological spectrum and may have a fasci- 1999). It is characterized by a dominant prolifer-
cular, storiform, or haphazard growth pattern ation of spindle cells displaying pale eosinophilic
(Fig. 1c, H&E) with infiltrative borders (Lakhani cytoplasm and slender nuclei with mild cytologic
et al. 2012). The nuclear atypia varies from mod- atypia (Fig. 1d H&E, and Fig. 2a and b, H&E)
erate to high grade. An inflammatory infiltrate of (Gobbi et al. 1999). The stroma shows varying
I
lymphocytes and dendritic cells is often found degree of collagenization. Focal plump fusiform
(Lakhani et al. 2012). and polygonal tumor cells, with more rounded
The presence of a carcinomatous component nuclei, arranged in “epithelioid” clumps can be
in the mixed tumors makes the diagnosis rela- observed. Spindle cells are often arranged in
tively straightforward. On the other side, the wavy interlacing fascicles (Lakhani et al. 2012).
diagnosis of high-grade spindle cell carcinoma In addition, foci of glandular or squamous ele-
with no morphological evidence of epithelial dif- ments associated with the spindle cells can be
ferentiation is challenging (Rakha et al. 2016). encountered posing issues in differential diagno-
This represents another scenario in which exten- sis with ▶ low grade adenosquamous carcinoma
sive sampling and thorough immunohistochemi- (see below); in fibromatosis-like carcinomas, foci
cal investigation with a panel of markers of glandular or squamous elements should repre-
including more than one cytokeratin are useful sent less than 5% of the overall tumor cell com-
(Collins and Schnitt 2013; Rakha et al. 2016). As ponent. Ductal carcinoma in situ (▶ Ductal
discussed above for metaplastic carcinomas with carcinoma in situ) can be associated (Gobbi
mesenchymal differentiation, foci of ductal car- et al. 1999).
cinoma in situ (▶ Ductal Carcinoma In Situ) or Cytokeratin expression is typically
small cohesive epithelial foci should be sought. found; however it is important to note that it
A pure spindle cell malignancy with no evidence can be focal and occasionally restricted to the
of these features or even focal cytokeratin plump spindle and more epithelioid cells.
expression should prompt to consider, in the dif- Expression of p63 is invariably observed in
ferential diagnosis, malignant phyllodes tumor these lesions.
(▶ Phyllodes Tumor), sarcomas, and metastatic
sarcomatoid tumors (Collins and Schnitt 2013; Low-Grade Adenosquamous Carcinoma
Rakha et al. 2016). This is a rare histologic type of metaplastic
A low-grade form of spindle cell carcinoma carcinoma showing a distinctive combination of
has also been described and is labeled as glandular and squamous differentiation. It is
“Fibromatosis-like Metaplastic Carcinoma” and characterized by well-developed gland/tubule
is discussed here below. formation intimately admixed with solid
nests of squamous cells in a spindle cell back-
Fibromatosis-like Metaplastic Carcinoma ground. Despite the presence of metaplastic
This tumor type, described by Gobbi et al. (1999), elements, these tumors display a low-grade
represents a low-grade variant of metaplastic histological pattern. In agreement with their
Invasive Metaplastic Carcinoma, Fig. 2 A core biopsy atypia (A,B). The neoplastic cells show mild
sample showing a spindle cell proliferation in the mam- pancytokeratin expression (C), focal CK5/6 expression
mary gland featuring fusiform cells displaying pale eosin- (D), and more pervasive and intense CK14 expression
ophilic cytoplasm and slender nuclei with bland cytologic (E). The lesion shows diffuse p63 expression (F)
low-grade morphological features, the majority lymph node metastasis (Collins and Schnitt
of low-grade adenosquamous carcinomas exhibit 2013). A proportion of cases, however, can
an excellent prognosis, with a low incidence of behave in a locally aggressive manner.
A more detailed description of this entity can Molecular Features

be found in the chapter entitled ▶ Low-Grade
Adenosquamous Carcinoma. In a way akin to TNBC, metaplastic carcinomas
are characterized by high levels of genetic insta-
bility showing a similar constellation of gene
Immunophenotype copy number alterations (Hennessy et al. 2009).
Amplification of the epidermal growth factor
The large majority (>90%) of these tumors receptor (EGFR) gene with associated over-
are of triple-negative phenotype, i.e., they expression has been reported in a subset of meta-
lack expression of estrogen receptor (ER), plastic carcinomas and seems to be prevalent
progesterone receptor (PR), and HER2. The in tumors with squamous and/or spindle cell mor-
search for an epithelial phenotype is of key phology (Geyer et al. 2010). At the transcriptomic
importance for the differential diagnosis. Any level, metaplastic carcinomas preferentially per-
positivity for an epithelial marker would sup- tain to the basal-like or claudin-low molecular
port a diagnosis of metaplastic carcinoma. subtypes; those displaying spindle cell morphol-
A large panel of epithelial markers has to be ogy are the ones more likely to be classified as
assessed, taking into account pancytokeratins claudin-low (Hennessy et al. 2009: Lien et al.
I
(such as AE1/AE3, KL1), EMA, and 2004; Weigelt et al. 2009). When using the six
E-cadherin. Luminal cytokeratins (CKs) such molecular subtype classification of TNBC pro-
as CK8/18 can be expressed but in a low posed by Lehmann and colleagues (Lehmann
proportion of cases (Collins and Schnitt et al. 2011), it has been observed that MBCs are
2013; Rakha et al. 2017). Of note, expression preferentially of mesenchymal-like and mesen-
of high molecular weight (basal) CKs, includ- chymal stem-like subtype (Weigelt et al. 2015).
ing CK5/6, CK5, CK14, and CK17, is fre- On the other side, if the integrative clustering
quently observed (Collins and Schnitt 2013; approach is employed, metaplastic carcinomas
Rakha et al. 2017) (Fig. 2 (c) pancytokeratin; preferentially belong to IntClust 4, IntClust 1,
(d) CK5/6; (e) CK14; (f) p63). Indeed, it has IntClust 8, and IntClust 9 (Weigelt et al. 2015).
been shown that 90.8% of MBCs show a Interestingly, it has also been shown that dif-
basal-like immunophenotype (Reis-Filho ferent histologic components of metaplastic car-
et al. 2006). cinomas are associated with specific molecular
Expression of markers usually expressed in features (Weigelt et al. 2015). As an example,
normal myoepithelial cells, such as p63 and samples exclusively or predominantly composed
smooth muscle actin, is also frequently encoun- of areas of spindle cells or showing chondroid
tered and orients the diagnosis toward a morphology are of claudin-low intrinsic mole-
metaplastic carcinoma (Collins and Schnitt cular subtype and of mesenchymal-like subtype,
2013; Rakha et al. 2017). The expression of respectively, whereas those samples exclu-
such markers should not be misinterpreted sively or predominantly composed of squamous
as synonymous of a myoepithelial carcinoma cells show a higher degree of heterogeneity.
(▶ Myoepithelial Carcinoma of the Breast). A characterization of the landscape of somatic
Luminal cells, in a way akin to all breast carci- genetic alterations in metaplastic breast carcino-
nomas, including triple-negative breast cancers, mas has been recently provided (Ng et al. 2017).
represent the cells of origin of metaplastic Although metaplastic carcinomas and common
carcinomas. forms of TNBC harbor a similar mutational
A recent study has comprehensively analyzed frequency in the TP53 gene, they seem to be
a wide panel of immunohistochemical markers genetically distinct. Indeed, metaplastic carcino-
across a large series of metaplastic carcinomas mas show more frequent mutations in PIK3CA,
reported in the literature (Rakha et al. 2017), and PIK3R1, PTEN, and Wnt pathway genes, to the
results are summarized in Table 1. extent that 57% and 51% of cases harbor somatic
Invasive Metaplastic Carcinoma, Table 1 Expression carcinomas. This table has been modified and adapted
of CKs and epithelial differentiation markers in the main from Table 2 reported in Rakha et al. (2017). Number of
subgroups of metaplastic carcinomas. Data are extracted positive cases/total number of cases (percentages). LGASC
from a series of published cohorts of metaplastic low-grade adenosquamous carcinoma
Metaplastic carcinoma Fibromatosis-
Squamous with mesenchymal Spindle cell like
carcinoma differentiation carcinoma carcinoma LGASC
Cytokeratins AE1/ 11/13 (85) 36/36 (100) 99/117 (85) 30/30 (100) 13/14 (93)
AE3
CK8/18 17/18 (94) 7/13 (94) 14/54 (26) 1/2 (50) 18/21 (86)
CK7 // 4/4 (100) 0/2 (0) 0/25 (0) 21/22 (95)
CK19 // 5/7 (71) 0/2 (0) // 2/2 (100)
MNF116 // 7/10 (70) 38/40 (95) // 2/2 (100)
34bE12 // 10/15 (67) 7/9 (78) 28/28 (100) 23/23
(100)
CK5/6 59/63 (94) 41/56 (73) 25/34 (74) 6/6 (100) 25/27 (93)
CK14 17/19 (89) 38/52 (73) 35/43 (81) // 2/3 (67)
CK17 // 5/9 (56) 6/7 (86) // //
Myoepithelial p63 46/53 (87) 58/84 (69) 73/100 (73) 7/7 (100) 32/88 (84)
markers SMA 3/6 (50) 14/30 (47) 77/92 (84) 22/30 (73) 5/23 (22)
SMM // 2/16 (12) 1/10 (10) 0/24 (0) 0/19 (0)
CD10 // 9/18 (50) 14/15 (93) // 0/17 (0)
Calponin // 24/30 (80) 1/7 (14) // 0/7 (0)
S100 // 59/63 (94) 32/86 (37) 1/5 (20) //
Epithelial EGFR 95/114 47/76 (62) 35/49 (71) // //
differentiation (83)
EMA 0/3 (0) 14/15 (93) 32/101 (32) // //
E-CAD 18/20 (90) 0/19 (0) 0/10 (0) 0/3 (0) //
mutations in genes of the PI3K/AKT/mTOR path- differentiation and is associated with conven-
way and of the Wnt pathway, respectively tional mammary invasive or in situ carcinoma,
(Ng et al. 2017). These data are of clinical interest the diagnosis of a metaplastic carcinoma is usu-
as they provide a molecular basis for the recent ally straightforward. If these features are absent,
preclinical and clinical observations that Wnt and evidence for epithelial differentiation of the neo-
PI3K/AKT/mTOR pathway inhibition may be plastic cells should be provided by using immu-
beneficial for a subset of patients with metaplastic nohistochemistry (Fig. 2) (Rakha et al. 2017).
carcinoma (Ng et al. 2017). A wide spectrum of benign, locally aggressive,
and highly aggressive lesions has to be taken
in account for the differential diagnosis (Rakha
Differential Diagnosis et al. 2017). For instance, in order to render
a diagnosis of primary squamous cell carcino-
Due to the rarity and the histological diversity of mas of the breast, a squamous cell carcinoma
metaplastic carcinoma of the breast, its diagnosis of other sites, and in particular of the skin and
in routine diagnostic practice can be sometimes of the lung, should be ruled out (Lakhani
challenging (Rakha et al. 2017). et al. 2012).
As a general rule, if an invasive lesion of the Clinical history and radiological findings
breast shows mesenchymal or squamous would be crucial in this scenario. However, if
there is no evidence of an in situ carcinoma, References and Further Reading

the differential diagnosis may be not possible.
There is no specific marker that is preferentially Collins, L. C., & Schnitt, S. (2013). Biopsy interpretation
of the breast (2nd ed.). Philadelphia: Lippincott
expressed in lung versus breast squamous cell
Williams & Wilkins.
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be of help, and markers such as p40, p63, or basal de Biase, D., Vatcheva, R., Savage, K., Mackay, A.,
CKs are usually expressed by both entities. Ashworth, A., & Reis-Filho, J. S. (2010). Molecular
analysis reveals a genetic basis for the phenotypic
GATA3 expression is not consistently found in
diversity of metaplastic breast carcinomas. The Journal
metaplastic carcinomas (Wendroth et al. 2015; of Pathology, 220(5), 562–573.
Hattori et al. 2015) and, although rarely, can be Gobbi, H., Simpson, J. F., Borowsky, A., Jensen, R. A., &
found in lung squamous cell carcinomas (Hattori Page, D. L. (1999). Metaplastic breast tumors with a
dominant fibromatosis-like phenotype have a high risk
et al. 2015). Other markers of breast origin
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fluid protein-15 (GCDFP-15), an apocrine differ- D. L. (2003). Metaplastic spindle cell breast tumors aris-
entiation marker. Mammaglobin is reported not ing within papillomas, complex sclerosing lesions, and
nipple adenomas. Modern Pathology, 16(9), 893–901.
to be expressed by metaplastic carcinomas
Hattori, Y., Yoshida, A., Yoshida, M., Takahashi, M., &
(Reyes et al. 2012); GCDFP15 expression is Tsuta, K. (2015). Evaluation of androgen receptor and I
detected in a minority of metaplastic carcinomas GATA binding protein 3 as immunohistochemical
and can be occasionally encountered in squa- markers in the diagnosis of metastatic breast carcinoma
to the lung. Pathology International, 65(6), 286–292.
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Hennessy, B. T., Gonzalez-Angulo, A. M., Stemke-Hale, K.,
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Another example is given by low-grade Fridlyand, J., Sahin, A., Agarwal, R., Joy, C., Liu, W.,
fibromatosis-like metaplastic carcinomas, which Stivers, D., Baggerly, K., Carey, M., Lluch, A.,
Monteagudo, C., He, X., Weigman, V., Fan, C.,
have to be distinguished from desmoid-
Palazzo, J., Hortobagyi, G. N., Nolden, L. K.,
type fibromatosis or other benign spindle Wang, N. J., Valero, V., Gray, J. W., Perou, C. M., &
cell lesions of the breast (Marchiò et al. 2016). Mills, G. B. (2009). Characterization of a naturally
Furthermore, low-grade adenosquamous carci- occurring breast cancer subset enriched in epithelial-
to-mesenchymal transition and stem cell characteris-
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tics. Cancer Research, 69(10), 4116–4124.
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(▶ Tubular Carcinoma) or syringomatous tumors Park, C., Kwon, Y., Kim, E. A., Ko, K. L., Shin, K. H.,
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Hsieh, C. M., Chen, S. T., Kuo, S. J., Su, C. C., &
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Johnson, K. N., Shyr, Y., Moses, H. L., Sanders, M. E., plastic breast carcinomas are basal-like breast cancers:
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Rakha, E. A., Aleskandarany, M. A., Lee, A. H., & Invasive micropapillary carcinoma (IMPC) is a
Ellis, I. O. (2016). An approach to the diagnosis of special type of invasive breast carcinoma (IBC)
spindle cell lesions of the breast. Histopathology, characterized by cancer cells with eosinophilic or
68(1), 33–44. granular cytoplasm, forming morule-like clus-
Rakha, E. A., Coimbra, N. D., Hodi, Z., Juneinah, E.,
Ellis, I. O., & Lee, A. H. (2017). Immunoprofile of ters, surrounded by clear stromal spaces. Tumor
metaplastic carcinomas of the breast. Histopathology, cells have characteristic reverse polarity, also
70(6), 975–985. known as an “inside-out” growth pattern: the
Reis-Filho, J. S., Milanezi, F., Steele, D., Savage, K., apical pole of tumor cells faces the empty stromal
Simpson, P. T., Nesland, J. M., Pereira, E. M.,
Lakhani, S. R., & Schmitt, F. C. (2006). Metaplastic spaces.
breast carcinomas are basal-like tumours. Histopathol-
ogy, 49(1), 10–21.
Reyes, C., Gomez-Fernández, C., & Nadji, M. (2012).
Metaplastic and medullary mammary carcinomas
Clinical Features
do not express mammaglobin. American Journal of
Clinical Pathology, 137(5), 747–752. • Incidence
Sneige, N., Yaziji, H., Mandavilli, S. R., Perez, E. R., Pure IMPC is a rare subtype of invasive breast
Ordonez, N. G., Gown, A. M., & Ayala, A. (2001).
Low-grade (fibromatosis-like) spindle cell carcinoma
cancer, accounting in its pure form for 0.9–2%
of the breast. American Journal of Surgical Pathology, of IBCs. The reported incidence of IBC with a
25(8), 1009–1016. micropapillary component is up to 8%.
Invasive Micropapillary Carcinoma 229
• Age Microscopy
The reported median age of IMPC is from
48 to 62 years, consistent with that of IMPC is characterized by cell clusters arranged
patients with estrogen receptor (ER) in pseudopapillary structures, devoid of fibrovas-
positive IBC. cular cores and surrounded by clear stromal spaces,
• Sex delineated by delicate fibers of a fibro-collagenous
IMPC usually affects women, but single cases stroma (Fig. 1a. H&E: shows the low power pattern
of male IMPC had been reported. In studies on of IMPC). The empty spaces surrounding the
male breast cancer, the reported incidence of tumor cell morules resemble lymphatic channels
IBC with micropapillary features varies but lack endothelial lining (Fig. 1b. H&E: lack of
between 0% and 11%. endothelial lining of stromal spaces).
• Site The amount of a micropapillary component
No specific site within the breast parenchyma required for the diagnosis of IMPC in a tumor is
was identified for these tumors. not yet established. Some authors have used the
• Treatment diagnosis of IMPC in tumors with at least a 50%
Currently stage I and II tumors are treated as micropapillary component, while others require
IBC of no special type (IBC NST) (▶ Invasive that the entire tumor should demonstrate the char-
I
Carcinoma NST); however there are some sug- acteristic micropapillary growth pattern in order
gestions that modification of current to be diagnosed as pure IMPC. For practical
locoregional treatment would be beneficial in reasons at least 75% of the tumor should demon-
cases of IMPC: wider surgical margins and strate the characteristic micropapillary growth in
more aggressive axillary and supraclavicular order to be characterized as pure IMPC. There are
management would enhance local disease con- some suggestions that IBC with any well-defined
trol (Yu et al. 2015). micropapillary carcinoma component should pro-
• Outcome mpt the diagnosis of IMPC and the percentage of
Since the incidence of IMPC is low, studies the micropapillary component clearly stated in the
on its outcome are sparse. It seems that pathology report (Yi-Ling et al. 2016) (Fig. 2.
despite the reported unfavorable tumor char- H&E: mixed IBC NST and IMPC).
acteristics of IMPC (higher nuclear grade, The tumor cells of IMPC usually have eosino-
frequent lymphovascular invasion (LVI), philic cytoplasm, and they demonstrate a charac-
lymph node metastases (LNM), and extra- teristic reverse polarity (“inside-out” pattern): the
capsular spread) (Chen et al. 2014; Yu et al. apical surface of the cells facing the empty stromal
2015) the overall prognosis of IMPC patients spaces and not the central pseudolumen, if pre-
in multivariate analysis – when stratified for sent. In some cases apocrine features can be iden-
number of positive lymph nodes and other tified. True tubule formation is lacking; nuclear
prognostic factors – is comparable to that of pleomorphism is only rarely pronounced. Number
IBC NST patients (Yu et al. 2015). of mitoses is usually low to moderate. Most
According to Chen’s study of 624 patients IMPCs are grade 2 or 3 lesions. Necrosis, tumor
with IMPC, the prognosis is poor if the tumor infiltrating lymphocytes (TILs) are not common.
is ER negative. Peritumoral LVI is detected in up to 70% of
IMPC cases, while the LVI rate of IBC NST cases
is 20% (Gruel 2014). It seems that neither the
Macroscopy tumor size alone nor the extent of the micro-
papillary component but the presence of the
IMPCs do not have any particular features on micropapillary pattern correlates with the agg-
grossing. The reported mean tumor size is between ressive locoregional presentation of the tumor
1.5 cm and 3.9 cm, not significantly different from (Yi-Ling et al. 2016).
that of IBC NST (▶ Invasive Carcinoma NST) The majority of patients – up to 84% – present
(Yi-Ling et al. 2016). with axillary LNM at initial diagnosis. This rate is
Invasive Micropapillary Carcinoma, Fig. 1 A: Low power pattern of IMPC (H&E); B: Lack of endothelial lining of
stromal spaces around the morule-like clusters formed by tumor cells (H&E)
significantly higher than that of IBC NST patients American Pathologists (CAP) 2013 guidelines for
with LNM, and the number of lymph nodes HER2 testing suggest that micropapillary carci-
involved by metastatic disease is also higher in noma with HER2 immunohistochemistry staining
IMPC than in IBC NST cases. that is intense but incomplete (basolateral or
Associated intraductal carcinoma (DCIS) U-shaped) and therefore would be considered
(▶ Ductal Carcinoma In Situ) is usually of micro- score 1+ may actually be amplified by fluorescent
papillary architecture with high-grade nuclei. in situ hybridization (FISH). Thus the guideline
Necrosis and microcalcifications may also be recommends that these IMPC cases should be
present. reported as equivocal (score 2+), and alternative
testing should be carried out. This recommendation
of the 2013 ASCO/CAP guideline was based solely
Immunophenotype on the results of a single study, which was
reinforced later by others.
IMPC is frequently positive for ER (66–94%) and Epithelial membrane antigen (EMA) or mucin
progesterone receptor (PR) (50–84%). The prog- 1 (MUC1 [CD227]) is a high-molecular weight
nosis of ER-negative IMPCs is usually poor. In (>400 kDa), type I membrane-tethered glycopro-
reported series to date, basal cytokeratins are not tein that may serve to demonstrate the reverse
expressed in IMPCs. Pure IMPCs are likely to polarity of IMPC cells by staining the apical sur-
have high Ki67 index, and cyclin D1 is also highly face of tumor cells facing the empty stromal
expressed (Marchiò et al. 2008). spaces (Fig. 3a: EMA immunohistochemistry
The reported incidence of HER2-positive IMPC showing positive reaction at the periphery of
is inconsistent, which varies between 8.3% and the morule-like micropapillary tumor cell clusters
95% (Yi-Ling et al. 2016). The American Society highlighting their inverse polarity in a pure IMPC
of Clinical Oncology (ASCO) and the College of case and Fig. 3b, in the IMPC component of a
The genes SEC63 and FOXO3 were found to

be downregulated in IMPCs; their protein prod-
ucts play a role in cell polarity control. SEC63
protein also plays a role in trafficking of proteins
in ciliogenesis. FOXO3 regulates LKB1 tran-
scription. LKB1 protein has a role in maintaining
cell polarity during cell division. These findings
suggest the possible role of SEC63 and FOXO3 in
altered polarity of IMPC cells (Gruel et al. 2014).
The most frequent amplifications were found
on chromosome 17q22-q23.3. The second most
common region recurrently amplified was the
ERBB2 region (Gruel 2014). MYC amplification,
compared to IBC NST cases, is significantly more
common in pure IMPC. An interesting observa-
tion was, that despite these tumors belonging to
the luminal molecular subtype, ESR1 amplifica-
I
tion is not a common genomic alteration (Marchiò
et al. 2008).
Consistent with the frequent ER expression
Invasive Micropapillary Carcinoma, Fig. 2 Mixed observed in IMPCs, microarray-based gene
breast carcinoma: IBC NST and IMPC (H&E)
expression profiling also revealed that these
tumors frequently harbor genetic aberrations
mixed breast carcinoma). High expression of vas- similar to those detected in IBCs of the luminal
cular endothelial growth factor (VEGF)-C and B subtype (Natrajan et al. 2014).
VEGF-receptor-3 by IMPC cells facilitates LNM When analyzing the transcriptomes of IMPC
by increasing lymphatic vessel density. cases by deep sequencing, 45 microRNAs
(miRNA) were shown differently expressed in
IMPC and in IBC NST. A miRNA-specific RT
Molecular Features qPCR-based analysis revealed significant differ-
ences of let-7b, miR-30c, miR-148a, miR-181a,
Genetic heterogeneity is a characteristic feature of and miR-181b expression levels between IMPCs
IMPCs. Some cases show duplication or deletion and IBC NSTs (Li et al. 2012).
of long segments of a few chromosomes, or mul- Promoter hypermethylation of leucine zipper
tiple segments of duplications and deletions may putative tumor suppressor 1 (LZTS1), located on
be present throughout the whole genome, or mul- 8p – leading to downregulation of the gene – is
tiple amplicons on single chromosome arms may frequently observed in IMPCs associated with
be identified (Marchiò et al. 2008). LNM (Wang et al. 2015).
Microarray-based comparative genomic hybrid-
ization studies demonstrated that pure IMPCs and
IBC NST cases with micropapillary features are Differential Diagnosis
remarkably similar and harbor genetic alterations
distinct from that of grade- and ER-matched cases IMPC should be distinguished from ▶ mucinous
of IBC NST (▶ Invasive Carcinoma NST). Recur- carcinoma, which displays abundant extracellular
rent gains in regions of 8p, 8q, 17q, and 20q, while mucin, absent in IMPC. Invasive micropapillary
losses of 1p, 8p, 13q, and 20q, were more prevalent carcinoma with mucinous differentiation (Fig. 4a
in IMPC than in IBC NST (Marchiò et al. 2009; Li H&E) and invasive mucinous carcinoma with
et al. 2012; Wang et al. 2015). micropapillary carcinoma growth pattern
Invasive Micropapillary Carcinoma, Fig. 3 EMA of cancer cells and (B) of a mixed IBC NST and IMPC,
immunohistochemical reaction (A) of a pure IMPC with where the characteristic pattern of EMA positivity high-
EMA positivity at the periphery of the morule-like micro- lights the IMPC component of the tumor
papillary tumor cell clusters showing the inverse polarity
Invasive Micropapillary Carcinoma, Fig. 4 A: IMPC with mucinous differentiation (H&E); B: Invasive mucinous
carcinoma with IMPC growth pattern (IMMPC) (H&E)
(IMMPC) (Fig. 4b H&E) are relatively newly References and Further Reading
described entities.
Serous ovarian carcinoma metastatic to the breast Chen, A. C., Paulino, A. C., Schwartz, M. R.,
Rodriguez, A. A., Bass, B. L., Chang, J. C., &
may mimic the histological features of IMPC and
Teh, B. S. (2014). Population-based comparison of
usually also displays lymphatic tumor emboli. How- prognostic factors in invasive micropapillary and inva-
ever, the presence of psammoma bodies and the sive ductal carcinoma of the breast. British Journal of
immunoreactivity for WT1 together with the clinical Cancer, 111, 619–622.
Fisher, E. R., Palekar, A. S., Redmond, C., Barton, B., &
history may assist to make the right diagnosis. The
Fisher, B. (1980). Pathologic findings from the
caveat here is that IMPCs may express WT1, albeit National Surgical Adjuvant Breast Project (protocol
infrequently (Lee et al. 2007). no. 4). VI. Invasive papillary cancer. American Journal
IMPC should be distinguished from IBC NST of Clinical Pathology, 73, 313–322.
Gruel, N., Benhamo, V., Bhalshankar, J., Popova, T.,
(▶ Invasive Carcinoma NST) with widespread
Freneaux, P., Arnould, L., Mariani, O., Stern, M. H.,
lymphovascular invasion. Although the clear Raynal, V., Sastre-Garau, X., Rouzier, R., Delattre, O.,
spaces around the morule-like clusters of IMPC & Vincent-Salomon, A. (2014). Polarity gene alter-
cells resemble lymphatic channels, they are ations in pure invasive micropapillary carcinomas of
the breast. Breast Cancer Research, 16, R46. https://
devoid of endothelial cell lining. The characteris-
doi.org/10.1186/bcr3653
tic reverse polarity of IMPC cells is usually not Lee, A. H., Paish, E. C., Marchio, C., Sapino, A., I
observed in IBC NST. Schmitt, F. C., Ellis, I. O., & Reis-Filho, J. S. (2007).
It is important that widespread retraction arti- The expression of Wilms’ tumour-1 and Ca125 in
invasive micropapillary carcinoma of the breast.
fact be not overdiagnosed as IMPC.
Histopathology, 51(6), 824–828.
Li, S., Yang, C., Zhai, L., Zhang, W., Yu, J., Gu, F.,
Fact sheet
Lang, R., Fan, Y., Gong, M., Zhang, X., & Fu, L.
Definition (2012). Deep sequencing reveals small RNA charac-
Rare type of invasive breast cancer displaying tumor terization of invasive micropapillary carcinomas of the
cell clusters in empty spaces. The tumor cells have breast. Breast Cancer Research and Treatment, 136(1),
inverse polarity. 77–87.
Microscopy Marchiò, C., Iravani, M., Natrajan, R., Lambros, M. B.,
The inverse polarity of tumor cells can be Savage, K., Tamber, N., Fenwick, K., Mackay, A.,
demonstrated by EMA immunohistochemistry. Senetta, R., Di Palma, S., Schmitt, F. C., Bussolati, G.,
The cells may form morule-like clusters or Ellis, I. O., Ashworth, A., Sapino, A., & Reis-Filho, J. S.
pseudotubules. (2008). Genomic and immunophenotypical characteri-
Lymphovascular invasion is a common feature. zation of pure micropapillary carcinomas of the breast.
Immunohistochemistry The Journal of Pathology, 215, 398–410.
IMPCs are usually ER/PR positive. Some cases belong Marchiò, C., Iravani, M., Natrajan, R., Lambros, M. B.,
to the HER2-positive subtype. Few IMPCs belong to the Geyer, F. C., Savage, K., Parry, S., Tamber, N.,
triple-negative non-basal group of breast carcinomas. Fenwick, K., Mackay, A., Schmitt, F. C., Bussolati, G.,
Ellis, I., Ashworth, A., Sapino, A., & Reis-Filho, J. S.
Molecular features
(2009). Mixed micropapillary-ductal carcinomas of the
IMPCs are characterized by genetic heterogeneity.
breast: A genomic and immunohistochemical analysis
Gains and losses of large chromosomal segments are
of morphologically distinct components. The Journal
common. Genes responsible for cell polarity were found
of Pathology, 218(3), 301–315.
to be downregulated.
Natrajan, R., Wilkerson, P. M., Marchiò, C., Piscuoglio, S.,
Treatment Ng, C. K., Wai, P., Lambros, M. B., Samartzis, E. P.,
Wide excision with sentinel lymph node (▶ Sentinel Dedes, K. J., Frankum, J., Bajrami, I., Kopec, A.,
Node) biopsy. IMPCs are more likely to develop axillary Mackay, A., A’Hern, R., Fenwick, K., Kozarewa, I.,
LN metastases than IBC NSTs. Hakas, J., Mitsopoulos, C., Hardisson, D., Lord, C. J.,
Outcome Kumar-Sinha, C., Ashworth, A., Weigelt, B., Sapino, A.,
According to recent large studies with follow-up data, the Chinnaiyan, A. M., Maher, C. A., & Reis-Filho, J. S.
outcome is not worse than that of stage-matched ER-positive (2014). Characterization of the genomic features and
IBC NSTs. ER-negative IMPCs have poor prognosis. expressed fusion genes in micropapillary carcinomas of
Differential diagnosis the breast. The Journal of Pathology, 232(5), 553–565.
Widespread lymphovascular invasion in IBC NST Peterse, J. L. (1993). Breast carcinomas with an
Mucinous carcinoma with micropapillary features unexpected inside-out growth pattern: rotation of
Metastatic serous papillary ovarian carcinoma polarization associated with angioinvasion. (Abstract).
Retraction artifact in poorly fixed specimens Pathology Research and Practice, 189, 780.
234 Invasive Mucinous Carcinoma
Siriaunkgul, S., & Tavassoli, F. A. (1993). Invasive micro- diagnosis of MC, the mucinous component should
papillary carcinoma of the breast. Modern Pathology, represent over 90% of the tumor (Harris
6, 660–662.
Wang, X. X., Liu, B. B., Wu, X., Su, D., Zhu, Z., & Fu, L. et al. 2011).
(2015). Loss of leucine zipper putative tumor supp-
ressor 1 (LZTS1) expression contributes to lymph
node metastasis of breast invasive micropapillary car- Clinical Features
cinoma. Pathology Oncology Research: POR, 21(4),
1021–1026.
Weigelt, B., Horlings, H. M., Kreike, B., Hayes, M. M., • Incidence
Hauptmann, M., Wessels, L. F. A., de Jong, D., Van de Pure mucinous carcinoma (PMC) of the breast
Vijver, M. J., Van’t Veer, L. J., & Peterse, J. L. (2008). represents one of the rarest subgroups (Park
Refinement of breast cancer classification by molecular
characterization of histological special types. The Jour- et al. 2010) and accounts for approximately
nal of Pathology, 216, 141–150. 2% of all breast carcinomas (Bussolati and
Yi-Ling, Y., Bing-Bing, L., Xinmin, Z., & Li, F. (2016). Sapino 2012; Harris et al. 2011).
Invasive micropapillary carcinoma of the breast: An • Age
update. Archives of Pathology and Laboratory Medi-
cine, 140, 799–805. Compared to conventional invasive breast
Yu, J. I., Choi, D. H., Huh, S. J., Cho, E. Y., Kim, K., carcinoma, PMC tends to affect an older pop-
Chie, E. K., Ha, S. W., Park, I. A., Ahn, S. J., Lee, J. S., ulation, typically in the postmenopausal age
Shin, K. H., Kwon, Y., Kim, Y. B., Suh, C. O., group (Park et al. 2010).
Koo, J. S., Kim, J. H., Jeong, B. G., Kim, I. A.,
Lee, J. H., & Park, W. (2015). Differences in prognostic • Sex
factors and failure patterns between invasive micro- While MC of the breast primarily affects
papillary carcinoma and carcinoma with micropapillary women, isolated case reports of male breast
component versus invasive ductal carcinoma of the MC exist. Furthermore, some of these
breast: Retrospective Multicenter Case-Control Study
(KROG 13-06). Clinical Breast Cancer, 15, 353-361. cases of male breast MC have presented
e351-352. with metastasis to axillary lymph nodes.
Metastasis to the lung has also been
documented.
• Symptoms and Imaging Findings
Invasive Mucinous Carcinoma The presentation is similar to other breast carci-
nomas. Patients typically present with a palpable
James S. DeGaetano and Ian Said Huntingford mass. Not surprisingly, the radiological findings
Pathology Department, Mater Dei Hospital, can mimic those of a benign neoplasm, typically
Msida, Malta presenting as a lobulated and well-circumscribed
lesion (Park et al. 2010). The majority of tumors
show high signal intensity on T2 weighted and
Synonyms short tau inversion recovery (STIR) magnetic
resonance imaging (MRI). This is due to the
Colloid carcinoma; Gelatinous carcinoma; high water content owing to the copious amounts
Mucinous adenocarcinoma; Mucoid carcinoma of extracellular mucin seen in such lesions.
• Treatment
By definition, these are rare cancers hence most
Definition of the data on management is based on smaller
case series as well as isolated case reports. Man-
Mucinous carcinoma (MC) of the breast forms part agement is usually no different to the more
of the special type of breast cancers and common invasive breast carcinoma of no spe-
is characterized histologically by aggregates or cial type (IBC NST) (▶ Invasive Carcinoma
clusters of typically uniform cells floating within NST). Breast conserving therapy is typically
copious amounts of extracellular mucin (Bussolati undertaken, interestingly with a similar rate of
and Sapino 2012). In order to qualify for a local recurrence compared to IBC NST. Since
Invasive Mucinous Carcinoma 235
PMC is regarded to have a good prognosis, the size does not have such an important impact on
need to undergo axillary dissection was histori- overall prognosis, since there typically is over-
cally a rather contentious issue; although, this is estimation of tumor size owing to the presence
less so given that most patients undergo sentinel of abundant extra-cellular mucin. Other studies
node (▶ Sentinel Node) biopsy in the first (Di Saverio et al. 2008) still utilize tumor size as
instance, ultimately dictating whether axillary an independent prognostic factor, although it
dissection is required (Dieci et al. 2014). The has less relevance compared to nodal status
National Comprehensive Cancer Network and stage. When compared to IBC NST
(NCCN) guidelines state that adjuvant endo- (▶ Invasive Carcinoma NST), MC displays bet-
crine therapy should be considered if the case ter disease-free survival; however, overall sur-
is hormone receptor (HR) (▶ Hormone Recep- vival appears to be similar.
tors in Breast Cancer) positive, node negative A study (Tseng et al. 2013) retrospectively
(or nodal metastasis size is equal to or less than reviewed 93 cases of PMC and amongst other
2 mm), and the tumor size is less than 3 cm. If aspects looked at the effects that the various
the tumor size is less than 1 cm, then adjuvant clinicopathological features had on disease-
endocrine therapy is mainly indicated for risk free and overall survival. These factors
reduction. If the tumor size is equal to or greater included age, tumor size, grade (I vs. II), HR
I
than 3 cm, then endocrine therapy is definitely status, HER2 status, primary treatment status
recommended. If the tumor is HR positive yet (mastectomy vs. lumpectomy with and without
there is ipsilateral axillary nodal involvement radiotherapy), as well as systemic therapy
(one or more ipsilateral metastases greater than (endocrine therapy alone vs. with chemother-
2 mm), then adjuvant chemotherapy may be apy). A univariate analysis of these character-
indicated in addition to adjuvant endocrine ther- istics interestingly revealed that none of these
apy. In the context of HR negative cases, the HR factors had an impact on survival.
status should be re-evaluated, and if it is It is important to distinguish between PMC
reconfirmed that the case is HR negative, then and mixed mucinous carcinoma (MMC), since
the treatment follows that of IBC NST (NCCN the prognosis between the two is different. Stud-
2017). ies have estimated the 10 year survival rate of
• Outcome PMC to be 90.4% while that of MMC to be 66%.
PMC has an excellent prognosis with a low rate The importance of this distinction is further
of local recurrence and a 5-year disease-free highlighted since MMC demonstrates a higher
survival rate ranging from 81% to 94%. The rate of recurrence. The study also confirmed that
disease-specific survival rate is quoted at in particular MC, Type A, with a high mucin
95.3%, while the overall 5-year survival rate is content has a favorable prognosis. When dealing
80%. Lymph node involvement plays an impor- with Type B MC, treatment should be based on
tant role in determining survival rates with the whether there is lymph node involvement or not.
overall 5-year survival rate increasing to 86% if As shall be eluded to later, there is no significant
there is no nodal involvement (Harris et al. difference in survival between the two main his-
2011). Case series have estimated the axillary tological types of PMC: Type A and Type B.
lymph node involvement rate at about 12%
(Di Saverio et al. 2008). The greater the nodal
involvement, the higher the likelihood of death Macroscopy
from malignancy and the greater the risk of
tumor recurrence (Harris et al. 2011). Tumor The typical appearance is that of a gelatinous
size has an impact on the incidence of lymph lesion reflecting the high mucinous component
node involvement, with tumors less than 10 mm (Bussolati and Sapino 2012) (Fig. 1). The tumor
displaying a low risk of lymph node metastasis, size typically ranges from 3 to 120 mm and has an
namely, 0–4%. Some reports show that tumor average dimension of 20 mm (Harris et al. 2011).
Histopathology
MC of the breast is characterized by copious pools
of extraceullar mucin-containing free floating
tumor cells typically arranged as nests, trabeculae,
sheets, or acini. The nuclear grade is usually low
to intermediate (Harris et al. 2011); however, rare
cases with pronounced atypia and mitoses have
been reported (Bussolati and Sapino 2012).
PMC has been traditionally subtyped into Type
A and Type B. Type A is described as the hypo-
cellular variant and displays a variety of architec-
tural pattern ranging from cribriform, tubular,
cord like, papillary, as well as micropapillary
(Fig. 3). Type B is the hypercellular variant and
grows in solid nests (Fig. 3). Type B mucinous
carcinomas often show neuroendocrine differen-
tiation (Capella et al. 1980). The morphological
similarities are also confirmed at molecular level
(Weigelt et al. 2009).
MMC is a well-described entity, and the most
common admixture is with IBC NST (▶ Invasive
Carcinoma NST) and lobular carcinoma
(▶ Invasive Lobular Carcinoma) (Fig. 3).
A particular histological variant, namely, mucin-
ous micropapillary carcinoma (▶ Invasive Micro-
papillary Carcinoma), is associated with higher
Invasive Mucinous Carcinoma, Fig. 1 Classic macro-
scopic appearance of mucinous carcinoma. One can
rates of lymphovascular invasion, lymph node
appreciate the mucinous cut surface involvement, and greater expression of human epi-
dermal growth factor receptor 2 (HER2) positivity.
This entity is characterized by the coexistence of
Microscopy mucinous and micropapillary morphology. Charac-
teristic histological features of this entity include
Role of Fine Needle Aspiration (FNA) Biopsy in the presence of a micropapillary pattern, a mucin-
Diagnosis of Mucinous Carcinoma ous appearance, psammomatous calcifications,
Fine needle aspiration can play an important role hobnailing, and an intermediate/high grade nuclear
in the diagnosis of both PMC and MMC (Cyrta cytology. The study (Barbashina et al. 2013)
et al. 2013). The most common features encoun- described 15 cases and found that 60% of cases
tered on cytology include copious mucin and showed lymphovascular invasion, with 33%
bland nuclear cytology (regular nuclear con- of patients displaying synchronous axillary lymph
tours, small nuclear size) (Fig. 2). If the lesion node involvement.
is mixed, one can expect sparser mucin content
and more pronounced nuclear cytological fea-
tures such as larger nuclei, nuclear contour irreg- Immunophenotype
ularity, and prominent nucleoli. The presence of
necrosis is also suggestive of a mixed mucinous The receptor status profile of MC has also
component. been studied quite intensely. It is typically
Invasive Mucinous Carcinoma, Fig. 2 FNA of mucinous carcinoma (H&E, clockwise, x4, x10, x20, x40). Groups of
fairly monomorphic tumor cells float in a sea of mucinous material
associated with a higher expression rate of Molecular Features

Estrogen receptor (ER) and Progesterone recep-
tor (PR) compared to IBC NST with studies Role of Mucins
suggesting prevalence rates of 73–94% and At a cellular level, it is believed that complex
63–90%, respectively (Fig. 4). There are also rearrangements in glycoproteins occurs in cancer-
lower rates of HER2 expression compared to ous mucinous cells compared to normal ductal
IBC NST quoted at 0–14% (Hugen et al. cells (Adsay et al. 2003). In this study, MUC1
2014). Both PMC and MMC express WT-1 stains highlighted a shift of glycoproteins to the
(Bussolati and Sapino 2012). A study analyzed stroma facing aspects of the cancerous cells com-
the immunohistochemical profile of 40 cases of pared to the typical luminal surface position
mucinous carcinoma (De Andrade et al. 2017) normally seen in ductal epithelial cells. This alter-
with 85% of cases expressing either GCDFP15 ation in position probably explains the accumula-
and mammoglobin. No cases expressed CDX-2, tion of mucin within stroma in mucinous
while the Type B mucinous carcinomas showed carcinoma. Within the neoplastic cells, mucigen
higher expression rates of Ki67 and were more granules also adopted a clustered configuration.
likely to express markers of neuroendocrine dif- The type of mucin expressed is MUC2, which
ferentiation (Fig. 5). might also explain the more indolent nature of
Invasive Mucinous Carcinoma, Fig. 3 Types and pat- C), mucinous carcinoma solid papillary architecture (H&E,
terns of mucinous carcinoma. Mucinous carcinoma B), mucinous carcinoma with invasive breast carcinoma
Type A (H&E, A), mucinous carcinoma Type B (H&E, (H&E, D)
Invasive Mucinous Carcinoma, Fig. 4 Diffuse, strong ER positivity (A); diffuse, strong PR positivity (B); HER2
negative expression (C); unusual HER2 expression in Type B mucinous carcinoma (D)
mucinous carcinoma since it is believed that differences in MUC protein expression profiles
MUC2 has tumor suppressor activity and forms between the two types of MC. Type A breast
a rather viscid tumor environment perhaps mucinous carcinoma shows luminal and apical
inhibiting spread of cancer cells. There are even expression of MUC proteins, while the expression
Invasive Mucinous Carcinoma, Fig. 5 Mucinous (B). Mucinous carcinoma Type B neuroendocrine marker
carcinoma Type A Ki67 proliferation index (A). expression (Synaptophysin (C) and Chromogranin (D))
Mucinous carcinoma Type B Ki67 proliferation index
profile in Type B is membrano-cytoplasmic. Inter- breast MC, which is a similar finding in various
estingly MUC2 expression is inversely associated other types of cancers including prostate, colon,
with the rate of lymph node involvement and bladder, amongst others (Feng et al. 2013).
lymphovascular invasion in non-mucinous inva- miR-143 downregulation is also associated with
sive carcinomas. MUC6 expression is also asso- mucinous phenotype within colon cancer, hence it
ciated with MC (Rakha et al. 2005). is plausible to consider miR-143 downregulation
The pathogenesis of MC is also thought to as an important common factor in the mucinous
result from altered expression of MUC2 within cancer pathway. Interestingly, unlike in colonic
normal breast tissue. The study also concluded mucinous cancer, microsatellite instability is not
that out of all mucins it is MUC1 and MUC3 a prevalent occurrence (Hugen et al. 2014).
which have the most profound impact on out- Studies have shown that specialized breast
come. MUC1 expression appears to be associated cancers typically adopt a particular category of
with a better prognosis mostly because it is molecular profiling with mucinous cancer
associated with more well differentiated neo- expressing a luminal phenotype (Weigelt et al.
plasms. Tumors expressing MUC3 (membranous 2010). As has already been stated, there is consid-
staining) tend to have a higher rate of lymph node erable overlap between Type B mucinous carci-
involvement and local recurrence as well as being noma and neuroendocrine carcinoma (▶ Invasive
associated with poorer histological parameters Carcinoma with Neuroendocrine Differentiation),
(such as worse grade) (Rakha et al. 2005). and this is mirrored at the genetic level, with both
types of tumors exhibiting identical genomic
Molecular Profile profiles (Weigelt et al. 2009). They are also
MicroRNA has been the subject of intense genomically distinct from conventional IBC
research and is enabling us to better understand NST (▶ Invasive Carcinoma NST) (Lacroix-
the molecular pathways involved in cancer. There Triki et al. 2010). The pure variant typically
is downregulation of miR-143 and miR-224-5p in shows genetic stability and characteristically
lacks 1q gain and 16q loss which is typically seen Hruban, R. H., & Klimstra, D. S. (2003). Pathogenesis
in low grade IBC NST (Lacroix-Triki et al. 2010; of colloid (pure mucinous) carcinoma of exocrine
organs: Coupling of gel-forming mucin (MUC2)
Dieci et al. 2014; Hugen et al. 2014). They also production with altered cell polarity and abnormal
demonstrate a low incidence of PIK3CA muta- cell-stroma interaction may be the key factor in the
tions (Dieci et al. 2014). Studies which carried out morphogenesis and indolent behavior of colloid carci-
hierarchical molecular clustering revealed that noma carcinoma in the breast and pancreas. American
even mixed mucinous carcinomas are Barbashina, V., Corben, A. D., Akram, M., Vallejo, C., & Tan,
genomically very similar to pure mucinous carci- L. K. (2013). Mucinous micropapillary carcinoma of
noma rather than IBC NSTs (Lacroix-Triki the breast: An aggressive counterpart to conventional
et al. 2010). pure mucinous tumors. Human Pathology, 44,
1577–1585.
Bussolati, G., & Sapino, A. (2012). Mucinous carcinoma
and carcinomas with signet-ring-cell differentiation.
Differential Diagnosis In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H. Tan, &
M. J. van de Vijver (Eds.), WHO classification of
tumours of the breast (pp. 60–61). Lyon: IARC Press.
The differential diagnosis of mucinous carcinoma Capella, C., Eusebi, V., Mann, B., & Azzopardi, J. G.
typically includes the following: Mucocele-like (1980). Endocrine differentiation in mucoid carcinoma
lesion (▶ Mucocele-like Lesion), Mucinous of the breast. Histopathology, 6, 174–188.
DCIS, CIS with mucocele-like lesion and signet Cyrta, J., Andreiuolo, F., Azoulay, S., Balleyguier, C.,
Bourgier, C., Mazouni, C., Mathieu, M. C.,
ring cell carcinoma (▶ Invasive Carcinoma with Delaloge, S., & Vielh, P. (2013). Pure and mixed
Signet Ring Cell Differentiation). A newly mucinous carcinoma of the breast: Fine needle aspira-
described entity of invasive lobular carcinoma tion cytology findings and review of the literature.
(ILC) (▶ Invasive Lobular Carcinoma) with Cytopathology, 24, 377–384.
De Andrade, N. R., Derchain, S. F., Pavanello, M.,
extracellular mucin production certainly enters Paiva, G. R., Sarian, L. O., & Vassallo, J. (2017).
into the differential diagnosis. This entity can be Expression of unusual immunohistochemical markers
easily confused with mucinous carcinoma in mucinous breast carcinoma. Acta Histochemica, 119,
exhibiting a separate lobular component. Obvi- 327–336.
Di Saverio, S. D., Guitierrez, J., & Avisar, E. (2008).
ously if one overlooks the lobular component, A retrospective review with long term follow up of
then an incorrect diagnosis of PMC can easily be 11,400 cases of pure mucinous breast carcinoma.
made. There do exist a number of useful histolog- Breast Cancer Reserch and Treatment, 111, 541–547.
ical clues when making a diagnosis of this entity. Dieci, M. V., Orvieto, E., Dominici, M., Conte, P., &
Guarnieri, V. (2014). Rare breast cancer subtypes:
These include the presence of classical ILC Histological, molecular,and clinical peculiarities.
(▶ Invasive Lobular Carcinoma) around and not The Oncologist, 19, 805–881.
necessarily within the mucinous lakes. The iden- Feng, Z., Shuai, L., Meng, H.-M., Li-Qiang, Q., &
tification of lobular neoplasia (▶ Lobular In Situ Lin, G. (2013). MicroRNA and histopathological
characterization of pure mucinous breast carcinoma.
Neoplasia) is another helpful feature. Also impor- Cancer Biology and Medicine, 10, 22–27.
tant is the lack of E-cadherin staining, and cyto- Harris, G. C., O’Malley, F. P., & Pinder, S. E. (2011).
plasmic expression of p120 by tumor cells in the Invasive carcinoma: Special Types. In F. P. O’Malley,
mucinous areas. One may also include solid pap- S. E. Pinder, & A. M. Mulligan (Eds.), Breast
pathology: A volume in the foundations in diagnostic
illary carcinoma (SPC) (▶ Solid Papillary Carci- pathology series (2nd ed., pp. 235–237). London:
noma) in the differential diagnosis since there may Elsevier Saunders.
be co-existing mucin, and it is not unusual for Hugen, N., Simons, M., Halilovic, A., Van der Post, R. S.,
SPC to demonstrate neuroendocrine differentia- Bogers, A. J., Marijnissen-Van Zanten, M. A. J., de Wilt,
J. H. W., & Nagtegaal, I. D. (2014). The molecular
tion similar to Type B MC. background of mucinous carcinoma beyond MUC2.
The Journal of Pathology: Clinical Research, 1, 3–17.
Lacroix-Triki, M., Suarez, P. H., MacKay, A.,
Lambros, M. B., Natrajan, R., Savage, K.,
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Invasive Oncocytic Carcinoma 241
National Comprehensive Cancer Network, Clinical Oncocyte is a Greek term, first applied to sal-
Practice Guidelines in Oncology. NCCN guidelines, ivary glands by Hamperl (1931) in 1931, which
Breast Cancer v2.2.2017. Available at http://www.
nccn.org/professionals/physician_gls/pdf/breast.pdf. means “swollen cell.” Under light microscope,
Accessed 15 Aug 2017. oncocytes are characterized by abundant granular
Park, S., Koo, J., Kim, J. H., Yang, W. I., Park, B. W., & eosinophilic cytoplasm due to a high content of
Lee, K. S. (2010). Clinicopathological characteristics mitochondria, demonstrable at ultrastructural
of mucinous carcinoma of the breast in Korea:
Comparison with invasive ductal carcinoma-not other- level (Roth et al. 1962). By definition, mitochon-
wise specified. Journal of Korean Medical Science, 25, dria must occupy at least 60% of the total cyto-
361–368. plasmic volume (Ghadially 1985) and confer an
Rakha, E. A., Boyce, R. W. G., Abd El-Rehim, D., intense cytoplasmic granular positivity for anti-
Kurien, T., Green, A. R., Paish, E. C.,
Robertson, J. F. R., & Ellis, I. O. (2005). Expression of mitochondrion antibody (Damiani et al. 1998;
mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and Ragazzi et al. 2011). Namely, a carcinoma can
MUC6) and their prognostic significance in human be classified as oncocytic if it shows a strong
breast cancer. Modern Pathology, 18, 1295–1304. cytoplasmic positivity for anti-mitochondrion
Tseng, H. S., Lin, C., Chan, S. E., Chien, S. Y., Kuo, S. J.,
Chen, S. T., Chang, T. W., & Chen, D. R. (2013). antibody in at least 70% of tumor cells.
Pure mucinous carcinoma of the breast. World Journal
of Surgical Oncology, 11, 139.
Weigelt, B., Geyer, F. C., Horlings, H. M., Kreike, B., I
Clinical Features
Halfwerk, H., & Reis-Filho, J. S. (2009). Mucinous
and neuroendocrine breast carcinomas are transcrip-
tionally distinct from invasive ductal carcinomas of • Incidence
no special type. Modern Pathology, 22, 1401–1414. This tumor is considered very rare, but is
Weigelt, B., Geyer, F. C., & Reis-Filho, J. S. (2010). suspected to be overlooked, and probably mis-
Histological types of breast cancer: How special are
they? Molecular Oncology, 4, 192–208. diagnosed as apocrine carcinoma. The largest
series on record retrospectively evaluating
76 consecutive breast carcinomas using immu-
nohistochemistry for anti-mitochondrion
antibody reported an incidence of 19.6%
Invasive Oncocytic Carcinoma (Ragazzi et al. 2011).
• Age
Dario de Biase1 and Moira Ragazzi2 Patient age ranges from 26 to 94 years with an
1
Department of Pharmacy and Biotechnology, average age at presentation of 67 years (Costa
University of Bologna, Bologna, Italy and Silverberg 1989; Damiani et al. 1998;
2
Department of Oncology and Advanced Ragazzi et al. 2011; Marla et al. 2013; Itagaki
Technologies, Operative Unit of Pathology, et al. 2017).
Azienda USL-IRCCS, Reggio Emilia, Italy • Sex
Thirty-seven cases of invasive oncocytic carci-
noma have been reported in English-language
Synonyms literature. Among them, four cases occurred
in men.
Malignant oncocytoma • Site
All breast quadrants can be affected and a
multifocal and bilateral case has also been
Definition reported (Itagaki et al. 2017).
• Treatment
Invasive oncocytic carcinoma (OC) is a “special Clinical features of oncocytic carcinomas are
type” of breast carcinoma that is composed of at similar to those of invasive carcinomas, no
least 70% of cells with oncocytic features special type (NST) (▶ Invasive Carcinoma
(so-called oncocytes) on both morphologic and NST) (Ragazzi et al. 2011). Thus, the thera-
immunophenotypic grounds (Lakhani et al. 2012). peutic strategies are the same. Resistance to
242 Invasive Oncocytic Carcinoma
radiotherapy has been hypothesized just as it pushing (Fig. 1). The main difference between OC
has been reported in oncocytic tumors at other and carcinoma NST resides in cytologic features.
sites, including the rectum, thyroid, and menin- OCs are typically composed of large polygonal
ges, but it has been never investigated in the cells with abundant granular eosinophilic cyto-
breast. plasm, neat cytoplasmic borders, centrally located
• Outcome nuclei, and prominent nucleoli (Fig. 2).
Presently, knowledge available on the prog- A moderate to marked nuclear pleomorphism is
nostic impact of oncocytic differentiation in often observed. Coherently, OCs are mostly grade
breast carcinomas is scant. According to the 3 (53%) according to the Nottingham scoring
largest series reported (Ragazzi et al. 2011), system, but they can be also grade 2 (36%),
prognosis depends on grading and staging while a minority of cases is grade 1 (11%).
and is similar to the matched breast carcinomas A discrete lymphoid infiltrate can be also seen in
NST (▶ Invasive Carcinoma NST). the majority of cases. Invasive carcinoma is asso-
ciated with an in situ component in a prevalence
of cases.
Macroscopy
In a retrospective series, tumors with oncocytic
features were originally diagnosed as invasive car-
Tumor size ranges from 0.8 to 9 cm (mean 3 cm).
cinoma NST in the majority of patients (78%) but
On cut section, OCs are mainly well-defined, solid,
special-types were also present including pure
and firm, from whitish to tan brown nodules.
mucinous carcinomas (▶ Invasive Mucinous Car-
cinoma), apocrine (▶ Apocrine Carcinoma), and
neuroendocrine carcinomas (▶ Invasive Carci-
Microscopy
noma with Neuroendocrine Differentiation)
(Ragazzi et al. 2011). One tall cell variant of pap-
OC shows the spectrum of different architectural
illary breast carcinoma (▶ Tall Cell Variant of Pap-
patterns seen in invasive carcinoma NST (▶ Inva-
illary Breast Carcinoma) was also reported in that
sive Carcinoma NST), even if a solid growth
series (Fig. 3). In these mixed cases, aspects of both
pattern with nests, sheets, and cords is
differentiations usually coexist.
characteristic. Tumor margins are more frequently
Invasive Oncocytic
Carcinoma,
Fig. 1 Invasive oncocytic
carcinoma (OC), low
magnification: Nodule has
typically pushing margins
and solid architecture
(H&E)
Invasive Oncocytic Carcinoma, Fig. 2 Invasive Antimitochondrion antibody shows intense and diffuse
oncocytic carcinoma (OC), higher magnification: (a) Neo- positivity; (c) A discrete lymphocytic infiltrate is often
plastic cells have abundant eosinophilic and finely granular present at the edge of the tumour (H&E); (d) Tumour
cytoplasm, with neat borders, centrally located round cells forming cords in desmoplastic stroma can be seen
nuclei, and prominent nucleoli (H&E); (b) (H&E)
Immunophenotype and basal-type cytokeratins (CK5 or CK5/6)

(Bhargava et al. 2017).
By definition, OCs show an intense and diffuse
anti-mitochondrion antibody positivity in at least
70% of tumor cells (Ragazzi et al. 2011). Molecular Features
In addition, OCs have mostly a “luminal” phe-
notype with expression of CK7, EMA, and con- Using the array comparative genomic hybridiza-
sistent positivity for hormone receptors. HER2 tion (aCGH) technique on a cohort of OCs and
positivity has been detected in 25% of tested mitochondrion-rich breast carcinomas compared
cases. Few triple-negative cases are also on with matched invasive ductal carcinomas NST
record, and in these cases, androgen receptor (▶ Invasive Carcinoma NST), Geyer et al. found
(AR) should be performed to rule-out apocrine that the formers are characterized by gains of
differentiation. Most importantly, a tall cell vari- 5p13.33, 11q13.1-q13.2, 16p13.3, 17q25.3, and
ant of papillary breast carcinoma should be 19p13 (Geyer et al. 2012). These chromosomal
excluded: it is AR negative and can co-express regions host several nuclear genes with mitochon-
luminal-markers (CK7, EMA, GATA 3), S100, drial functions (Geyer et al. 2012). Intriguingly, in
244 Invasive Oncocytic Carcinoma
Invasive Oncocytic Carcinoma, Fig. 3 Tall cell variant composed of columnar cells with abundant granular cyto-
of papillary breast carcinoma: (a) Follicular structures plasm and grooved nuclei (H&E); (c) Tumour cells show
filled with colloid-like material with scalloped borders. intense and diffuse positivity for antimitochondrion anti-
Small papillae are evident as well as some calcifications body (Courtesy of Professor Vincenzo Eusebi)
(H&E). (b) High magnification of a solid structure
the 5p13.33 region, the Telomerase Reverse Tran- notably increase of SOD2 immunostaining in a
scriptase (TERT) gene has been mapped and it has series of OC breast carcinomas compared with
been established that TERT protein can localize to non-OC. These high SOD2 levels seem to be cor-
the mitochondrion and modulate its activity related with the high activity of the SIRT/FOXO/
(Sahin et al. 2011). Based on these data, Geyer SOD2 axis. Moreover, the authors observed that
et al. concluded that OCs of the breast are a group patients with high SOD2 expression tumors had a
of tumors with a distinctive pattern of chromo- significantly worse outcome and that a SOD2 pos-
somal aberrations, previously associated with itive expression correlated with lymph nodal
OCs of other anatomical sites (e.g., oncocytic involvement (Kenny et al. 2017).
tumors of the kidney and thyroid) (Geyer
et al. 2012).
A recent in vitro study, performed on six breast Differential Diagnosis
cancer cell lines, investigated the role of SIRT/
FOXO/SOD2 axis of the mitochondrial unfolded Carcinoma with apocrine differentiation (▶ Apo-
protein response in promoting breast tumor inva- crine Carcinoma): The differential diagnosis
siveness. In the same paper, Kenny et al. found a between OC and carcinomas with apocrine
features is usually difficult on morphology and Eusebi, V., Damiani, S., Ellis, I. O., Azzopardi, J. G., &
mainly relies on immunohistochemistry. Apo- Rosai, J. (2003). Breast tumor resembling the tall cell
variant of papillary thyroid carcinoma: Report of
crine carcinomas are positive for GCDFP-15 and 5 cases. American Journal of Surgical Pathology, 27,
AR, while hormone receptors are typically nega- 1114–1118.
tive and antibodies for mitochondria are seen in Eusebi, V., Tallini, G., & Rosai, J. (2004). Nuclear alter-
cells below 50% of the total neoplastic prolifera- ations and RET/PTC activation. American Journal of
Surgical Pathology, 28, 974–975.
tion. Occasional cases, however, are oncocytic Foschini, M. P., Asioli, S., Foreid, S., Cserni, G., Ellis,
and apocrine at the same time. I. O., Eusebi, V., & Rosai, J. (2017). Solid papillary
Acinic cell carcinoma (ACC) (▶ Acinic Cell breast carcinomas resembling the tall cell variant of
Carcinoma): Granular cytoplasm in ACC is due to papillary thyroid neoplasms: A unique invasive tumor
with indolent behavior. American Journal of Surgical
zymogen granules that are evidenced by PAS after Pathology, 41, 887–895.
diastase digestion. Anti-mitochondrion antibodies Geyer, F. C., de Biase, D., Lambros, M. B., Ragazzi, M.,
are negative. Tumor cells in ACC show serous Lopez-Garcia, M. A., Natrajan, R., Mackay, A.,
differentiation and are positive with salivary type Kurelac, I., Gasparre, G., Ashworth, A., Eusebi, V.,
Reis-Filho, J. S., & Tallini, G. (2012). Genomic profil-
amylase, lysozyme, and alpha-1-antichimotrypsin ing of mitochondrion-rich breast carcinoma: Chromo-
immunostains. In addition, ACC cells are typi- somal changes may be relevant for mitochondria
cally immunoreactive for S-100 and they are triple accumulation and tumour biology. Breast Cancer
Research and Treatment, 132, 15–28. I
negative with no expression of both estrogen and
Ghadially, F. N. (1985). Diagnostic electron microscopy of
progesterone receptors and no Her2 amplification. tumours (2nd ed.). London: Butterworth & Company.
Neuroendocrine carcinoma (▶ Invasive Carci- Hamperl, H. (1931). Beiträge zur normalen und
noma with Neuroendocrine Differentiation): pathologischen Histologie menschlieher
Well-differentiated neuroendocrine carcinoma of Speicheldriisen. Zeitschrift für Mikroskopisch-
Anatomische Forschung, 27, 1–55.
the breast could be very similar to low-grade Itagaki, H., Yamamoto, T., Hiroi, A., Kawanishi, K., Nogu-
OC. Expression of chromogranin and/or syn- chi, E., Ohchi, T., Kamio, T., Kameoka, S., Oda, H., &
aptophysin in the majority of tumor cells is char- Nagashima, Y. (2017). Synchronous and bilateral
acteristic of neuroendocrine differentiation. oncocytic carcinoma of the breast: A case report and
review of the literature. Oncology Letters, 13,
Granular cell tumors (▶ Granular Cell Tumor): 1714–1718.
They are composed of cells with eosinophilic Kenny, T. C., Hart, P., Ragazzi, M., Sersinghe, M., Chipuk,
granular cytoplasm that can mimic oncocytes, J., Sagar, M. A. K., Eliceiri, K. W., LaFramboise, T.,
but they derive from Schwann cells of peripheral Grandhi, S., Santos, J., Riar, A. K., Papa, L., D'Aurello,
M., Manfredi, G., Bonini, M. G., & Germain,
nerves. Accordingly, neoplastic cells in granular D. (2017). Selected mitochondrial DNA landscapes
cell tumors are strongly and diffusely positive for activate the SIRT3 axis of the UPRmt to promote
S100 and CD68 immunostains while they are metastasis. Oncogene, 36, 4393–4404.
negative for keratins. Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van
de Vijver, M. J. (2012). WHO classification of tumours
of the breast (4th ed.). Lyon: IARC.
Marla, N. J., Pai, M. R., Swethadri, G. K., & Fernandes,
References and Further Reading H. (2013). Male breast cancer-review of literature on a
rare microscopic variant (oncocytic carcinoma). Indian
Bhargava, R., Florea, A. V., Pelmus, M., Jones, M. W., Journal of Surgery, 75(Suppl 1), 240–242.
Bonaventura, M., Wald, A., & Nikiforova, M. (2017). Masood, S., Davis, C., & Kubik, M. J. (2012). Changing
Breast tumor resembling tall cell variant of papillary the term “breast tumor resembling the tall cell variant of
thyroid carcinoma: A solid papillary neoplasm with papillary thyroid carcinoma” to “tall cell variant of
characteristic immunohistochemical profile and few papillary breast carcinoma”. Advances in Anatomic
recurrent mutations. American Journal of Clinical Pathology, 19, 108–110.
Pathology, 147, 399–410. Ragazzi, M., de Biase, D., Betts, C. M., Farnedi, A.,
Costa, M. J., & Silverberg, S. G. (1989). Oncocytic carci- Ramadan, S. S., Tallini, G., Reis-Filho, J. S., & Eusebi,
noma of the male breast. Archives of Pathology and V. (2011). Oncocytic carcinoma of the breast: Fre-
Laboratory Medicine, 113, 1396–1399. quency, morphology and follow-up. Human Pathology,
Damiani, S., Eusebi, V., Losi, L., D’Adda, T., & Rosai, 42, 166–175.
J. (1998). Oncocytic carcinoma (malignant Roth, S. I., Olen, E., & Hansen, L. S. (1962). The eosino-
oncocytoma) of the breast. American Journal of Surgi- philic cells of the parathyroid (oxyphil cells), salivary
cal Pathology, 22, 221–230. (oncocytes), and thyroid (Huerthle cells) glands. Light
246 Invasive Secretory Carcinoma
and electron microscopic observations. Laboratory very rarely in the elderly. The age range of
Investigation, 11, 933–941. the reported cases varies from 3 to 91 years.
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L.,
Guo, M., Cooper, M., Kotton, D., Fabian, A. J., • Sex
Walkey, C., Maser, R. S., Tonon, G., Foerster, F., Mainly observed in adult female and children of
Xiong, R., Wang, Y. A., Shukla, S. A., Jaskelioff, M., both sexes, very rare in men over the age of 30.
Martin, E. S., Heffernan, T. P., Protopopov, A., A case in a male-to-female transgender patient
Ivanova, E., Mahoney, J. E., Kost-Alimova, M.,
Perry, S. R., Bronson, R., Liao, R., Mulligan, R., has been described (Grabellus et al. 2005).
Shirihai, O. S., Chin, L., & DePinho, R. A. (2011). • Site
Telomere dysfunction induces metabolic and mito- ISC may appear in any part of the breast; how-
chondrial compromise. Nature, 470, 359–365. ever, a subareolar location is prevalent, particu-
larly in men and children, and frequently
associated with nipple discharge. The usual clin-
ical presentation is a slow growing nodule,
Invasive Secretory Carcinoma mobile, often present for a long time and easily
mistaken with a fibroadenoma (▶ Fibroadenoma)
Angelo Sidoni or a papilloma (▶ Intraductal Papilloma) on
Department of Experimental Medicine, Section of imaging studies. Rare cases are reported in the
Pathologic Anatomy and Histology, Medical axilla, conceivably originating from ectopic
School, University of Perugia, Perugia, Italy breast tissue or from skin appendage glands.
• Treatment
Treatment varies depending on the age and sex
Synonyms of patients. In children, considering the favor-
able prognosis and the need to safeguard the
Juvenile secretory carcinoma, Juvenile breast car- development of the breast, a conservative local
cinoma, Secretory carcinoma. excision is the most advisable treatment. In post-
menarchal girls and women wide local excision,
quadrantectomy, or mastectomy are reported
Definition based on tumor dimensions in order to obtain
negative surgical margins. In males, due to small
Invasive secretory carcinoma (ISC) is one of the dimension of breast, mastectomy is the rule.
rarest histological subtypes of breast cancer, of Sentinel lymph node (▶ Sentinel Node) map-
low-grade and translocation-associated. ISC ping is suggested. No definitive conclusions are
shows distinctive histological features consisting available on the benefits of systemic adjuvant
in intracellular and extracellular production of chemotherapy and radiotherapy.
secretory material. • Outcome
The clinical course of ISC is mainly character-
ized by favorable prognosis and a prolonged
Clinical Features survival, particularly in children and young
adults under 30 years of age, even in presence
• Incidence of lymph node metastasis (rarely are involved
Less than 0.15% of all breast carcinomas more than three lymph nodes). In adult women
(about 200 cases published in English ISC are more aggressive, especially if the
literature). tumor is of high-grade (see below) and locally
• Age advanced, although distant metastases are
Originally described in children and termed exceptional and still correlated with long sur-
“juvenile secretory carcinoma” (McDivitt and vival. Late local recurrence (even after
Stewart 1966), it appears that two thirds of the 20 years) may occur and a prolonged follow-
published cases actually occur in adults and up is necessary.
Invasive Secretory Carcinoma 247
Macroscopy apocrine features are polygonal with abundant

granular and eosinophilic cytoplasm, and their
ISC usually presents as a single firm nodule, with nuclei are round and uniform with discrete nucle-
well-defined smooth contour and a mean diameter oli. Mitotic activity and necrosis are
of 3 cm (range 0.5–12.5). The cut surface may be usually absent. An in situ component is often
lobulated with a central area of fibrosis and a color present with growth patterns similar to those
variable from grayish-white to yellow-tan. Occa- seen in conventional invasive carcinoma of no
sionally margins may be spiculated and the tumor special type, mainly of low grade (cribriform
may show microcystic nature with spongy consis- and papillary), but with the same cytological
tency. Multifocality is very uncommon. features of the ISC. Microcalcifications are rare
or absent.
Both intracellular and extracellular secretory
Microscopy material is diastase-PAS positive (Fig. 4 PAS
staining) and sialidase-Alcian blue (Fig. 5 Alcian
In prototypical ISCs tumor cells are arranged in blue) positive, indicating a composition rich in
varying patterns with a tubular, follicular, micro-
cystic (honeycomb) solid, and papillary architec-
I
ture (Fig. 1 H&E). Fibrous septa crossing the mass
may be present, explaining its lobulated appear-
ance. A striking feature is the presence of abun-
dant extracellular eosinophilic secretory material
reminiscent of thyroid colloid (Fig. 2 H&E).
Tumor borders are usually pushing but infiltrative
growth in the surrounding tissues may be
observed (Fig. 3 H&E).
Tumor cells show a variable combination of
secretory and apocrine features (Koerner 2014).
Secretory cells have a pale cytoplasm with numer-
ous vacuoles containing eosinophilic material.
Nuclei display low-grade features and are small Invasive Secretory Carcinoma, Fig. 2 Honeycomb pat-
and ovoid with inconspicuous nucleoli. Cells with tern resembling thyroid follicles (H&E)
Invasive Secretory Carcinoma, Fig. 1 Coexistence of Invasive Secretory Carcinoma, Fig. 3 Despite the well
solid, microcystic, follicular, tubular, and papillary patterns circumscribed appearance, invasion is present at the border
(H&E) (H&E)
248 Invasive Secretory Carcinoma
clusters partially surrounded by a basal lamina.

Large extracellular spaces are occupied by secre-
tory material.
Concluding the microscopic description of
ISCs, it is worth noting the singular resemblance
of ISC with a newly described salivary gland
tumor named “mammary analogue secretory car-
cinoma” (MASC). As the name implies, this
entity shows morphological, immunohistochemi-
cal, and genetic characteristics similar to those of
the breast counterpart. A cutaneous variant of
secretory carcinoma has been recently proposed
(Bishop et al. 2017).
Invasive Secretory Carcinoma, Fig. 4 Diastase-
periodic-acid-Schiff positivity of extracellular secretory
material
Immunophenotype
Immunohistochemically most of the ISC are

triple-negative (absence of estrogen receptors,
progesterone receptors, and HER2) and positive
for cytokeratin (CK) 5/6 and/or CK14 and for
epidermal growth factor receptor (EGFR), which
confirm a basal-like phenotype. S-100 protein is
typically strongly expressed as well as the signal
transducer and activator of transcription 5A
(STAT5a). Other markers, consistently expressed,
include epithelial membrane antigen (EMA), and
lactalbumin, while variable reactivity was
observed for polyclonal CEA, gross cystic disease
Invasive Secretory Carcinoma, Fig. 5 Sialidase-Alcian fluid protein-15 (GCDFP-15), E-cadherin, and
blue positivity of extracellular secretory material CD117. Tumor cells may at least focally express
CKs 8/18, 19, and various CK cocktails.
Myoepithelial cells are absent thus alpha-smooth-
acidic mucins, particularly sulfated mucopolysac- muscle actin, calponin, and p63 are negative.
charides and sialomucins. Reported Ki67 indexes varied from less than
The above histological description is 1–50%.
consistent with almost all cases of ISC; however,
a small subset of patients may present morpho-
logical aspect of aggressiveness (prevalent Molecular Features
solid pattern, scant secretory activity, strong
nuclear atypia, high mitotic rate, necrosis, The most relevant and specific molecular alter-
peritumoral lymphovascular involvement, and ation in ISC consists in a recurrent balanced chro-
metastatic behavior), which seems to correlate mosomal translocation, t(12;15) (p13;q25) with
with a specific genomic profile (Del Castillo an ETS variant 6–neurotrophic receptor tyrosine
et al. 2015). kinase 3 (ETV6–NTRK3) fusion gene (Tognon
At ultrastructural level tumor cells contain et al. 2002). This translocation had already been
secretory intracytoplasmic membrane-bound vac- described in pediatric spindle cell tumors, such as
uoles, bound with desmosome and grouped in infantile fibrosarcoma and cellular congenital
Invasive Secretory Carcinoma 249
mesoblastic nephroma, in some myeloid acute References and Further Reading

leukemia, and, subsequently, in mammary ana-
logue secretory carcinoma (MASC) of the sali- Bishop, J. A., Taube, J. M., Su, A., Binder, S. W., Kazakov,
D. V., Michal, M., & Westra, W. H. (2017). Secretory
vary gland.
carcinoma of the skin harboring ETV6 gene fusion.
A cutaneous analogue to secretory carcinomas of the
breast and salivary glands. American Journal of Surgi-
Differential Diagnosis cal Pathology, 41, 62–66.
Del Castillo, M., Chibon, F., Arnould, L., Croce, S.,
Ribeiro, A., Perot, G., Hostein, I., Geha, S., Bozon,
If the pathologist has sufficient material, the C., Garnier, A., Lae, M., Vincent-Salomon, A., &
diagnosis of ISC, despite its rarity, does not pre- MacGrogan, G. (2015). Secretory breast carcinoma.
sent any particular problems. Some difficulties A Histopathologic and genomic Spectrum character-
ized by a joint specific ETV6-NTRK3 gene fusion.
may arise in cases with predominant apocrine
American Journal of Surgical Pathology, 39,
aspects or against the recently described mam- 1458–1467.
mary acinic carcinoma (▶ Acinic Cell Carci- Grabellus, F., Worm, K., Willruth, A., Schmitz, K. J.,
noma). However, looking for a typical Otterbach, F., Baba, H. A., Kimming, R., & Metz,
K. A. (2005). ETV6-NTRK3 gene fusion in a secretory
histological pattern of ISC, the presence of intra-
carcinoma of the breast of a male-to-female transsex-
cellular and extracellular secretory material, ual. The Breast, 14, 71–74. I
tumor cells with granular eosinophilic to foamy Koerner, F. C. (2014). Secretory carcinoma. In S. A. Hoda,
cytoplasm and immunohistochemical features E. Brogi, F. C. Koerner, & P. P. Rosen (Eds.), ROSEN's
BREAST pathology (4th ed., pp. 689–701). Philadel-
(triple-negative and S-100-positive) are helpful
phia: Wolters Kluwer Lippincott Williams & Wilkins.
for the diagnosis. In difficult cases, FISH detec- McDivitt, R. W., & Stewart, F. W. (1966). Breast carci-
tion of an ETV6 rearrangement can be used to noma in children. JAMA, 195, 388–390.
make a correct diagnosis. On the contrary differ- Tognon, C., Knezevich, S. R., Huntsman, D., Roskelley,
C. D., Melnyk, N., Mathers, J. A., Becker, L., Carneiro,
ential diagnosis with other lesions containing
F., MacPherson, N., Horsman, D., Poremba, C., &
secretory aspects based on core needle biopsies Sorensen, P. H. (2002). Expression of the ETV6-
or fine needle aspiration cytology may be partic- NTRK3 gene fusion as a primary event in human
ularly challenging given their pathologic spec- secretory breast carcinoma. Cancer Cell, 2, 367–376.
Toll, A., Joneja, U., & Palazzo, J. (2016). Pathologic spec-
trum and frequently subtle morphology (Toll
trum of secretory and mucinous breast lesions. Archives
et al. 2016). of Pathology and Laboratory Medicine, 140, 644–650.
L
Lobular In Situ Neoplasia ALH and LCIS (Haagensen et al. 1978).

Additionally, the lobular neoplastic
Gyula Pekar lesions have also been classified using lobular
Division for Laboratory medicine, Department of intraepithelial neoplasia (LIN) as an alternative
Pathology, Lund University, Lund, Sweden nomenclature in WHO book in 2003, although
this terminology does not seem to have gained
wide acceptance. While the natural history of
Synonyms lobular neoplastic lesions is debatable, LCIS
clearly increases breast cancer risk in both
Lobular carcinoma in situ (LCIS); Lobular breasts. LCIS is often multifocal/multicentric
intraepithelial neoplasia (LIN) and is accompanied with a variable
transformation rate into invasive carcinoma,
suggesting it both as a nonobligate precursor
Definition and as a high-risk lesion (King et al. 2015).
In the eighth edition of the American Joint
Lobular carcinoma in situ (LCIS) is character- Committee for Cancer (AJCC) staging
ized by a neoplastic proliferation of small, classification system, LCIS is considered a risk
uniform, dyscohesive cells that expands at lesion and not anymore an in situ (pTis) cancer.
least 50% of one terminal ductal-lobular unit However, the AJCC expert panel still debates
(TDLU). Although the first pictures of “atypical on the management of pleomorphic LCIS
proliferation of acinar cells” were published in (LCIS-P).
1919 by Ewing, the term LCIS was introduced in
1941 by Foote and Stewart to describe the histo-
logical hallmarks of this lesion within breast Clinical Features
lobules. The description was restricted to a
well-developed example of classic LCIS • Incidence
(LCIS-C) as an established histopathological 0.5–4.0% of breast biopsies, depending
entity. In 1985, Dupont and Page described on diagnostic criteria, the amount of normal
the earlier stages of this lesion, such as breast tissue in biopsy specimens and mam-
atypical lobular hyperplasia (ALH). The term mographic appearance. LCIS prevalence is
lobular neoplasia (LN) denotes the full spectrum 0.5% in “benign” breast biopsies and higher
of proliferation of the characteristic “lobular” (3.2–4.0%) in biopsies performed because of
cells in acini with frequent coexistence of a mammographic abnormality.
https://doi.org/10.1007/978-3-319-62539-3
252 Lobular In Situ Neoplasia
• Age are often not at the site of core needle

The average age at diagnosis ranges from 44 to biopsy.
54 years, with the greatest incidence before – Surgical excision is suggested when any LCIS
menopause (80–90%). is associated with microcalcifications or
• Sex shows histological features of non-LCIS-C
Predominantly in women; however, very rare (e.g., LCIS-P or comedo necrosis). The find-
cases reported in men. The majority of LCIS ing of LCIS-C on surgical margins in excision
shows strong expression of estrogen receptor specimen does not require re-excision. When
(ER) and hormonal influence may play a role in LCIS-P is identified at a surgical margin, how-
neoplastic cells proliferation, but the incidence ever, a re-excision should be performed. There
is not higher in women using hormone replace- are no data on the optimal width of negative
ment therapy. margin or the benefit of radiation therapy for
• Site patients with LCIS-P.
LCIS has a propensity to develop in multiple
foci within the same or both breasts; up to 50%
of patients may have bilateral disease, and multi-
Outcome
centric foci have been described in up to 80% of
patients undergoing mastectomy for LCIS.
LCIS is an indolent lesion with very low malig-
• Presentation
nant potential, but it conveys 8–10 increased
There are no specific mammographic findings
risk for ipsilateral as well as contralateral invasive
associated with LCIS. LCIS may be associated
breast cancer comparing to general population.
with benign calcifying lesions such as atrophic
Epidemiologic studies demonstrated that the
lobules, flat epithelial atypia (FEA) (▶ Colum-
probability of developing invasive cancer is
nar Cell Lesions), sclerosing adenosis
increasing by roughly 1% per year, with a higher
(SA) (▶ Sclerosing Adenosis), and collage-
risk of developing ipsilateral than contralateral
nous spherulosis (▶ Collagenous Spherulosis)
invasive breast cancer either invasive lobular car-
are discovered coincidentally in apparently
cinoma (ILC) (▶ Invasive Lobular Carcinoma) or
normal tissue surrounding a benign (i.e.,
invasive carcinoma of no special type (NST)
▶ Fibroadenoma) or malignant tumor. LCIS
(▶ Invasive Carcinoma NST). However, mastec-
is part of the “Rosen triad” together with tubu-
tomy has never been shown to reduce mortality
lar carcinoma (TC) (▶ Tubular Carcinoma)
compared to observation alone. In some instances,
and columnar cell lesions. Calcifications are
LCIS-C cells may be clonally related to subse-
infrequently present in LCIS, but in cases of
quent ILC. LCIS-P has been more frequently
florid (LCIS-F) and pleomorphic type
associated with invasive disease and a more
(LCIS-P) comedo necrosis with calcium depo-
aggressive course (Pieri et al. 2014), with
sition frequently occur. Breast magnetic reso-
genetic similarities of synchronous pleomorphic
nance imaging (MRI) detects LCIS with higher
ILC (▶ Pleomorphic Lobular Carcinoma),
sensitivity than ultrasonography.
warranting a more aggressive therapeutic
• Treatment
approach. It is still debated whether LCIS detected
– Clinical follow-up may be an acceptable
in association with an invasive carcinoma
alternative to excisional biopsy when in
increases the risk of disease recurrence.
core needle biopsy LCIS is an incidental
finding to a target lesion and/or in cases
with limited volume lesions (less than
three TDLU involved). Likelihood of find- Macroscopy
ing cancer after excision is ~ 3% and typi-
cally it belongs to low-grade neoplasia LCIS per se usually does not form a macroscopic
group. Subsequent cancers in these patients alteration (except very rare cases with LCIS-F).
Lobular In Situ Neoplasia 253
Lobular In Situ Neoplasia, Fig. 1 (H&E) Proliferation nuclei are uniform with evenly distributed chromatin and
of monomorphic, evenly spaced cells that are loosely indistinct nucleoli (A). Intracytoplasmic lumina are often
cohesive and slightly larger than normal acinar cells. The present (B – arrows)
Microscopy include apocrine types of LCIS (Fig. 3 (A) H&E;

(B) E-Cadherin; (C) GCDFP-15 and (D) PAS),
LCIS-C LCIS-P, LCIS with comedo necrosis, and carci-
Proliferation of monomorphic, evenly spaced noma in situ with mixed ductal and lobular fea-
cells that are loosely cohesive and slightly larger tures. Clear cell and signet ring cell variants of
than normal acinar cells with uniform nuclei, LCIS have also been described. The natural his-
evenly distributed chromatin with indistinct tory is unknown. Likelihood of microinvasion L
nucleoli (Fig. 1A H&E). LCIS-C is lacking pleo- (▶ Microinvasive Carcinoma of the Breast) or
morphism and necrosis. Mitotic figures and invasion is higher than in LCIS-C.
hyperchromatism are not features of LCIS-C
but may occasionally be seen. Intracytoplasmic
lumina are often present (Fig. 1B H&E) and Pleomorphic LCIS (LCIS-P)
stain with alcian blue (AB) and/or Periodic acid- It occurs in older postmenopausal age group
Schiff reagent (PAS). The anatomical compared with LCIS-C. Although the cells
distribution can involve lobules causing their appear dyscohesive as in LCIS-C, they exhibit
expansion (Fig. 2A H&E and 2B E-cadherin high nuclear grade (nuclei are more than 3
immunostaining) or LCIS can spread along larger larger than lymphocytes) with multinucleation.
ducts or even along the main lactiferous ducts, Occasionally, the cytoplasm can appear eosino-
causing cloverleaf or necklace patterns (Fig. 2C philic and finely granular, giving the cells an
H&E and 2D E-cadherin), usually without apocrine appearance. Central comedo necrosis
intraepidermal spreading to the nipple. “Pagetoid and calcifications are quite commonly associated
spread” refers to continuous growth of tumor (Fig. 4 (A) H&E, (B) p120, (C) PAS-AB, (D) E-
cells beneath adjacent terminal duct epithelium. cadherin).
Additionally, LCIS-C may occur in SA (▶ Scle-
rosing Adenosis), radial scar (▶ Radial Scar), Florid LCIS (LCIS-F)
fibroadenoma (▶ Fibroadenoma), collagenous LCIS-F shows cohesive (solid) growth of cells
spherulosis (▶ Collagenous Spherulosis), or pap- with either low- or high-grade nuclear features.
illary lesions (▶ Intraductal Papilloma). Central necrosis and calcium deposition are
common. Clustered calcifications within central
Variants of LCIS necrosis are detected at mammography. Calcifica-
Rare, comprising <5% of all carcinoma in situ. tions may show a “linear” shape if extralobular
Several variants have been recognized, these duct(s) are involved.
Lobular In Situ Neoplasia, Fig. 2 LCIS distribution can spread along larger ducts or even along the main lactiferous
involve lobules causing expansion (A, H&E) and E- ducts, causing cloverleaf or necklace patterns (C, H&E). E-
cadherin immunostaining persists in myoepithelial cells cadherin negative LCIS cells spread along ducts between
around E-cadherin–negative LCIS cells (B). LCIS can E-cadherin positive epithelial and myopeithelial cells (D)
In Situ Carcinoma with Mixed Ductal and characteristically diffusely localized to the cyto-
Lobular Features plasm in cases of lobular neoplasia, whereas in
It is very rare. This is considered collision in situ ductal lesions it remains localized to the mem-
carcinoma containing both LCIS-C and ductal car- brane. Immunoreactivity for ER and progesterone
cinoma in situ (DCIS) within the same structure. receptor (PR) is found in virtually all LCIS-C, in
about 66% of LCIS-P and in less than 25% of
apocrine LCIS-P. PR expression is reduced in
Immunophenotype LCIS associated with ILC (▶ Invasive Lobular
Carcinoma). LCIS-C is typically negative for
LCIS-C and variants of LCIS can exhibit strong HER2 protein overexpression/gene amplification,
reactivity for the high-molecular-weight CK lacks p53 mutations, and has a low Ki67 labeling
34bE12 that is absent or weakly expressed in index. Conversely, variants of LCIS and LCIS-P
DCIS. E-cadherin expression can be reliably may show HER2 protein overexpression/gene
used as a marker to differentiate between ductal amplification (especially when associated with
and lobular neoplasia (>95% of cases of LCIS invasive carcinoma), p53 positivity and a moder-
lack E-cadherin). However, morphologically ate to high Ki67 labeling index. GCDFP-15 is
unequivocal cases of LCIS may demonstrate positive in >90% of LCIS-C, 75% of LCIS-P,
focal E-cadherin positivity. p120-catenin is and in virtually all cases of apocrine LCIS-P.
Lobular In Situ Neoplasia 255
Lobular In Situ Neoplasia, Fig. 3 Apocrine type of LCIS (A, H&E); E-Cadherin is negative in neoplastic cells (B);
GCDFP-15 (C) and PAS (D) are diffusely positive in apocrine LCIS
Molecular Features number of DNA copy number changes and more

complex chromosomal rearrangements were
E-cadherin alterations, low-grade neoplasia path- reported. Early onset of bilateral LCIS with or
way, and genetic predisposition: without ILC can be associated with CDH1
E-cadherin is encoded by the CDH1 gene on germline genetic aberration in women without a
chromosome 16q22, and loss of this protein is family history of gastric cancer.
believed to account for the dyscohesive nature of
the cells in LCIS and ILC. As a tumor suppressor
gene, biallelic inactivation is needed by somatic Differential Diagnosis
frameshift mutation (up to 50% of ILC have
CDH1 mutations), allelic deletion by loss of het- ALH
erozygosity or aberrant promoter methylation Distinction between ALH and LCIS is based on
(Mastracci et al. 2005). Genetic studies of colum- extent of lesion, and ALH is defined by its limited
nar cell lesions, ALH, and LCIS proved concor- extent with neoplastic cells only partially filling
dant genomic alterations, remarkably similar the lobular acini with residual lumina. The num-
to low-grade DCIS, NST grade 1, TC, tubulo- ber of acini involved is <50%.
lobular carcinoma, and ILC classic type,
suggesting them to be part of a morphologic con- Low-Grade DCIS, Solid Pattern
tinuum within the low-grade neoplasia pathway The presence of a dyscohesive growth pattern and
(Simpson et al. 2005). In cases of LCIS-P, higher prominent intracytoplasmic vacuoles favors a
Lobular In Situ Neoplasia, Fig. 4 Pleomorphic LCIS, The black arrows on pictures A-C point at the characteris-
central comedo necrosis (A, H&E); diffuse p120 cytoplas- tics multinucleation which is a distinctive feature of
mic positivity (B); PAS-AB staining (C); E-Cadherin (D). LCIS-P
diagnosis of lobular neoplasia. On the other hand, central necrosis and calcifications. The
the presence of distinct cell membranes supports a dyscohesive appearance, lack of E-cadherin
diagnosis of DCIS (▶ Ductal Carcinoma In Situ). expression and diffuse p120 staining of the cells
E-cadherin, p120 IHC can be particularly helpful. are helpful in making the LCIS-P diagnosis.
Benign Lesions Harboring LCIS Mimicking

Benign Cells
Invasive Carcinoma
Myoepithelial cells may be confused with lobu-
LCIS involving SA (▶ Sclerosing Adenosis)
lar neoplasia, particularly when these cells
can mimic invasive carcinoma. Lobulocentric
extend in a pagetoid manner into ducts and
proliferation of back-to-back ductules, often
show abundant clear cell change. IHC for spe-
with microcalcifications, is typical for SA.
cific myoepithelial markers can be helpful in
Myoepithelial markers are helpful in such cases.
problematic cases.
LCIS may grow in otherwise typical FA
(▶ Fibroadenoma), and it will not generate any
diagnostic concern.
LCIS-P Versus DCIS Haagensen, C. D., Lane, N., Lattes, R., & Bodian, C.
LCIS-P is very easily confused with high-grade (1978). Lobular neoplasia (so-called lobular carcinoma
DCIS, particularly when there is associated in situ) of the breast. Cancer, 42, 737–769.
Low-Grade Adenosquamous Carcinoma 257
King, T. A., Pilewskie, M., Muhsen, S., Patil, S., carcinomas. Such a variability of incidence is
Mautner, S. K., Park, A., Oskar, S., Guerini-Rocco, E., due to a plethora of terminologies used by
Boafo, C., Gooch, J. C., De Brot, M., Reis-Filho, J. S.,
Morrogh, M., Andrade, V. P., Sakr, R. A., & different authors to designate these tumors.
Morrow, M. (2015). Lobular carcinoma in situ: Consequently, it is not surprising that there
A 29-year longitudinal experience evaluating clinico- are series of metaplastic carcinomas that do
pathologic features and breast cancer risk. Journal of not even report a single case of LGASC,
Clinical Oncology, 33, 3945–3952.
Mastracci, T. L., Tjan, S., Bane, A. L., O’malley, F. P., & while other authors estimate their incidence
Andrulis, I. L. (2005). E-cadherin alterations in atypical around 0.58% of the total of invasive breast
lobular hyperplasia and lobular carcinoma in situ of the cancers. The real prevalence of this histotype is
breast. Modern Pathology, 18, 741–751. probably underestimated due to the diagnostic
Pieri, A., Harvey, J., & Bundred, N. (2014). Pleomorphic
lobular carcinoma in situ of the breast: Can the difficulties in recognizing it correctly. In any
evidence guide practice? World Journal of Clinical case this entity has to be considered exception-
Oncology, 5, 546–553. ally uncommon and no more than 130 cases
Simpson, P. T., Reis-Filho, J. S., Gale, T., & Lakhani, S. R. have been published in English literature
(2005). Molecular evolution of breast cancer. Journal
of Pathology, 205, 248–254. until now.
• Age
In the original series of Rosen and Ernsberger
(1987) the age of patients affected by LGASC
Low-Grade Adenosquamous ranged from 42 to 76 years with a mean age of
Carcinoma 59. In later studies the extent of age range was
19–88 years, with prevalence in the peri-
Angelo Sidoni meopausal or postmenopausal age.
Department of Experimental • Sex L
Medicine, Section of Pathologic Anatomy Female. No cases of LGASC in males have
and Histology, Medical School, been reported so far.
University of Perugia, Perugia, Italy • Site
LGASC may appear in any part of the breast
parenchyma not infrequently in peria-
Synonyms reolar location. The most frequent clin-
ical presentation is a palpable mass followed
Adenosquamous carcinoma; Infiltrative syringomatous by mammographic abnormalities or nipple dis-
adenoma; Syringomatous squamous tumor charge. Due to the frequent association with
other lesions imaging studies can be inconclu-
Definition sive or confounding.
• Treatment
Low-grade adenosquamous carcinoma (LGASC) Because of the paucity of reported cases, there
of the breast is exceedingly uncommon, and it is is no consensus on the optimal treatment of
characterized by well-developed gland formation LGASC. On the other hand, when compared
mixed with solid nests of squamous cells in a with the majority of metaplastic carcinomas,
spindle cell background. which are also triple negative but highly
aggressive and chemoresistant, LGASC por-
tends an indolent course with a low metastatic
Clinical Features potential and thus a complete local excision or
mastectomy to achieve clear margins appear
• Incidence appropriate.
LGASC belongs to the family of “metaplastic Lymph node metastases are exceedingly
breast cancers,” (▶ Invasive Metaplastic Car- rare and routine sentinel node biopsy and axil-
cinoma) representing 0.2 to 5% of all breast lary dissection may not be necessary. There is
258 Low-Grade Adenosquamous Carcinoma
no unequivocal evidence of the usefulness of H&E). Epithelial islands are irregularly distrib-
both adjuvant radiotherapy and chemotherapy. uted into an abundant collagenous and lamellar
• Outcome stroma rich in plump spindle cells, which subtly
Unlike the aggressive tumor behavior and poor merge with epithelial cells (Fig. 3 H&E). Some-
clinical outcomes seen in other forms of meta- times tubular structures appear to radiate from a
plastic mammary carcinomas, the majority of fibrosclerotic center similarly to a radial scar
LGASC have been described to have an excel- (▶ Radial Scar). Within glands, varying degrees
lent prognosis with greater predilection of squamous differentiation are observed
towards local recurrence, even multiple, (syringoid appearance), from focal not
which can occur within 2–3 years especially keratinizing lining of glandular lumens to sizable
in patients with excisional biopsy alone. Usu- squamous pearls (Fig. 4 H&E). An attenuated
ally all patients with recurrences remain dis- outer myoepithelial layer around glands and
ease free after definitive re-excision. The only cords can be seen (see below). Cytological atypia
particularly aggressive examples reported in
the literature are: one lethal case due to a recur-
rent tumor infiltrating the chest wall; one
patient with pulmonary metastasis and one
with a single lymph node metastasis.
Macroscopy
The macroscopic aspect of LGASCs can be

masked by the coexistence of other breast lesions
(see below); they tend to be firm, yellow-tan,
stellate or poorly circumscribed infiltrating
masses. The reported size varies from 0.5 to
8.0 cm (average about 2 cm). It must be Low-Grade Adenosquamous Carcinoma, Fig. 1 Low-
grade adenosquamous carcinoma. Ill-defined lesion
highlighted that both the macroscopic aspect (bottom) permeating the surrounding breast parenchyma
and the size of the LGASCs are quite different which contain an abundand lymphocytic infiltrate (top)
from the typical high-grade metaplastic breast (H&E)
carcinomas that usually are nodular masses, with
well circumscribed borders and a mean size of
3.9 cm. Three cases of LGASC reported in litera-
ture were bilateral (Senger et al. 2015).
Microscopy
At a low-power view LGASC shows infiltrative

borders with an intimate blend with adjacent
benign ducts and lobules; a brisk peripheral multi-
focal lymphocytic infiltration is typically present
(Fig. 1 H&E). At higher magnification the ep-
ithelial component consist of bland-looking
Low-Grade Adenosquamous Carcinoma, Fig. 2 Low-
glands and tubules with angulated edges, com-
grade adenosquamous carcinoma. Typical syringoid aspect
pressed cell clusters and cords often assuming with “tadpole” and “comma” shaped epithelial elements in
a “comma” or “tad pole” configuration (Fig. 2 a collagenized stroma (H&E)
Low-Grade Adenosquamous Carcinoma, Fig. 3 Low- Low-Grade Adenosquamous Carcinoma, Fig. 5 Low-
grade adenosquamous carcinoma. Fibrous stroma grade adenosquamous carcinoma. Peripheral staining for
containing numerous spindle cell elements disposed in a the myoepithelial marker p63 in the glandular elements and
lamellar pattern blending with epithelial component in the compressed epithelial cords (H&E)
(H&E)
scenarios, LGASC may be an incidental finding
on histological examination of excisional biopsy
or mastectomy specimens.
Immunophenotype L
Immunohistochemically most of the LGASCs

are triple-negative (absence of Estrogen re-
ceptors, Progesterone receptors and HER2) with
a frequently associated positivity for cytokeratin
(CK) 5/6 and/or CK 14 and for epidermal growth
factor receptor (EGFR) which confirm a basal like
phenotype (Geyer et al. 2010).
Low-Grade Adenosquamous Carcinoma, Fig. 4 Low- Gland-like structures of LGASCs demonstrated
grade adenosquamous carcinoma. A solid focus of squa- variable staining for both low and high molecular
mous differentiation (H&E) weight cytokeratins (Kawaguchi and Shin 2012)
and for myoepithelial markers (p63, smooth muscle
is mild with scant mitotic activity and absence of myosin, smooth muscle actin, CD10, calponin)
necrosis; however, areas of transition from confirming the presence of a peripheral
LGASC to a high-grade metaplastic carcinoma myoepithelial component, already visible in routine
have been described. An in situ component may staining (Fig. 5 p63 nuclear staining). The positiv-
be present, often with apocrine features. An ity of p63 in both myoepithelial and tumoral squa-
intriguing characteristic of LGASCs so far mous cells is expected; however, a higher intensity
described is the frequent association with other of immunoreactivity can be observed in the former.
breast lesions such as papillomas (▶ Intraductal Variable degrees and distribution patterns
Papilloma), fibroadenomas (▶ Fibroadenoma), of myoepithelial markers are identifiable also
various types of intraductal epithelial prolifera- in stromal cells (Fig. 6 p63 nuclear staining)
tions, in situ and invasive carcinomas, phyllodes which, moreover, can be focally positive for some
tumors (▶ Phyllodes Tumor) and fibrosclerosing cytokeratins (Kawaguchi and Shin 2012; Geyer et al.
lesions. Not surprisingly, in these clinical 2010).
260 Low-Grade Adenosquamous Carcinoma
distorted epithelial-glandular islands immersed

in a desmoplastic stroma can be very difficult,
if not impossible. Entities falling within the mor-
phological spectrum of LGASC are
syringomatous tumor of the nipple
(▶ Syringomatous Tumor of the Nipple), scle-
rosing adenosis (▶ Sclerosing Adenosis), radial
scar/complex sclerosing lesions (▶ Radial Scar,
▶ Complex Sclerosing Lesion), infiltrating
epitheliosis (▶ Usual Ductal Hyperplasia
(UDH)), and tubular carcinoma (▶ Tubular
Carcinoma).
Histological appearance of syringomatous
Low-Grade Adenosquamous Carcinoma, Fig. 6 Low- tumor of the nipple is virtually indistin-
grade adenosquamous carcinoma. Stromal spindle cells
showing focal positivity for p63 guishable from LGASC, the main difference
being its location: syringomatous tumor arises
in the nipple–areolar complex, whereas
Molecular Features LGAC occurs within breast parenchyma. There-
fore, if a LGASC involves the nipple diagnostic
Reports on molecular features of LGASC are scarce difficulties become insurmountable. On the
and fragmentary, because of the rarity of this entity. other hand LGASC and syringomatous tumor
At present the most relevant data show complex of the nipple are both locally aggressive lesions
genetic and genomic profiles that vary from case to with a propensity for local recurrence sharing
case but with convincing evidence on molecular morphological and molecular features and prob-
similarities between epithelial and stromal cells, ably they represent identical lesions arising in
suggesting that the latter originate from the former different anatomical locations (Boecker
through an epithelial-mesenchymal transition et al. 2014).
mechanism (Geyer et al. 2010), as already shown Benign fibrosclerosing lesions and the
in other more aggressive metaplastic carcinomas. histologically-related infiltrating epitheliosis of-
Of some interest are also recent demonstrations of ten show an adenosquamous component and
genetic aberrations (in particular PI3K pathway therefore form a continuous morphological spec-
genes) shared by various sclerosing lesions trum with LGASC, the latter typically being
(▶ Radial Scar, ▶ Complex Sclerosing Lesion and more extensive and without lobular configuration.
infiltrating epitheliosis (▶ Usual Ductal Hyperpla- Clinicopathological correlation and careful scru-
sia (UDH)) suggesting that these lesions may be tiny of histologic features along with accurate
neoplastic rather than hyperplastic and that, all evaluation of immunohistochemical markers for
together, are part of the spectrum of a single pathol- myoepithelial cells can assist in correct diagnosis.
ogy including also the LGASCs. The glandular structures of tubular carcinoma
are mostly angulated with open lumina and are
composed of single cell population (without
Differential Diagnosis myoepithelial cells) opposed to LGASC and
syringomatous tumor, which have a variable
The distinction of a LGASC from other forms amount of squamous metaplasia and typical
of metaplastic carcinoma (▶ Invasive Metaplas- “comma” or “tad pole” shapes.
tic Carcinoma) is an easy task due to its benign- In view of the abovementioned diagnostic
mimiking histology and absence of heterologous difficulties, it is strongly advisable to make a
elements. On the contrary differential diagnosis definitive diagnosis only on complete excision
with other lesions similarly constituted by biopsies and not on limited material such as
needle aspirates, core biopsy specimens, or frozen Badve, S., & Reis-Filho, J. S. (2010). Genomic and
sections. immunohistochemical analysis of adenosquamous car-
cinoma of the breast. Modern Pathology, 23, 951–960.
Kawaguchi, K., & Shin, S. J. (2012). Immuno-
histochemical staining characteristics of low-grade
References and Further Reading adenosquamous carcinoma of the breast. American
Boecker, W., Stenman, G., Loening, T., Andersson, M. K., Rosen, P. P., & Ernsberger, D. (1987). Low-grade
Sinn, H. P., Barth, P., Oberhellmann, F., adenosquamous carcinoma: A variant of metaplastic
Bos, I., Berg, T., Marusic, Z., Samoilova, V., & mammary carcinoma. American Journal of Surgical
Buchwalow, I. (2014). Differentiation and histogenesis Pathology, 11, 351–358.
of syringomatous tumour of the nipple and low-grade Senger, J. L., Meiers, P., & Kanthan, R. (2015). Bilateral
adenosquamous carcinoma: Evidence for a common synchronous low-grade adenosquamous carcinoma of
origin. Histopathology, 65, 9–23. the breast: A case report with review of current litera-
Geyer, F. C., Lambros, M. B. K., Natrajan, R., Mehta, R., ture. International Journal of Surgery Case Reports,
Mackay, A., Savage, K., Parry, S., Ashworth, A., 14, 53–57.
L
M
Male Breast Cancer • Age

Typically over 60, although all ages can be
Valerie Speirs1, Matthew P. Humphries1 and affected
Abeer M. Shaaban2 • Sex
1
Leeds Institute of Cancer and Pathology, Breast cancer is found predominantly in
University of Leeds, Leeds, UK women, but it can also affect men. Breast can-
2
Department of Cellular Pathology, cer in men is around 100 times less common
Queen Elizabeth Hospital Birmingham and than it is in women.
University of Birmingham, Birmingham, UK • Site
Breast tissue in men is typically situated
directly behind the nipple.
Synonyms • Clinical presentation
A unilateral, firm, painless, or minimally tender
MBC mass behind or adjacent to nipple or in axilla;
changes in appearance of the nipple, e.g., inver-
sion; and nipple discharge or bleeding. Because
Definition breast cancer is perceived by the majority of
general public as a gender-specific condition,
Male breast cancer (MBC) men often postpone presenting to doctors with
symptoms, which can result in delays in diag-
nosis. The diagnostic pathway for MBC is sim-
Clinical Features ilar to that used in women where breast cancer is
suspected. While screening mammography is
• Incidence not recommended, due to small amounts of
Breast cancer in men is rare and accounts for breast tissue in men, paradoxically this makes
1% of all breast cancer diagnoses. In the UK, palpation of a suspicious lesion easier. Diagno-
some 350 men are diagnosed annually with sis is based on physical examination and biopsy.
around 2470 in the USA. Data from cancer Sentinel lymph node biopsy is also used to
registries in the UK and USA suggests that identify positive nodes (▶ Sentinel Node).
the numbers of men receiving a breast cancer • Treatment
diagnosis has been rising gradually since the The absence of gender-specific trials for breast
1970s. cancer means that men are treated in exactly

https://doi.org/10.1007/978-3-319-62539-3
264 Male Breast Cancer
the same way as women. Usually this is mas- Survival rates for MBC are generally assumed
tectomy followed by chemotherapy and radio- to be lower than female breast cancer, probably
therapy. Some men opt for breast-conserving as a result of presentation at a more advanced
surgery, if appropriate, because of reduced stage than in women. However, in general, stud-
morbidity and a better cosmetic outcome. As ies in which male and female breast cancer are
most MBCs express estrogen receptor (ER), matched for key prognostic factors (size, grade,
they are suitable for treatment with endocrine and lymph node status) have refuted this, with
therapy, predominantly adjuvant tamoxifen. outcome almost identical between genders.
Data from clinical trials such as ATAC, in
which the efficacies of aromatase inhibitors
Macroscopy
(AIs) were compared to tamoxifen, have revo-
lutionized the treatment of ER positive breast
Most specimens are mastectomies (Fig. 1a) with
cancer in postmenopausal women, such that
either sentinel node biopsy or axillary node clear-
AIs are now considered standard therapy.
ance according to the presurgical nodal assess-
Despite the fact that aromatase is expressed
ment results. The macroscopic tumors are often
in MBC, initial case series have shown nega-
large, with frequent skin and nipple involvement
tive or equivocal results meaning the efficacy
(Fig. 1b). Similar to the female type, the tumor
of aromatase inhibition in men has been
may appear circumscribed and infiltrative or show
questioned. Because of the increase in testos-
cystic changes.
terone seen after aromatase inhibition, this may
overcome the effect of AI blockade, by
saturating the enzyme pathway with substrate,
resulting in only a modest suppression of estro- Microscopy
gen. Hence LHRH agonists are required to
reduce excessive substrate and maximize the The main histological types and their frequency
effect of aromatase inhibition. As a result, AIs in MBC are shown in Table 1. Of these, the
are generally contraindicated in MBC, unless commonest type of MBC is invasive carcinoma
used with medical or surgical orchiectomy. of no special type (NST) (▶ Invasive Carcinoma
• Outcome NST) of grade 2 differentiation (Fig. 2). The
About 80 men will die of breast cancer in the tumors comprise nests and trabeculae of malig-
UK each year. In the USA, this is around 460. nant cells within fibrous stroma. Invasive lobular
Male Breast Cancer, Fig. 1 (a) A mastectomy specimen surgical margin is painted. (b) Slicing of the posterior
with orientation sutures. It includes fibrofatty breast tissue surface shows a well-defined, grayish-white hemorrhagic
with an overlying nipple bearing ellipse of the skin. The tumor. The tumor is clear of surgical margins
Male Breast Cancer 265
Male Breast Cancer, Table 1 Main histological sub- reported from the EORTC10085, TBCRC, BIG,
types observed in MBC and their relative frequencies and NABCG International Male Breast Cancer
Histology % Frequency Program and other smaller studies from single
NST 85 centers. This is illustrated in Table 2. As with
Lobular 1–2 female breast cancer, ERa and PR are used to
Papillary 3–5 guide treatment and prognosis in MBC (▶ Hor-
Mucinous 1 mone Receptors in Breast Cancer). Other bio-
Medullary 0.5 markers that have been examined in MBC
Cribriform 0.5–1
using immunohistochemistry include AR,
Tubular 0.5
ERb1, ERb2, ERb5, Bcl-2, p53, E-cadherin,
Mixed 5
Ki67, survivin (both in the nucleus and cyto-
Data was obtained from several published articles, includ-
plasm), prolactin, and FOXA1. While these
ing the Veterans Affairs (VA) Central Cancer Registry and
Shaaban et al. (2012) biomarkers are not unique to MBC, some of
them, e.g., AR, is frequently expressed at
relativity high levels in men. Although AR is
currently not used for routine diagnostics
or management in MBC, its relative abundance
suggests that this could be used as a therapeutic
target for antiandrogen therapies. Examples
of ERa, PR, and AR expression in MBC are
shown in Fig. 3.
Although ERa expression is higher in
MBC than in female breast cancer (typically in
approximately 80% of MBCs vs. 60–70% of
female breast cancers), it has been proposed that
M
not all ERa-positive MBCs behave in the same
way as their female counterparts. This is founded
Male Breast Cancer, Fig. 2 (H&E) image of the most through observations of different grouping of hor-
frequent type of MBC, invasive carcinoma NST
mone receptor patterns when applying hierarchical
clustering. In female breast cancers, PR and ERa
carcinoma is extremely rare and so is lobular clustered together, while in MBC, ERa clustered
carcinoma in situ. Compared with female breast together with ERb and AR, with PR clustering
cancer, incidence of papillary carcinoma (both independently (Shaaban et al. 2012). Further clus-
intraductal and invasive) and mucinous ter analysis in MBC showed significant correlation
carcinoma is higher in the male breast (Shaaban of ERa, AR, and FOXA1 (Humphries et al. 2017).
et al. 2012). Ductal carcinoma in situ (DCIS; A number of cell cycle proteins have also been
▶ Ductal Carcinoma In Situ) is reported in examined in MBC. Enhanced proliferation seems
5–15% of cases. Reporting of MBC and cancer to be associated with poorer outcome in MBC,
datasets is the same as for female breast cancer. exemplified analysis of proliferation by mitotic
count, and the expression of cyclins -A, -B, and
D1 biomarkers.
Immunophenotype
A meta-analysis of 1986 cases, designed to iden- Molecular Features

tify common features of MBC, showed that
MBC is typically ERa- and PR-positive, with MBC is identical to female breast cancer
HER2 expression infrequent (Humphries et al. histologically; however data from molecular
2017). This is in line with preliminary results profiling studies using a variety of platforms is
266 Male Breast Cancer
Male Breast Cancer, Table 2 Overview of the clinico- group reported differential driver genes in MBC
pathological features of MBC in 16 published studies versus female breast cancer. Somatic genetic
examining a total of 1986 cases from 1996 to 2017
alterations typically seen in ERa-positive/HER2-
Feature Number (%) negative female breast cancers (the most common
Histology phenotype seen in MBC), e.g., PIK3CA and TP53
NST 1615 (84) mutations and 16q loss, were much less frequent in
Lobular 19 (1)
subtype-matched MBC, suggesting that MBC is
Other 239 (12)
driven by different somatic changes (Piscuoglio
N/A 60 (3)
et al. 2016). In a number of smaller studies,
Grade
gender-specific differentially expressed genes,
1 239 (13)
2 872 (48)
including those involved in translation, cell migra-
3 597 (33) tion/motility, immune response, membrane trans-
N/A 115 (6) port, apoptosis, and energy metabolism, have been
Node reported, adding weight to the hypothesis that male
+ 734 (42) and female breast cancers are biologically distinct.
742 (42) Promoter hypermethylation has been reported
N/A 275 (16) in MBC with methylation of a number of
ERa genes that are known to act as tumor suppressors.
+ 1584 (86) Accumulation of methylated genes and an overall
193 (10) high methylation pattern were correlated with a
N/A 74 (4) more aggressive phenotype and poorer survival.
PR Interestingly, RASSF1A, a well-characterized
+ 1321 (72) tumor suppressor gene, was significantly more
436 (24) frequently methylated in MBC than female breast
N/A 84 (5)
cancer, providing further evidence of likely bio-
HER2
logical differences between genders.
+ 160 (9)
Expression of microRNAs (miRs), small non-
1319 (77)
coding RNAs that alter gene expression at the
N/A 241 (14)
posttranscriptional level, has been examined in
Data adapted from Humphries et al. 2017, where details on
specific studies can be found MBC. Differential expression of several miRNAs
N/A not available has been reported between gynecomastia and
MBC and also between MBC and female breast
cancer. Despite these observational reports, the
starting to suggest there may be underlying role of miRs in MBC, and if this may contrast
gender-specific biological differences in their from female breast cancer, has not been studied
genomic landscapes, both genetically and fully.
epigenetically. Germline mutations of BRCA2 and, to a
As reported above, in general, the main histo- lesser extent, BRCA1 are associated with
logical subtype observed in MBC is invasive car- increased risk of men developing breast cancer
cinoma NST with the most common phenotype (approximately 5–10% and 1–5%, respectively).
ER- and/or PR-positive; HER2-negative, which A genome-wide association study of MBC
falls into the luminal A-like subgroup. However, identified a SNP in RAD51B which was associ-
one of the first gene profiling studies to compare ated with MBC susceptibility, but there is
male and female breast cancer showed two unique evidence that common variants associated
subgroups of MBC, termed luminal M1 and lumi- with female breast cancer may also impact
nal M2 (Johansson et al. 2012). These differed from MBC risk (Orr et al. 2012). More recent genotyping
the conventional molecular classifications observed of 1802 male carriers of BRCA1/2 mutations
in female breast cancer. Consequently, the same showed that weighted polygenic risk scores based
Male Breast Cancer 267
Male Breast Cancer, Fig. 3 Immunohistochemical examples of hormone receptors which are commonly expressed in
MBC. ERa (a), PR (b), and AR (c) are frequently expressed
M
on 88 female breast cancer susceptibility variants to the architectural features of hyperplasia, admix-
were similarly associated with breast cancer risk in ture of luminal and basaloid cells, and the absence
men (Lecarpentier et al. 2017). A large ongoing of significant atypia support a benign diagnosis.
study into the causes of MBC has identified several Basal cytokeratins such as CK5 and CK14 show a
genetic variations associated with risk of develop- three-layered ductal epithelium in gynecomastia
ing the disease. These genetic variations appear to (Kornegoor et al. 2012) and negative staining in
have a different effect on risk between genders, DCIS. Metastases to the breast should be identi-
lending further support to the idea that the biology fied by clinical correlation, unusual histological
of breast cancer is diverse in men and women. features, and a suitable panel of immunohisto-
chemical biomarkers.
The most important differentials are gynecomas-
tia, a benign enlargement of the male breast Humphries, M. P., Sundara Rajan, S., Honarpisheh, H.,
Cserni, G., Dent, J., Fulford, L., Jordan, L. B.,
(▶ Gynecomastia) and metastases to the breast,
Jones, J. L., Kanthan, R., Litwiniuk, M., et al. (2017).
such as metastatic prostatic carcinoma, mela- Characterisation of male breast cancer: A descriptive
noma, etc. Gynecomastia may present with florid biomarker study from a large patient series. Scientific
hyperplasia of the mammary ducts which can Reports, 7, 45293.
Johansson, I., Nilsson, C., Berglund, P., Lauss, M.,
mimic in situ carcinoma particularly on small
Ringner, M., Olsson, H., Luts, L., Sim, E.,
biopsy or in cytological preparations. Attention Thorstensson, S., Fjallskog, M. L., et al. (2012).
268 Malignant Adenomyoepithelioma (M-AME)
Gene expression profiling of primary male breast can- Definition

cers reveals two unique subgroups and identifies
N-acetyltransferase-1 (NAT1) as a novel prognostic
biomarker. Breast Cancer Research, 14, R31. M-AME is a malignant neoplasm of the breast that
Kornegoor, R., Verschuur-Maes, A. H., Buerger, H., & van is arising within or intimately associated with a
Diest, P. J. (2012). The 3-layered ductal epithelium in clinically and/or histologically definable benign
gynecomastia. The American Journal of Surgical adenomyoepithelioma or is a malignant neoplasm
Pathology, 36, 762–768.
Lecarpentier, J., Silvestri, V., Kuchenbaecker, K. B., showing concurrent epithelial and myoepithelial
Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P., differentiation. The entity of histologically benign
Leslie, G., Rizzolo, P., Navazio, A. S., et al. (2017). or borderline/atypical AME associated with
Prediction of breast and prostate cancer risks in male metastases (Nadelman et al. 2006) is not included
BRCA1 and BRCA2 mutation carriers using polygenic
risk scores. Journal of Clinical Oncology, 35, in this definition.
2240–2250.
Orr, N., Lemnrau, A., Cooke, R., Fletcher, O., Tomczyk, K.,
Jones, M., Johnson, N., Lord, C. J., Mitsopoulos, C.,
Zvelebil, M., et al. (2012). Genome-wide association Classification of M-AME
study identifies a common variant in RAD51B associ-
ated with male breast cancer risk. Nature Genetics, 44,
– Epithelial-myoepithelial carcinoma (EMEC)
1182–1184.
Piscuoglio, S., Ng, C. K., Murray, M. P., Guerini-Rocco, E., – AME containing in situ carcinoma
Martelotto, L. G., Geyer, F. C., Bidard, F. C., Berman, S., – AME associated with invasive carcinoma
Fusco, N., Sakr, R. A., et al. (2016). The genomic (carcinoma ex-AME):
landscape of male breast cancers. Clinical Cancer
• Breast carcinoma of no special type (NST)
Research, 22, 4045–4056.
Shaaban, A. M., Ball, G. R., Brannan, R. A., Cserni, G., • Invasive lobular carcinoma
Di Benedetto, A., Dent, J., Fulford, L., Honarpisheh, H., • Carcinoma of special types
Jordan, L., Jones, J. L., et al. (2012). A comparative Squamous or adenosquamous
biomarker study of 514 matched cases of male and
Spindle cell
female breast cancer reveals gender-specific biological
differences. Breast Cancer Research and Treatment, Carcinosarcoma
133, 949–958. Metaplastic matrix producing
Myoepithelial carcinoma
Malignant Clinical Features

Adenomyoepithelioma
(M-AME) • Incidence
M-AME is a rare breast neoplasm confined to
Malcolm Hayes individual case reports and small case series
Pathology Department, BC Cancer Agency, (Ali and Hayes 2012). However, since the
University of British Columbia, Vancouver, BC, malignant component often dominates within
Canada the tumor and recognition of an associated
“benign” AME is a prerequisite for the diag-
nosis in most cases, it is likely that the entity is
Synonyms under-recognized by pathologists. The EMEC
variant is often misclassified as a metaplastic
Adenomyoepithelial carcinoma; Adenomyoe- carcinoma.
pithelioma with malignant transformation; Carci- • Age
noma ex-adenomyoepithelioma; Carcinoma ex- M-AME is typically a neoplasm of postmeno-
pleomorphic adenoma; Epithelial-myoepithelial pausal women aged > 60 years. In the series of
carcinoma 30 patients of M-AME at the British Columbia
Malignant Adenomyoepithelioma (M-AME) 269
Cancer Agency, the mean age is 70.6 years, 26 months, and two are alive and well after
and the range is 42–96 years with only two local recurrences. Eleven patients are alive
2 patients aged <50 years. and one is dead with no evidence of disease
• Sex ranging from 6 to 130 months with a mean
The reported cases in the literature have been follow-up of 50 months.
females, and no males are recorded in the • Clinical Presentation
30 cases in our database. However, since Most cases present as a palpable mass. Some
there are rare case reports of benign AME in patients with M-AME report a long-standing
males, M-AME is most likely not confined to stable mass followed by a period of accelerated
females. growth. A few cases present on screening
• Site mammography as mass lesions.
No specific site in the breast
• Treatment
Macroscopy
Surgical excision of the primary tumor mass is
the mainstay of treatment. Since axillary lymph
M-AME with ductal carcinoma in situ
node involvement is rare, axillary node dissec-
(DCIS) typically presents as a multilobu-
tion is contraindicated in the absence of
lated circumscribed mass similar to that of
involved nodes on clinical or imaging studies,
benign AME.
but sentinel node biopsy is appropriate.
The mass is often reported to be firm, rubbery,
Regional radiation may be helpful and is used
and yellow-white in color. A few cases show
empirically by most oncologists. The value of
cystic change and necrosis. M-AME with an inva-
standard chemotherapy is unknown with few
sive carcinoma presents as an irregular infiltrative
positive responses reported, but most cases are
mass. The size ranges from 1.4 to 14 cm in
treated as for triple negative breast cancer of
usual or metaplastic type. In the case of NST
greatest dimension. Recognition of a pre-existing M
or associated low-grade or “benign” AME is key
carcinomas arising from AME, the manage-
to the diagnosis of carcinoma ex-AME. This
ment should be appropriate to the breast bio-
requires thorough sampling of the gross specimen
marker status of the malignant component.
to include any focal mass lesions within the con-
A recent case report describes the response of
fines of the main tumor. The precursor lesion is
M-AME to eribulin (Lee et al. 2015).
typically nodular but may be papillary in nature.
• Outcome
Many cases of EMEC are also associated with a
There is little data available on the outcome of
low-grade benign AME.
M-AME with invasive carcinoma due to the
rarity of the tumor, its occurrence in the older
age group where life span is already limited,
and poor follow-up in the small series of Microscopy
cases reported to date. There is some
evidence that M-AME with components of Malignant AME of biphasic epithelial-
squamous or spindle cell metaplastic carci- myoepithelial carcinoma (EMEC) type may
noma do better than those with components arise de novo without a precursor low-grade AME
of carcinosarcoma or metaplastic matrix- (Petrozza et al. 2013), but some cases appear to
producing carcinoma. In our records, 5 of represent high-grade dual-lineage transformation
23 patients with M-AME and follow-up data of a low-grade precursor lesion. The tumors are
died of disease at 3, 24, 31, 36, and 54 months. typically large and have a mixture of partially
Three patients died of unknown cause at circumscribed nodules and diffuse areas of growth
36, 44, and 132 months. One patient is alive with infiltrative borders. Glandular and papillary
with pulmonary and nodal metastases after structures exhibiting a disorganized architecture
Malignant Adenomyoepithelioma (M-AME), Fig. 1 (H&E) (a) EMEC showing lobulated architecture, (b, c)
disorganized ductal and myoepithelial elements, and (d) hyaline matrix material
are present, but the degree of cytological atypia necrosis. Commonly, the malignant spindle cell
varies from case to case and in different areas of component of the tumor outgrows the epithelial
the same tumor (Fig. 1). Often, in some foci, the component in many areas of the tumor. Metastatic
tumor retains a partially organized relationship EMEC may retain its dual phenotype in both nodal
between the luminal cells lining the tubules and and pulmonary metastases (Fig. 4).
papillary structures and the layers of underlying It is likely that the entity of “borderline” or
malignant myoepithelial cells (MECs) (Fig. 2). “atypical” AME represents the precursor lesion
Recognition of these poorly organized dual-lineage to this group of tumors. Borderline AME has the
foci is key to differentiating this neoplasm from the morphological appearance of benign AME but
more common breast metaplastic carcinoma of car- with superimposed cytological atypia and an
cinosarcoma or matrix-producing type (Yoon and increased proliferative rate. Its non-infiltrative
Chitale 2013). It is these areas that should be care- growth pattern and generally benign clinical
fully scrutinized using immunohistochemistry in behavior suggest that these “borderline” lesions
order to confirm the dual lineage of the cells for are better grouped with the benign AME category
diagnostic purposes. The MEC component of for practical purposes. However, one has to be
EMEC is typically plump spindle cells that encircle aware that even so-called “benign” AME has the
the epithelial structures and extend as infiltrative potential to recur locally and even rarely metasta-
sheets and strands into the surrounding native size (Nadelman et al. 2006).
breast stroma (Fig. 3). Again, the morphology of The key to the diagnosis of carcinoma ex-AME
this component of the tumor is exceedingly vari- is the recognition of the underlying precursor low-
able between different cases and even within the grade or benign AME within the background of the
same tumor. Areas with a bland spindle cell mor- carcinoma (Fig. 5). The precursor lesion can be
phology often associated with production of hya- detected grossly or on low-power examination of
line collagenous matrix are seen. Elsewhere the the tumor where it appears as a multilobulated
cells may exhibit marked cytological atypia, complex mass, sometimes with a papillary compo-
numerous mitoses, matrix production, and nent. High-power examination will reveal the
Malignant Adenomyoepithelioma (M-AME), Fig. 2 myoepithelial components; (Immunohistochemistry-IHC)

(H&E) (a) EMEC showing disorganized glands; (b, c) (d) CK 5/6 highlights the MEC component
cytological features of malignancy in both luminal and
Malignant Adenomyoepithelioma (M-AME), Fig. 3 (IHC) (a) CK18 and (b) estrogen receptors (ER) label the
epithelial component; (c) CD10 and (d) smooth muscle heavy chain myosin (SMM) label the MEC component
typical combination of luminal cells arranged in exceeding one cell thickness, and nests of cells
ducts and chords surrounded by numerous atypical that have larger nuclei than normal MECs often
MECs. The MEC component forms layers have abundant eosinophilic or clear cytoplasm
Malignant Adenomyoepithelioma (M-AME), Fig. 4 (H&E) (a) Metastases of EMEC to lymph node and (c) to lung
retaining dual lineage. (IHC) (b, d) p63 highlights MECs
Malignant Adenomyoepithelioma (M-AME), Fig. 5 (H&E) (a) Carcinoma ex-AME: low-grade AME component;
(IHC) (b) CK14, (c) p63, and (d) SMM
Malignant Adenomyoepithelioma (M-AME), Fig. 6 Carcinoma ex-AME. (H&E) (a) Malignant component – disor-
ganized ducts and (b); atypical spindle cells immunostained by (c) p63 and (d) CK14
and show mitotic activity. The cell shape of the The morphology of the invasive carcinoma
M
MECs varies from polygonal through to spindled ex-AME depends on the type of carcinoma that
and often lies within an eosinophilic hyaline col- evolves (see classification above). The most com-
lagenous or chondroid matrix. The luminal cells mon variant is metaplastic carcinoma with spindle
may show squamous or sebaceous metaplasia. cells and foci of squamous differentiation, which
The spectrum of pathological changes seen in varies from low-grade through to tumors that have
benign AME has been published in detail else- the morphology of high-grade carcinosarcoma
where (Ali and Hayes 2012). Many cases of (Fig. 6). Sometimes the metaplastic carcinoma
AME, both benign and malignant, are initially mis- produces malignant chondroid tissue or osteoid
classified as invasive NST carcinoma or invasive and woven bone and may contain osteoclast-like
metaplastic carcinoma especially on core biopsy. giant cells (Fig. 7). Rare cases resemble carci-
Malignant transformation of the luminal cells may noma ex pleomorphic adenoma of salivary
result in the classical morphology of lobular carci- gland, which may be considered an entity distinct
noma in situ or low-grade cribriform DCIS with from malignant AME.
rounded uniform nuclei evenly spaced and polar-
ized around secondary lumens (Warrier et al. 2013).
Transformation to high-grade DCIS can also occur Ultrastructural Features
within an AME, a diagnosis that is based on the
cytological atypia, mitotic activity, and necrosis Electron microscopy may be helpful in confirming
and encompassing the morphological range of myoepithelial differentiation within M-AME. The
DCIS encountered unassociated with AME. myoepithelial cells exhibit the presence of both
AMEs harboring such in situ neoplastic prolifera- tonofilaments and myofibrils in their cytoplasm.
tions are probably best regarded as “borderline” or Pinocytotic vesicles are also seen. A thick basal
“atypical” AME rather than frankly malignant. lamina surrounds the cells, and hemidesmosomes
Malignant Adenomyoepithelioma (M-AME), Fig. 7 (H&E) (a) AME (b) transforming to EMEC and (c) metaplastic
chondroid and (d) osseous metaplasia in the MEC component
attach the MECs to adjacent cells and to the base- encounter positive staining of the luminal cell
ment membrane (Trojani et al. 1992). component for high molecular weight keratins,
and occasionally CD10 and SMM, especially
when the cells show squamous metaplasia but
Immunophenotype even when they resemble typical luminal epithe-
lial cells on morphology. Similarly, the MECs
The diagnosis of M-AME is often suspected can show staining for low molecular weight ker-
based on the morphology of the H&E stained atins, but this is usually much weaker than that
sections but is greatly supported by the use of seen in the luminal cell component of the lesion.
immunohistochemistry (Ali and Hayes 2012). Often the MECs lose their expected
The aim is to delineate a dual population of immunoprofile in an unpredictable pattern.
luminal cells and MECs within the lesion. In Thus, some MECs lose the myogenic markers
theory, this is simpler than in practice because and other cytoplasmic markers but retain the
the staining pattern of both the MECs and the nuclear markers, but the reverse pattern also
luminal cells in M-AME may be aberrant. occurs. The expression of the cytoplasmic
Classically, the luminal cells stain for low molec- markers is unpredictable and variable. Therefore
ular weight keratins such as CK18, CK7, and a wide range of immunostains may be required in
CAM5.2, and the MEC component stains with order to investigate a particular case thoroughly
nuclear markers p63 and p40 and cytoplasmic as sometimes only one of the many markers is
markers CD10 and S-100 protein, myogenic expressed. The immunostain for Ki-67 enables
markers (SMM, calponin, and actin), and high assessment of the degree of proliferative activity
molecular weight keratins CK 34-beta-E12, of M-AME (which typically has an index
CK5/6, and CK14. The expression of these of >15%) and indirectly reflects the malignant
markers varies from case to case and in different potential of the neoplasm (Hungermann et al.
areas of the same tumor. It is frequent to 2005). With regard to breast biomarkers, stains
for ER and progesterone receptors are patchy borderline) precursor AME intimately associ-
positive or completely negative in the luminal ated with the high-grade malignant epithelial
cell compartment in most M-AMEs especially or myoepithelial component of the neoplasm.
those with a metaplastic component, but some This depends on the history suggesting a pre-
cases show strong diffuse staining. These stains existing stable mass followed by a phase of
are negative in the myoepithelial or spindle cell accelerated growth, a careful gross examina-
compartment of the neoplasm. Staining for tion to search for such a precursor lesion,
androgen receptor does not appear to have been and/or a thorough sampling of the tumor.
studied in these neoplasms. HER2 is typically 3. Distinction from malignant myoepithelioma
not overexpressed or amplified. (▶ Myoepithelial Carcinoma of the Breast)
depends on the demonstration of both luminal
and MEC components in M-AME, whereas
Molecular Features luminal components are not seen in pure
malignant myoepithelioma.
A few cases of AME have been subject to genetic
and molecular analysis, and no clear pattern
has emerged. A p53 mutation has been identified References and Further Reading
in several cases of M-AME (Angèle et al. 2004;
Han et al. 2006) and a balanced t(8;16)(p23;q21) Ali, R. H., & Hayes, M. M. (2012). Combined epithelial-
translocation in a benign AME (Gatalica et al. myoepithelial lesions of the breast. Surgical Pathology
2005). A case report of a M-AME associated Clinics, 5(3), 661–699.
Angèle, S., Jones, C., Reis Filho, J. S., Fulford, L. G.,
with GIST tumors, both exhibiting c-kit mutation Treilleux, I., Lakhani, S. R., & Hall, J. (2004).
in a patient with NF-1, has also been reported Expression of ATM, p53, and the MRE11-Rad50-
(Hegyi et al. 2009). Comparative genomic hybrid- NBS1 complex in myoepithelial cells from benign
ization (CGH) analysis of benign AME showed and malignant proliferations of the breast. Journal of M
Clinical Pathology, 57(11), 1179–1184.
alterations comprising 13 gains and 5 losses Gatalica, Z., Velagaleti, G., Kuivaniemi, H., Tromp, G.,
of chromosomal regions in 5 of 7 cases. In Palazzo, J., Graves, K. M., Guigneaux, M., Wood, T.,
M-AME 14 of 18 cases showed DNA copy num- Sinha, M., & Luxon, B. (2005). Gene expression pro-
ber changes. Changes on chromosome 8 and 17p file of an adenomyoepithelioma of the breast with a
reciprocal translocation involving chromosomes 8 and
were most frequent (Hungermann et al. 2005). 16. Cancer Genetics and Cytogenetics, 156(1), 14–22.
Han, B., Mori, I., Nakamura, M., Wang, X., Ozaki, T.,
Nakamura, Y., & Kakudo, K. (2006). Myoepithelial car-
Differential Diagnosis cinoma arising in an adenomyoepithelioma of the breast:
Case report with immunohistochemical and mutational
analysis. Pathology International, 56(4), 211–216.
1. The differential diagnosis of M-AME Hegyi, L., Thway, K., Newton, R., Osin, P., Nerurkar, A.,
of EMEC type is from “benign” or “border- Hayes, A. J., & Fisher, C. (2009). Malignant
line” AME (▶ Adenomyoepithelioma). The myoepithelioma arising in adenomyoepithelioma of
the breast and coincident multiple gastrointestinal stro-
“malignant” designation is based on the pres- mal tumors in a patient with neurofibromatosis
ence of marked cytological atypia, presence of type 1. Journal of Clinical Pathology, 62(7), 653–655.
numerous mitoses and corresponding high Hungermann, D., Buerger, H., Oehlschlegel, C., Herbst, H.,
Ki-67 index (>15%), presence of necrosis, & Boecker, W. (2005). Adenomyoepithelial tumors and
myoepithelial carcinomas of the breast – A spectrum of
and an infiltrative growth pattern. monophasic and biphasic tumors dominated by imma-
2. Distinction between M-AME of carcinoma ture myoepithelial cells. BMC Cancer, 5, 92.
ex-AME type and metaplastic carcinoma Lee, S., Oh, S. Y., Kim, S.-H., et al. (2015). Malignant
(▶ Invasive Metaplastic Carcinoma) of the adenomyoepithelioma of the breast and responsive-
ness to eribulin. Journal of Breast Cancer, 18(4),
breast (including poorly differentiated 400–403.
myoepithelial-rich carcinoma) depends on the Nadelman, C. M., Leslie, K. O., & Fishbein, M. C. (2006).
demonstration of a low-grade (benign or “Benign,” metastasizing adenomyoepithelioma of the
276 Mammary Myofibroblastoma
breast: A report of 2 cases. Archives of Pathology & immunohistochemical, and ultrastructural level
Laboratory Medicine, 130(9), 1349–1353. (Wargotz et al. 1987b; Magro et al. 2001, 2002a,
Petrozza, V., Pasciuti, G., Pacchiarotti, A., et al. (2013).
Breast adenomyoepithelioma: A case report with 2016; Magro 2008). Other tumors, such as the
malignant proliferation of epithelial and benign fibroblastic spindle cell tumor, the spindle
myoepithelial elements. World Journal of Surgical cell lipoma of the breast, and tumors with hybrid
Oncology, 11, 285. features, have a fibroblastic profile, with cells
Trojani, M., Guiu, M., Trouette, H., De Mascarel, I., &
Cocquet, M. (1992). Malignant adenomyo- stained with vimentin and CD34 by means of immu-
epithelioma of the breast. An immunohistochemical, nohistochemistry (Magro et al. 2001, 2002a).
cytophotometric, and ultrastructural study of a case Although MFB was originally described as a spindle
with lung metastases. American Journal of Clinical cell tumor, over time several morphological variants
Pathology, 98(6), 598–602.
Warrier, S., Hwang, S., Ghaly, M., & Matthews, A. (2013). have been recognized: fibrous/collagenized,
Adenomyoepithelioma with ductal carcinoma in situ: myxoid, epithelioid/deciduoid cell, lipomatous, and
A case report and review of the literature. Case Reports palisaded/Schwannian-like variant (Magro et al.
in Surgery, 2013, 521417. 2000a; Reis-Filho et al. 2001; Simsir et al. 2001;
Yoon, J. Y., & Chitale, D. (2013). Adenomyoepithelioma of
the breast: A brief diagnostic review. Archives Magro 2008; Laforga and Escandón 2017).
of Pathology & Laboratory Medicine, 137(5), 725–729.
Clinical Features
Mammary Myofibroblastoma • Incidence

MFB of the breast is an uncommon tumor, with
Gaetano Magro and Lucia Salvatorelli approximately 100 cases reported in the
Department of Medical and Surgical Sciences and English literature so far (Magro 2016). In the
Advanced Technologies, G.F. Ingrassia, Azienda last two decades, there has been an increased
Ospedaliero-Universitaria “Policlinico-Vittorio incidence likely due to an increased mammo-
Emanuele,” Anatomic Pathology Section, School graphic screening (Magro 2008).
of Medicine, University of Catania, Catania, Italy • Age
This tumor can occur at any age, including
infants and adolescents (Alam et al. 2002;
Synonyms Soyer et al. 2012; Magro 2016), but is usually
diagnosed in older men and postmenopausal
Benign spindle cell tumor; Fibroma; Myogenic women (Magro et al. 2012a; Magro 2016).
stromal tumor • Sex
Although most cases of MFB were originally
described in adult men, this tumor occurs with
Definition equal frequency among males and females
(Magro et al. 2012a; Magro 2016). MFB has
Myofibroblastoma (MFB) is a relatively rare benign no predilection for any particular race and it
stromal tumor of the breast (Wargotz et al. 1987b; usually occurs sporadically, with a few cases
Magro et al. 2001, 2012a; Magro 2016), which diagnosed in association with gynecomastia
belongs to the family of the “benign spindle cell (Yoo et al. 1998; Reis-Filho et al. 2001). Only
tumors of the mammary stroma” (Magro et al. rarely this tumor can be bilateral or multi-
2001, 2002a). These tumors are closely related centric (Hamele-Bena et al. 1996).
lesions within a continuous morphological spec- • Clinical Presentation
trum, variably composed of cells ranging from spin- Clinically MFB presents as a unilateral, slow-
dly fibroblastic-like cells to plump myofibroblasts growing, painless, nontender nodule (Magro
(Magro et al. 2001, 2002a). As its name implies, 2008, 2016). Imaging features are not specific
MFB is composed of cells which show and MFB is usually confused with
myofibroblastic differentiation at morphological, fibroadenoma (Magro 2008, 2016).
Mammary Myofibroblastoma 277
• Radiographic Findings millimeters to 13 cm, with a smooth, sometimes

Ultrasonography shows a well-circumscribed, lobulated, external surface (Magro 2008, 2016).
round to oval, homogeneous, slightly hypo- The cut surface usually shows a firm lesion,
echoic mass suggestive of fibroadenoma. Sim- white to grayish in color. Occasionally, tumor
ilarly, mammography reveals a well- may have whorled appearance similar to a uter-
circumscribed dense mass, devoid of calcifica- ine leiomyoma. Myxoid changes or a
tions. Magnetic resonance shows a well- fatty component may be variably present in a
circumscribed nodular mass with homoge- minority of cases. Necrosis and hemorrhage are
neous enhancement and internal septations. absent.
• Treatment
Adequate treatment for MFB is local excision.
Clinical behavior is indolent with no local
Microscopy
recurrence after surgical treatment (Magro
2008, 2016).
Classic-type MFB is a well-circumscribed but
nonencapsulated, bland-looking spindle cell
Macroscopy tumor which usually does not contain entrapped
mammary ducts/lobules (Fig. 1a; Table 1). Neo-
Grossly, MFB presents as a well-circumscribed plastic cells have a myofibroblastic appearance,
round to oval mass, ranging in size from a few with relatively abundant pale to slightly or deeply
Mammary Myofibroblastoma, Fig. 1 Classic-type arranged in short fascicles interrupted by keloid-like colla-
myofibroblastoma. Tumor showing well-circumscribed gen fibers (c) (H&E), are stained with desmin (d), CD34
borders (a) (H&E), bland-looking spindle cells and (e), alpha-smooth muscle actin (f) and estrogen
keloid-like collagen fibers (b) (H&E). Neoplastic cells, receptors (g)
Mammary Myofibroblastoma, Table 1 Mammary medium-sized vessels, often with hyalinization

Myofibroblastoma: morphological, immunohistochemical and foamy histiocytes in their walls. Scattered
and cytogenetic features
mast cells can be usually found. Small islands of
Classic-type myofibroblastoma adipose tissue and/or focal myxoid stromal
Histological features changes can be observed throughout the tumor.
Margins: Well circumscribed; sometimes lobulated; In an otherwise classic-type MFB, the following
rarely focally infiltrative
unusual morphological features can be encoun-
Cells: Bland-looking spindle cells; a few oval to
epithelioid cells tered: focally infiltrative margins (Teng and You
Cytoplasm: Pale to deeply eosinophilic 2005), high cellularity (Gurzu and Jung 2012),
Nuclei: Round to oval with one or two small nucleoli; nuclear pleomorphism (moderate to high grade)
focal mild to moderate atypia; sometimes nuclear (Hamele-Bena et al. 1996; Lázaro-Santander et al.
grooves and/or pseudoinclusions 1999), multinucleated floret-like cells (Gocht
Growth pattern: Short, haphazardly intersecting et al. 1999; Magro et al. 1999), intracytoplasmic
fascicles; focal storiform or neural-like patterns
and extracellular hyaline globules (Ozerdem et al.
Mitotic count: 0–2 mitoses 10 high power field
Stroma: Fibrous to focally myxoid; thick, keloid-like
2015), extensive myxo-edematous stromal
collagen fibers among neoplastic cells changes (Magro et al. 2014), blood vessels
Vasculature: Small to medium-sized blood vessels; containing fibrinoid material and foamy histio-
often hyalinization and foamy macrophages in their walls cytes in their walls (Magro et al. 2014), and
Additional intratumoral tissue components: Often heterologous mesenchymal components
mature lipomatous and more rarely leiomyomatous,
(mature lipomatous, leiomyomatous, cartilagi-
cartilaginous, osseous tissues
Inflammatory component: Mast cells variably
nous, osseous tissue) (Fukunaga et al. 1996;
interspersed among spindle cells Kobayashi et al. 1996; Fukunaga and Ushigome
Immunohistochemistry 1997; Thomas et al. 1997; Mnif et al. 2013).
Positive markers: Vimentin, desmin, CD34 and Several morphological variants on the basic
estrogen (ER), progesterone/androgen receptors common theme of the classic-type MFB have
Variable expression: Alpha-smooth muscle actin, been recognized in the last two decades
calponin, CD10, bcl-2, CD99
(Table 2). “Fibrous/collagenized MFB” is char-
Negative markers: Cytokeratins, EMA, S-100
protein, ALK-1, beta-catenin, STAT6
acterized by a diffuse fibro-sclerotic stroma
Cytogenetics which can obscure the neoplastic spindle cell
Cytogenetic analysis: Partial monosomy 13q; less component (Fig. 2) (Simsir et al. 2001). “Myxoid
frequently partial monosomy 16q MFB” is a tumor composed entirely or predom-
FISH analysis: Loss of RB/13q14 and FOX01 inantly of myxoid extracellular matrix
(FKHR)/13q14 loci (70% of cases). containing both spindle- to stellate-shaped cells
and only a few keloid-like collagen fibers
(Magro et al. 2007a) (Fig. 3). Neoplastic cells
eosinophilic cytoplasm with distinct cell borders may show mild to moderate nuclear pleomor-
and centrally located oval to round nuclei with phism (Magro et al. 2007a) (Fig. 3b). The term
small nucleoli. Nuclear grooves or pseudo- “epithelioid cell MFB” is referred to those
inclusions can be encountered. These cells are tumors composed predominantly (>50% of the
closely arranged in short, haphazardly inter- entire tumor) of medium-sized cells with epithe-
secting fascicles interrupted by brightly eosino- lioid morphology (Reis-Filho et al. 2001; Magro
philic keloid-like collagen fibers (Fig. 1b, c). 2009, 2012; Magro et al. 2013a). These cells, set
Rarely amianthoid-like collagen fibers, focal in a variably fibrous to myxoid stroma, often
storiform, and hemangiopericytoma-like and exhibiting mild to moderate nuclear pleomor-
nuclear palisading patterns can be seen. Mitoses phism, are arranged in various growth patterns,
are rare (2 mitoses per 10 high-power fields). including nests, solid sheets, micronodular,
Necrosis and atypical mitoses are absent. The pseudo-alveolar, or trabecular growth patterns
vasculature is mainly represented by small- to (Reis-Filho et al. 2001; Magro 2009; Magro
Mammary Myofibroblastoma, Table 2 Mammary Mammary Myofibroblastoma, Table 2 (continued)

Myofibroblastoma: morphological variants
Morphological variants of myofibroblastoma
Morphological variants of myofibroblastoma Keloid-like collagen fibers interspersed in the fibrous
Fibrous/collagenized myofibroblastoma areas
Hypocellular tumor Mild to moderate nuclear atypia
Exclusive or predominant fibrous stroma Differential diagnosis: Desmoid-type fibromatosis;
Blood vessels with degenerative changes: Fibrinoid low-grade (fibromatosis-like) spindle cell carcinoma
material and foamy histiocytes in their walls Palisaded/schwannoma-like myofibroblastoma
Differential diagnosis: Reactive sclerotic nodule; Tumor with prominent (>50% of the entire tumor)
sclerotic area in fibrocystic changes nuclear palisading and formation of numerous Verocay-
Myxoid myofibroblastoma like bodies
Hypocellular tumor Minor component of classic-type myofibroblastoma
Exclusive or predominant myxoid stroma Differential diagnosis: Schwannoma
Spindle- and stellate-shaped cells
Mild to moderate nuclear atypia
Isolated keloid-like collagen fibers within myxoid et al. 2013a) (Fig. 4). In some areas, they can be
stroma arranged in single cells or single cell files,
Differential diagnosis: Myxoma; nodular fasciitis resulting in a pseudo-infiltrative growth pattern,
(myxoid variant); low-grade sarcomas with myxoid
stromal changes (myxoid liposarcoma; low-grade
closely reminiscent of invasive lobular carci-
myxofibrosarcoma) noma (▶ Invasive Lobular Carcinoma) (Magro
Epithelioid myofibroblastoma 2009). Keloid-like collagen fibers can encase
Tumor with prominent (>50% of the entire tumor) some cellular nests with formation of nerve-like
epithelioid cell component structures (Magro 2016). Rarely epithelioid cells
Medium-sized, epithelioid mono- or bi-nucleated cells can adopt a deciduoid-like morphology with
with deeply eosinophilic cytoplasm;
more abundant eosinophilic to amphophilic
Mild to moderate degree of nuclear pleomorphism
cytoplasm and large vesicular nuclei with prom-
M
fibrous stroma with interspersed keloid-like collagen
fibers inent nucleoli (Magro et al. 2008). Due to a close
Growth patterns: Single cells, single cell files, nests, resemblance to decidua, tumors exclusively/pre-
pseudo-alveolar, solid, trabecular, multinodular dominantly composed of such cells have been
Small islands of intratumoral adipocytes labeled as “deciduoid cell MFBs” (Fig. 5)
Differential diagnosis: Invasive lobular carcinoma (Magro et al. 2008). The term “lipomatous
Deciduoid myofibroblastoma MFB” has been coined for those tumors
Tumor with deciduoid cell component (>50% of the containing a prominent (>50% of the entire
entire tumor)
tumor) mature fatty component (Magro et al.
Large-sized, mono-or multinucleated, deciduoid-like
cells with abundant cytoplasm; more rarely cells with 2000a). This variant of MFB resembles a fibro-
rhabdoid morphology fatty tumor and is misdiagnosed as fibro-lipoma
Moderate to severe nuclear pleomorphism or spindle cell lipoma (Magro et al. 2000a;
Fibrous stroma with interspersed keloid-like collagen Magro et al. 2001). It consists of a prominent
fibers mature fatty component in which there are dis-
Growth patterns: Solid-sheets, nests persed nodular, or more frequently, irregularly
Differential diagnosis: Invasive pleomorphic lobular
shaped fibrous areas with a finger-like pattern
carcinoma; apocrine carcinoma; high-grade metastatic
tumors similar to that seen in desmoid-type fibromatosis
Lipomatous myofibroblastoma (Magro et al. 2000a; Baxendine-Jones et al.
Tumor with prominent (>50% of the entire tumor) 2001) (Fig. 6). In these fibrous areas, the typical
fatty component features of MFB, at least focally, can be recog-
Admixture of adipocytes and fibrous areas nized: short, haphazardly intersecting fascicles
Nonadipocytic component: Spindle to epithelioid cells interrupted by keloid-like collagen fibers
Growth patterns: Finger-like pseudoinfiltrative (Fig. 6c). Mild to moderate nuclear pleomor-
(continued) phism is usually seen (Magro et al. 2000a).
Mammary Myofibroblastoma, Fig. 2 (H&E) Fibrous/ and histiocytes in their walls (a). Spindle cells, arranged in
collagenized myofibroblastoma. Low magnification show- distorted fascicles, are seen at higher magnification (b)
ing a fibrous lesion containing blood vessels with fibrin
Mammary Myofibroblastoma, Fig. 3 Myxoid myo- fibers (a) (H&E). Neoplastic cells show focal nuclear atypia
fibroblastoma. Tumor with extensive myxoid stroma (b) (H&E) and are stained with desmin (c)
containing spindle- to stellate-shaped cells and thick collagen
Mammary Myofibroblastoma, Fig. 4 (H&E) Epitheli- magnification showing mono- or bi-nucleated cells with
oid myofibroblastoma. Tumor is composed predominantly of mild to moderate nuclear atypia. Mitoses are absent (b)
epithelioid cells set in a fibrous stroma (a). Higher
M
“Palisaded/Schwannian-like MFB” is composed of some cases, can be absent. Accordingly, the major-
bland-looking spindle cells with a diffuse nuclear ity of mammary MFBs are desmin-positive
palisading and formation of numerous Verocay- myofibroblastic tumors which usually express estro-
like bodies (Magro et al. 2013b; Laforga and gen, progesterone, and androgen receptors (Magro
Escandón 2017) (Fig. 7). Keloid-like collagen et al. 2000b, 2012a; Magro 2008, 2016). Calponin,
fibers, a typical feature of classic-type MFB, are bcl-2 protein, CD99, and CD10 are also variably
seen. This tumor is closely reminiscent of expressed (Magro et al. 2007b; Magro 2016).
schwannoma and immunohistochemistry is helpful H-caldesmon expression can be focally observed
for a correct diagnosis (absence of S100 protein (Magro et al. 2003). Epithelial markers
along with the expression of myogenic markers). (cytokeratins, EMA) and S100 protein are negative.
Immunophenotype Molecular Features
Classic-type MFB and all its morphological vari- Cytogenetic studies have showed that MFB is a
ants show a myofibroblastic profile. The neoplastic tumor with the loss of material from chromosome
cells are characteristically stained with desmin in 13 and less frequently from chromosome
addition to vimentin and CD34 (Magro 2008, 16 (Pauwels et al. 2000). FISH analyses, using
2016). Alpha-smooth muscle actin is also locus specific probes, reveal that about 70–80% of
expressed, but with a more intralesional and mammary MFB exhibits the loss of the 13q14
interlesional heterogeneous distribution and, in region, which can be shown by the losses of
Mammary Myofibroblastoma, Fig. 5 Deciduoid mono- or multinucleated cells with abundant cytoplasm
myofibroblastoma. Tumor is composed of closely packed and large nuclei with evident nucleoli (b) (H&E). Neoplas-
large-sized cells closely reminiscent of decidua (a) (H&E). tic cells are diffusely stained with desmin (c)
Higher magnification showing alarming features: large
RB/13q14 and/or FOX1(FKHR)/13q14 loci in mitoses 10 high power fields), atypical mitoses,
tumor cells (Magro et al. 2012b; Trépant et al. necrosis, and extensive infiltrative margins are not
2014). Interestingly similar results have been features of MFB. The diagnosis is challenging on
reported in extra-mammary MFB (Maggiani core biopsy, but MFB can be suspected if tumor has
et al. 2006; Magro et al. 2012b). As spindle cell pushing borders (imaging information) and the
lipoma and cellular angiofibroma share with MFB spindle cells are positive for desmin, CD34,
the same chromosomal alterations (Maggiani alpha-smooth muscle actin, estrogen/progesterone
et al. 2007; Flucke et al. 2011), it has been receptors and negative for epithelial markers,
suggested a genetic link among these three tumors h-caldesmon, beta-catenin, S100 protein, and
(Flucke et al. 2011; Magro et al. 2012b). STAT6. The differential diagnosis includes all the
bland-looking tumor or tumor-like spindle cell
lesions arising in the breast parenchyma, such as
Differential Diagnosis the fascicular variant of pseudoangiomatous
stromal hyperplasia (▶ Pseudoangiomatous Stro-
The diagnosis of classic-type MFB is relatively mal Hyperplasia), reactive spindle cell nodule,
straightforward in surgical specimens if strict nodular fasciitis, inflammatory pseudotumor/
morphological criteria are applied. MFB of the inflammatory myofibroblastic tumor (▶ Inflamma-
breast should be suspected when dealing with a tory Myofibroblastic Tumor of the Breast),
pure spindle cell lesion with pushing borders, leiomyoma, solitary fibrous tumor, desmoid-type
composed of bland-looking spindle cells, fibromatosis, low-grade (fibromatosis-like) spindle
arranged in short, haphazardly intersecting fasci- cell carcinoma (▶ Invasive Metaplastic Carci-
cles with interspersed keloid-like collagen fibers noma), and low-grade myofibroblastic sarcoma
(Magro 2008, 2016). High mitotic count (>3 (Table 3). Among these lesions, the distinction
Mammary Myofibroblastoma, Fig. 6 Lipomatous growth pattern (b) (H&E). Fibrous area exhibiting the
myofibroblastoma. Low-magnification showing a fibro- characteristic features of classic-type myofibroblastoma M
fatty tumor with well-circumscribed borders (a) (H&E). (c) (H&E). The spindle cells are diffusely stained
In some areas, there is a close admixture of fibrous areas with CD34 (d)
with adipose tissue, resulting in a pseudo-infiltrative
from inflammatory pseudotumor/inflammatory involves both perilobular (more frequently) and

myofibroblastic tumor, desmoid-type fibromatosis, intralobular stroma, containing mammary ducts/
low-grade (fibromatosis-like) spindle cell carci- lobules (Magro and Bisceglia 2005; Virk and
noma, and low-grade myofibroblastic sarcoma is Khan 2010; Lee et al. 2016). Reactive spindle
crucial for their tendency to local recurrence. In cell nodule is an exuberant myofibroblastic spin-
addition the latter two tumors are capable of distant dle cell proliferation in response to a tissue
metastases. trauma. Accordingly, the clinical history of a pre-
Pseudoangiomatous stromal hyperplasia is vious biopsy or fine-needle aspiration (FNA) is
characterized by a proliferation of bland-looking extremely helpful for making the correct diagno-
spindle cells set in a fibrous stroma with the for- sis (Gobbi et al. 2000; Garijo et al. 2008; Sciallis
mation of anastomosing pseudovascular spaces et al. 2012). The recognition of entrapped/
(Virk and Khan 2010). Focally this proliferation displaced epithelial mammary structures, hemo-
can be more cellular (fascicular variant), adopting siderin (in the stroma or within macrophages),
a MFB-like appearance with obliteration of the lymphocytes, plasma cells, fat necrosis, and for-
spaces (Magro and Bisceglia 2005). Although eign body giant cell reaction, are all morphologi-
pseudoangiomatous stromal hyperplasia may pre- cal features which support the diagnosis (Gobbi
sent as a nodular mass (Lee et al. 2016), it is et al. 2000; Garijo et al. 2008; Sciallis et al. 2012).
usually an incidental histological finding (Virk Unlike MFB, nodular fasciitis has, at least focally,
and Khan 2010). Unlike MFB, the proliferation irregular margins, a more abundant myxoid
Mammary Myofibroblastoma, Fig. 7 (H&E) picture is highly suggestive of schwannoma (a). High mag-
Palisaded/Schwannian-like myofibroblastoma. Low- nification showing the cellular details (b). Neoplastic cells
magnification showing a tumor with well-circumscribed are stained with desmin (inset)
borders and numerous Verocay-like bodies. The overall
stroma and a tissue culture/granulation-like h-caldesmon, while CD34 is lacking (Jones et al.
appearance (Kang et al. 2015; Paliogiannis et al. 1994; Vecchio et al. 2013). As solitary fibrous
2016; Hayashi et al. 2017). Numerous mitoses tumor and MFB share several morphological and
and entrapped ducts/lobules can be seen, espe- immunohistochemical features, some authors
cially at the periphery of the lesion. The cells of have used interchangeably their names in the
nodular fasciitis are diffusely stained with alpha- past (Damiani et al. 1994; Magro et al. 2002a).
smooth muscle actin but are usually negative However, unlike MFB, SFT shows nuclear
for desmin and CD34 (Kang et al. 2015; expression of STAT6 (Magro et al. 2016) and is
Paliogiannis et al. 2016; Hayashi et al. 2017). usually desmin-negative. Desmoid type-
Unlike MFB, inflammatory pseudotumor/inflam- fibromatosis differs from MFB in that it is an
matory myofibroblastic tumor contains spindle infiltrative lesion composed of spindle cells, usu-
cells admixed with chronic inflammatory infiltrate ally aligned parallel to one another, separated by
of plasma cells, lymphocytes, and less frequently fibrous stroma and arranged in long fascicles
eosinophils and neutrophils. The spindle cells (Wargotz et al. 1987a; Devouassoux-Shisheboran
show a variable expression of alpha-smooth mus- et al. 2000; Magro et al. 2002b). In addition, the
cle actin, while desmin and CD34 are usually cells are usually stained with beta-catenin (nuclear
negative or only focally positive (Vecchio et al. staining) and alpha-smooth muscle actin, while
2011; Zhou et al. 2013; Bosse et al. 2014). ALK-1 they are negative for desmin and CD34 (Magro
protein can be expressed in about 40–50% of 2016). Unlike MFB, low-grade (fibromatosis-
cases (Zhou et al. 2013; Bosse et al. 2014). like) spindle cell carcinoma exhibits, at least
Apart from the more eosinophilic cytoplasm of focally, infiltrative margins with projections into
the cells and the more organized fascicular growth adjacent mammary parenchyma (Wargotz et al.
pattern, leiomyoma can be distinguished from 1989; Gobbi et al. 1999; Sneige et al. 2001; Carter
MFB by demonstrating diffuse coexpression of et al. 2006; Dwyer and Clark 2015).
desmin, alpha-smooth muscle actin, and Immunostaining of neoplastic cells, at least
Mammary Myofibroblastoma, Table 3 Mammary Myofibroblastoma: differential diagnosis

Differential diagnosis of myofibroblastoma
Myofibroblastoma Imaging features: Well-circumscribed nodule
Histology: Short, haphazardly intersecting fascicles interrupted by
keloid-like collagen fibers
Immunohistochemistry: Staining with desmin, CD34, estrogen, and
progesterone receptors; variable expression of alpha-smooth muscle
actin, bcl2, CD10, CD99; pancytokeratins, S100 protein, beta-catenin,
and STAT6 are negative
PASH (fascicular variant) Imaging features: Not detectable; occasionally nodule with
circumscribed margins
Histology: Short fascicles of spindle cells set in a fibrous stroma
Immunohistochemistry: Staining with CD34; variable expression of
alpha-smooth muscle actin and desmin
Reactive spindle cell nodule Imaging features: Nodule with circumscribed margins, following
biopsy or FNAC
Histology: Short fascicles; focal storiform pattern; haemosiderin
deposition; foamy and hemosiderin-laden macrophages,
lymphocytes and plasma cells; fat necrosis and foreign body giant
cell reaction
Immunohistochemistry: Staining with alpha-smooth muscle actin;
CD34, desmin, beta-catenin and pancytokeratins are negative
Nodular fasciitis Imaging features: Ill-defined margins, at least focally
Histology: Short, focally intersecting fascicles; foci of extravasated red
blood cells and lymphocytes; tissue culture-like appearance
CD34, desmin, beta-catenin and pancytokeratins are negative
Inflammatory pseudotumor/ Imaging features: Well-circumscribed nodule M
inflammatory myofibroblastic tumor Histology: Spindle cell proliferation, often with swirling storiform
pattern, admixed with inflammatory cells (mainly lymphocytes and
plasmacells)
Immunohistochemistry: Variable staining with alpha-smooth muscle
actin, desmin, ALK-1 and pancytokeratins; CD34, beta-catenin and
STAT6 are negative
Leiomyoma Imaging features: Well-circumscribed nodule
Histology: Deeply eosinophilic spindle cells with cigar-shaped nuclei,
arranged in intersecting fascicles
Immunohistochemistry: Staining with desmin, alpha-smooth muscle
actin and h-caldesmon; CD34, pancytokeratins, beta-catenin and STAT6
are negative
Solitary fibrous tumor Imaging features: Well-circumscribed nodule
Histology: Short fibroblast-like spindle to round/ovoid cells, haphazardly
arranged; focal storiform pattern
Immunohistochemistry: Staining with CD34 and STAT6; desmin,
alpha-smooth muscle actin and pancytokeratins are negative
Desmoid-type fibromatosis Imaging features: Ill-defined, often infiltrative margins
Histology: Long fascicles, focally intersecting
Immunohistochemistry: Staining with alpha-smooth muscle actin
and beta-catenin; CD34, desmin, pancytokeratins and STAT6 are
negative
Low-grade (fibromatosis-like) spindle Imaging features: Fairly defined margins
cell carcinoma Histology: Proliferation of spindle cells with, at least focally, mild to
moderate nuclear atypia; scattered clusters of epithelioid to polygonal
(continued)
Mammary Myofibroblastoma, Table 3 (continued)

Differential diagnosis of myofibroblastoma
cells; occasionally small squamous-glandular structures and/or foci of in
situ or invasive carcinoma
Immunohistochemistry: Staining with pancytokeratins and p63;
variable expression of alpha-smooth muscle actin and desmin; CD34,
beta-catenin and STAT6 are negative
Low-grade myofibroblastic sarcoma Imaging features: Fairly circumscribed nodule
Histology: Proliferation of spindle cells with fascicular arrangement; low
to focally moderate nuclear pleomorphism; occasionally severe nuclear
pleomorphism
desmin, pancytokeratins, beta-catenin, CD34 and STAT6 are negative
focally, with epithelial (cytokeratins) and progesterone receptors, while it is negative for
myoepithelial (p63) markers is mandatory for beta-catenin (Magro et al. 2000a). Epithelioid-
making the diagnosis of spindle cell carcinoma. cell MFB may be misinterpreted as an invasive
Apart from the spindle cells, cytokeratins usually lobular carcinoma (▶ Invasive Lobular Carci-
highlight the neoplastic cells with epithelioid to noma) as the neoplastic cells may adopt a single
polygonal morphology, often arranged in small cell and/or single-cell files growth patterns
cohesive clusters (Dwyer and Clark 2015). This (Magro 2009, 2012; Magro et al. 2013a). How-
finding is an important diagnostic clue. Finally, ever, lobular carcinoma has infiltrative margins,
low-grade myofibroblastic sarcoma (low-grade expresses epithelial markers (cytokeratins and
myofibrosarcoma) is a tumor with higher mitotic EMA), and is negative for myogenic markers
activity (7 to 35 mitoses per10 high power fields) (desmin, alpha-smooth muscle actin). Patholo-
and stained with alpha-smooth muscle actin, gists should also keep in mind that epithelioid
while the expression of desmin and CD34 is cells may occasionally exhibit a deciduoid-like
lacking (Taccagni et al. 1997; Gocht et al. 1999; appearance, making more difficult the recognition
Lucin et al. 2003; Morgan et al. 2005). of a tumor as MFB (Magro et al. 2008). Deciduoid
Among the morphological variants of MFB, cell MFB should be distinguished from malignant
lipomatous and epithelioid/deciduoid cell MFB tumors such as invasive pleomorphic lobular carci-
are unusual enough to deserve a separate differ- noma, apocrine carcinoma, metastatic pleomorphic
ential diagnosis. Due to their alarming morphol- rhabdomyosarcoma, melanoma, or malignant
ogy, they can represent potential diagnostic rhabdoid tumor (Magro et al. 2008). The well-
pitfalls and confused with more aggressive circumscribed margins, the absence or low mitotic
lesions, especially in core biopsies (Magro 2009; count (up 2 mitoses 10 HPF), the presence of
Wahbah et al. 2011; Bakuła-Zalewska et al. 2012; keloid-like collagen fibers, and the expression of
Alizadeh et al. 2015; Arafah et al. 2015). The myogenic markers are all features supporting the
former is an uncommon variant, which shows a diagnosis of MFB (Magro et al. 2008).
close admixture of spindle cells with adipocytes, Interestingly some cases of mammary MFB
resulting in a fibromatosis-like growth pattern. may exhibit hybrid features with a lipomatous com-
However, lipomatous MFB has well- ponent intermingling with epithelioid cells
circumscribed margins and the lipomatous com- (Wahbah et al. 2011; Alizadeh et al. 2015). These
ponent is an integral part of the tumor and not are diagnostically challenging cases which are
entrapped tissue due to infiltration of neoplastic often misdiagnosed as invasive lobular carcinomas
cells into adjacent breast parenchyma (Magro (▶ Invasive Lobular Carcinoma) in core biopsy due
et al. 2000a). Unlike desmoid-type fibromatosis, to the apparent pseudo-infiltrative pattern of epithe-
it is stained with desmin, CD34, and estrogen/ lioid cells, singly dispersed or arranged in files,
admixed with the intratumoral fatty tissue. The Flucke, U., van Krieken, J. H., & Mentzel, T. (2011).
diagnosis of invasive lobular carcinoma will prompt Cellular angiofibroma: Analysis of 25 cases emphasiz-
ing its relationship to spindle cell lipoma and
pathologists to perform immunohistochemical ana- mammary-type myofibroblastoma. Modern Pathology,
lyses for defining the tumor profile and the demon- 24, 82–89.
stration of estrogen/progesterone receptors, Fukunaga, M., & Ushigome, S. (1997). Myofibroblastoma
typically observed in MFB, will further support of the breast with diverse differentiation. Archives of
Pathology & Laboratory Medicine, 121, 599–603.
the mistaken diagnosis of carcinoma (Magro 2009; Fukunaga, M., Endo, Y., & Ushigome, S. (1996). Atypical
Wahbah et al. 2011). Awareness of the lipomatous leiomyomatous features in myofibroblastoma of the
and epithelioid/deciduoid cell MFB is crucial for breast. Histopathology, 29, 592–593.
pathologists, who should always correlate morphol- Garijo, M. F., Val-Bernal, J. F., Vega, A., & Val, D. (2008).
Postoperative spindle cell nodule of the breast: Pseudo-
ogy with clinico-radiologic information. Immuno- sarcomatous myofibroblastic proliferation following
histochemistry, including myogenic and epithelial endosurgery. Pathology International, 58, 787–791.
markers, is mandatory in ambiguous cases. Gobbi, H., Simpson, J. F., Borowsky, A., Jensen, R. A., &
Page, D. L. (1999). Metaplastic breast tumors with a
dominant fibromatosis-like phenotype have a high risk
of local recurrence. Cancer, 85, 2170–2182.
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& Simpson, J. F. (2000). Reactive spindle cell nodules
Alam, F. M., Samarasinghe, D. S., & Pillai, R. G. (2002). of the breast after core biopsy or fine-needle aspiration.
Myofibroblastoma of the breast in an adolescent. Saudi American Journal of Clinical Pathology, 113,
Medical Journal, 23, 232–233. 288–294.
Alizadeh, L., Alkhasawneh, A., Reith, J. D., & Gocht, A., Bosmuller, H. C., Bassler, R., Tavassoli, F. A.,
Al-Quran, S. Z. (2015). Epithelioid myofibro- Moinfar, F., Katenkamp, D., Schirrmacher, K., Lüders,
blastoma of the breast: A report of two cases with P., & Saeger, W. (1999). Breast tumors with
discussion of diagnostic pitfalls. The Breast Journal, myofibroblastic differentiation: Clinicopathological
21, 669–673. observations in myofibroblastoma and
Arafah, M. A., Ginter, P. S., D’Alfonso, T. M., & Hoda,
S. A. (2015). Epithelioid mammary myofibroblastoma
myofibrosarcoma. Pathology, Research and Practice,
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mimicking invasive lobular carcinoma. International Gurzu, S., & Jung, I. (2012). Male breast cellular myofibro-
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A potential pitfall in core needle biopsy of breast & Rosen, P. P. (1996). Uncommon presentation of
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Baxendine-Jones, J., Theaker, J. M., & Baldwin, L. J. 786–790.
(2001). Predominant fatty variant of myofibrolastoma Hayashi, S., Yasuda, S., Takahashi, N., Okazaki, S.,
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Vecchio, G. M., Cavaliere, A., Cartaginese, F., a glandular proliferation of uncertain malignant
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290 Microglandular Adenosis
is used when the glandular structures are more • Outcome

crowded, with a back-to-back architecture and Most case reports of MGA indicate an indolent
higher variation in size and shape; epithelial pro- behavior (Tavassoli and Norris 1983) with an
liferation, as well as nuclear atypia and mitotic excellent clinical outcome. However, carcino-
activity, can be present. mas arising from or in conjunction with micro-
glandular adenosis have been reported in a
nonnegligible fraction of cases (up to 27%)
Clinical Features (Shui and Yang 2009). The prognosis of
CaMGA depends on the histologic type, grade,
• Incidence and stage of the invasive component.
MGA is an exceedingly rare breast lesion.
• Age
Macroscopy
It affects patients with an age range between
adolescence and senescence.
On gross examination, microglandular adenosis
• Sex
may be undetectable or appear as a poorly
All reported patients with microglandular
circumscribed dense area (Lakhani et al. 2012).
adenosis are female.
• Site
There is no predilection for a particular quad-
rant in the breast. MGA can be unifocal or Microscopy
multifocal (Clement and Azzopardi 1983).
• Clinical Presentation Microscopically, MGA is a non-lobulocentric
MGA usually is asymptomatic and may pre- proliferation of microglandular structures that
sent as a microscopic lesion or as a palpable features an infiltrative growth pattern in adipose/
mass (Rosen 1983). It can be associated with fibrotic mammary stroma, without a desmoplastic
other benign breast lesions (cysts, sclerosing reaction. At low magnification, the glands
adenosis, and fibroadenoma) (Clement and appear round, regular, similar in size, with open
Azzopardi 1983). A specific mammographic lumina (Fig. 1a) but they appear haphazardly
pattern has not been described; nevertheless, arranged. Eosinophilic, periodic acid-Schiff
MGA can present on radiograms as an area (PAS)-positive, and diastase-resistant material
of increased density or show calcifications is frequently present in glandular lumina
only (Rosenblum et al. 1986). (Lakhani et al. 2012), occasionally forming
AMGA and carcinoma arising in calcium deposits. The tubules are covered by a
microglandular adenosis (CaMGA) appear single epithelial cell layer and they lack
mammographically as an infiltrative lesion myoepithelial cells (Clement and Azzopardi
(Khalifeh et al. 2008). 1983), even though they are surrounded by a
• Treatment basement membrane. MGA cells are cuboidal
Since MGA and AMGA may recur or flat, have clear to eosinophilic cytoplasm
if incompletely resected, excision with free without apical snouts; nuclei are cytologically
margins represents the standard treatment bland, mitotic figures are uncommon. On the
when a diagnosis of MGA without evidence contrary, AMGA presents cytologic abnormalities
of an invasive carcinoma is performed on such as architectural complexity, irregular glands,
core needle biopsy (Khalifeh et al. 2008; cellular expansion in lumina, prominent nucleoli,
Salarieh and Sneige 2007). Close follow-up rare mitoses, and focal apoptotic figures (Shin
is recommended, especially for AMGA et al. 2009).
(Rosen 1983). Mastectomy and axillary dissec- A large number of breast malignancies, includ-
tion are recommended when carcinoma ing ductal and lobular carcinoma in situ (▶ Ductal
in MGA is detected (James et al. 1993). Carcinoma In Situ, ▶ Lobular In Situ Neoplasia),
Microglandular Adenosis 291
M
Microglandular Adenosis, Fig. 1 Representative pho- for S100 protein. (c) Estrogen and progesterone receptors
tomicrographs of microglandular adenosis diagnosed are not expressed. (d) Absence of a myoepithelial cell layer
on core biopsy. (a) The microglandular proliferation around the glandular structures, as shown by immunohis-
shows an infiltrative growth pattern and is haphazardly tochemistry with anti-p63 antibody (a normal lobule serves
distributed in the fibro-fatty mammary tissue (H&E). (b) as internal positive control)
The cells lining the tubules show strong nuclear staining
adenomyoepithelioma (▶ Adenomyoepithelioma), HER2 (Fig. 1c). In addition, MGA/AMGA typically

basal-like carcinoma, adenoid cystic carcinoma show S100 protein expression (Fig. 1b), as well as
(▶ Adenoid Cystic Carcinoma), matrix-producing positivity for low-molecular-weight cytokeratin
carcinoma, and spindle cell carcinoma (▶ Invasive markers (CAM 5.2, AE1 or CK8-18). Myoepithelial
Metaplastic Carcinoma) can be seen in conjunction markers are undetectable as a myoepithelial cell
with microglandular adenosis (Foschini and Eusebi layer is missing (Fig. 1d) (Tavassoli and Bratthauer
2018). 1993); however, collagen IVand laminin expression
Cartilaginous or chondroid metaplasia also confirms the presence of a basement membrane. The
has been reported in AMGA and CaMGA. proliferation index evaluated by Ki67 expression is
generally low.
Immunophenotype
Molecular Features
MGA and AMGA are characterized by a triple
negative phenotype, lacking expression for Genetic analyses by array-based comparative
estrogen receptor, progesterone receptor, and genomic hybridization and next-generation
292 Microglandular Adenosis
sequencing have shown that MGA and AMGA AMGA, the glandular distribution of tubular car-
associated with triple negative carcinomas share cinoma is usually stellate, the glands are angular
clonal genetic alterations with invasive carcino- and the stroma is frequently desmoplastic. Most
mas, such as TP53 mutations (Guerini-Rocco important, tubular carcinomas typically are estro-
et al. 2016; Geyer et al. 2009, 2012; Shin et al. gen receptor positive.
2009). Of note, pure MGA/AMGA (i.e., with MGA and AMGA also share striking similarities
no association with an infiltrative carcinoma) fea- with acinic cell carcinomas (▶ Acinic Cell Carci-
ture simpler genetic profiles and lack TP53 muta- noma), showing a microglandular growth pattern, a
tions (Guerini-Rocco et al. 2016; Geyer et al. triple negative phenotype, and S100 protein expres-
2012). Taken together, these data suggest that sion. Contrary to MGA/AMGA, acinic cell carcino-
a subset of MGA/AMGA can be considered as mas may display a solid pattern with comedo-like
a clonal neoplastic lesion and a non-obligate pre- necrosis and intracytoplasmic zymogen-type gran-
cursor of high-grade, triple negative breast cancer, ules, relevant mitotic activity and express high
underpinned by TP53 mutations. levels of EMA and acinar differentiation markers
It is interesting to note that MGA/AMGA (lysozyme and amylase) (Lakhani et al. 2012).
and acinic cell carcinomas (ACC) (▶ Acinic Cell
Carcinoma), a special histologic subtype of
triple negative breast cancer, share histologic and References and Further Reading
immunophenotypic similarities. When analyzed at
the genetic level, no significant differences Clement, P. B., & Azzopardi, J. G. (1983). Microglandular
in mutation burden and repertoire were detected adenosis of the breast – A lesion simulating tubular
carcinoma. Histopathology, 7, 169–180.
between MGA/AMGA/ACC analyzed (either indi- Foschini, M. P., & Eusebi, V. (2018). Microglandular
vidually or as a whole group) and conventional adenosis of the breast: A deceptive and still mysterious
triple negative breast carcinomas (Geyer et al. benign lesion. Human Pathology, 82, 1–9.
2017). These data support the existence of a “low- Geyer, F. C., Kushner, Y. B., Lambros, M. B., Natrajan, R.,
Mackay, A., Tamber, N., . . . & Reis-Filho, J. S. (2009).
grade breast neoplasia family,” which encompasses Microglandular adenosis or microglandular adenoma?
triple negative lesions such as MGA, AMGA, and A molecular genetic analysis of a case associated with
ACC that, despite their low-grade morphology and atypia and invasive carcinoma. Histopathology, 55,
good outcome, recapitulate the complex genomic 732–743.
Geyer, F. C., Lacroix-Triki, M., Colombo, P. E., Patani, N.,
landscape of common forms of triple negative Gauthier, A., Natrajan, R., . . . & Marchio, C. (2012).
breast cancers (Geyer et al. 2017). Molecular evidence in support of the neoplastic and
precursor nature of microglandular adenosis.
Histopathology, 60, E115–E130.
Geyer, F. C., Berman, S. H., Marchiò, C., Burke, K. A.,
Differential Diagnosis Guerini-Rocco, E., Piscuoglio, S., . . . & Schnitt, S. J.
(2017). Genetic analysis of microglandular adenosis and
Numerous breast lesions may display a micro- acinic cell carcinomas of the breast provides evidence for
glandular pattern, such as sclerosing adenosis the existence of a low-grade triple-negative breast neo-
plasia family. Modern Pathology, 30, 69.
(▶ Sclerosing Adenosis), adenomyoepithelial Guerini-Rocco, E., Piscuoglio, S., Ng, C. K., Geyer, F. C.,
adenosis (▶ Adenosis, Other Types), or tubular De Filippo, M. R., Eberle, C. A., . . . & Yatabe, Y. (2016).
carcinoma (▶ Tubular Carcinoma), and can be Microglandular adenosis associated with triple-negative
misinterpreted as MGA (Foschini and Eusebi breast cancer is a neoplastic lesion of triple-negative
phenotype harbouring TP53 somatic mutations. The
2018). Contrary to MGA, sclerosing adenosis Journal of Pathology, 238, 677–688.
shows a dense and hyalinized stroma that creates James, B. A., Cranor, M. L., & Rosen, P. P. (1993).
distorted glandular structures. Of note, sclerosing Carcinoma of the breast arising in microglandular
adenosis and adenomyoepithelial adenosis retain adenosis. American Journal of Clinical Pathology,
100, 507–513.
a myoepithelial cell layer (Foschini and Eusebi Khalifeh, I. M., Albarracin, C., Diaz, L. K.,
2018). Adenomyoepithelial adenosis also is Symmans, F. W., Edgerton, M. E., Hwang, R. F., &
strongly immunoreactive for GCDFP-15. Unlike Sneige, N. (2008). Clinical, histopathologic, and
Microinvasive Carcinoma of the Breast 293
immunohistochemical features of microglandular Definition

adenosis and transition into in situ and invasive
carcinoma. The American Journal of Surgical
Pathology, 32, 544–552. Microinvasive carcinoma (MIC) of the breast was
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., & not clearly characterized until 1997 when the
van de Vijver, M. J. (2012). WHO classification of Union for International Cancer Control (UICC)
tumors of the breast (pp. 106–107). World Health first included pT1mic in the TNM classification
Organization. Lyon, France. ISBN-10: 9283224337.
Rosen, P. P. (1983). Microglandular adenosis. A benign lesion of breast carcinoma. It was defined as “invasive
simulating invasive mammary carcinoma. The American mammary carcinoma with no focus exceeding
Journal of Surgical Pathology, 7, 137–144. 1 mm in greatest dimension.”
Rosenblum, M. K., Purrazzella, R., & Rosen, P. P. (1986). This definition has been carried through many
Is microglandular adenosis a precancerous disease?
A study of carcinoma arising therein. The American editions of the Cancer Staging Manual published
Journal of Surgical Pathology, 10, 237–245. by American Joint Committee on Cancer (AJCC)
Salarieh, A., & Sneige, N. (2007). Breast carcinoma arising in until the current edition (Amin et al. 2017) where
microglandular adenosis: A review of the literature. it is reported as “an invasive carcinoma with no
Archives of Pathology & Laboratory Medicine, 131,
1397–1399. focus measured larger than 1 mm and classified
Shin, S. J., Simpson, P. T., Da Silva, L., Jayanthan, J., as pT1mi. MIC is reported as nearly always
Reid, L., Lakhani, S. R., & Rosen, P. P. (2009). encountered in a setting of ductal carcinoma in
Molecular evidence for progression of microglandular situ (DCIS) (▶ Ductal Carcinoma In Situ)
adenosis (MGA) to invasive carcinoma. The American
Journal of Surgical Pathology, 33, 496–504. (Fig. 1, (a) H&E. (b) Immunostaining for
Shui, R., & Yang, W. (2009). Invasive breast carcinoma smooth-muscle myosin heavy chain highlights
arising in microglandular adenosis: A case report and myoepithelial cells around the DCIS, while it is
review of the literature. The Breast Journal, 15, absent in the invasive focus) or, infrequently,
653–656.
Tavassoli, F. A., & Bratthauer, G. L. (1993). lobular carcinoma in situ (LCIS) (▶ Lobular In
Situ Neoplasia) (Fig. 2, H&E), where small foci
Immunohistochemical profile and differential
diagnosis of microglandular adenosis. Modern Pathol- of tumor cells invaded through the basement
M
ogy, 6, 318–322. membrane into the surrounding stroma, although
Tavassoli, F. A., & Norris, H. J. (1983). Microglandular
adenosis of the breast. A clinicopathologic study rare cases are encountered in the absence on non-
of 11 cases with ultrastructural observations. The invasive disease” (Fig. 3, H&E) (Bianchi and
American Journal of Surgical Pathology, 7, 731–737. Vezzosi 2008).
The most recent World Health Organization
(WHO) Classification of Tumors of the Breast
(Pinder et al. 2012) defines MIC “as a lesion
Microinvasive Carcinoma of characterized by one or more clearly separate
the Breast microscopic foci of infiltration of tumor cells
into the mammary stroma, each less than or
Simonetta Bianchi and Vania Vezzosi equal to 1 mm in size, and most commonly seen
Division of Pathological Anatomy, in the background of high nuclear grade DCIS.”
Department of Surgery and Translational This definition is very restrictive and tumors
Medicine, University of Florence, fulfilling the criteria are consequently rare.
School of Human Health Sciences, Historically, there has been wide variation in
Florence, Italy the definition of MIC of the breast. The term
“microinvasion” was introduced in breast pathol-
ogy by Lagios in 1982 as synonymous of invasion
Synonyms less than 1 mm. Although this term has been
reported for many years, it has not been applied
Microinvasive carcinoma, pT1mi, Invasive carci- in a consistent, standardized manner. A variety
noma less than or equal to 1 mm in greatest of different definitions have been used for MIC
dimension such as:
294 Microinvasive Carcinoma of the Breast
Microinvasive Carcinoma of the Breast, mononuclear cell infiltrate. (b) (Immunohistochemistry):

Fig. 1 Microinvasive carcinoma. (a) (H&E): A duct These irregular small tumor cell nests lack a surrounding
with high grade ductal carcinoma in situ and an area myoepithelial cell layer, consistent with stromal invasion
with irregular small tumor cell nests surrounded by a
Microinvasive Carcinoma of the Breast, Fig. 2 Microinvasive Carcinoma of the Breast, Fig. 3
(H&E): Microinvasive lobular carcinoma associated (H&E): Microinvasive lobular carcinoma not associated
with LCIS with ductal or lobular carcinoma in situ
• DCIS with limited microscopic stromal inva-

• DCIS with evidence of stromal invasion sion below the basement membrane but not
• DCIS showing focal microinvasion below the invading more than 10% of the surface of the
basement membrane in one or several individ- histological sections examined
ual ducts but not more than 10% of the surface • The maximal extent of invasion is not more
of the histological sections examined than 2 mm or comprising <10% of the tumor,
• Breast cancer cells confined to the duct system with 90% of DCIS
of the breast with only a microscopic focus of • A single focus of invasive carcinoma 2 mm
malignant cells invading beyond the basement or up to three foci of invasion each not more
membrane of the duct as determined by light than 1 mm in greatest dimension
microscopy • A few single infiltrating tumor cells (from
• One or more microscopic foci of possible inva- 1 to 15) or a few infiltrating tumor cell clusters,
sion not >1 mm in greatest dimension defined as ductal carcinoma in situ with
microinvasion (DCIS-MI) type 1 and type 2, accepted agreement particularly about the maxi-
respectively. mum diameter compatible with a diagnosis of
microinvasion.
This lack of a uniform definition for MIC has In the fourth edition of the European Guide-
clearly contributed to the confusion regarding this lines for Quality Assurance in Breast Cancer
entity. Screening and Diagnosis published in 2006,
The fifth edition of the AJCC Cancer Staging formed on the major basis of UK guidelines,
Manual published in 1997 recognizes a specific MIC was defined as a “tumor in which the dom-
T substage for MIC, defined as “the extension of inant lesion is in-situ carcinoma (usually exten-
cancer cells beyond the basement membrane into sive high nuclear grade DCIS, rarely other types
the adjacent tissues with no focus more than of DCIS or LCIS) but in which there are one or
0.1 cm in greatest dimension” and formally more, clearly separate, foci of infiltration of non-
reported it as pT1mic. The AJCC Cancer Staging specialized interlobular or interductal fibrous or
Manual further stated that “when there are multi- adipose tissue, none measuring more than 1 mm
ple foci of microinvasion, the size of only the (about 2 high power fields) in maximum diameter.
largest focus is used to classify the microinvasion When there are multiple foci of MIC only the
and that the size of the individual foci should not size of the largest focus is used to classify the
be added together; the presence of multiple foci of microinvasion; the presence of multiple foci of
microinvasion should however be noted and/or microinvasion should however be noted and/or
quantified, as it is with multiple larger invasive quantified.”
carcinomas”. Not all authors accept the definition of MIC
Following the establishment of a National that requires “clearly separate foci of infiltration
Breast Screening Programme in the United of nonspecialized interlobular stroma”: tumor
Kingdom, a Working Group of the Royal Col- cells are, in fact, not known to leap or jump
lege of Pathologists produced in 1990 a docu- or dissociate from the in situ component in order
M
ment on Pathology Reporting in Breast Cancer to invade the stroma, in three dimension micro-
Screening where MIC was defined as “a tumor in invasive tumor foci would be seen to grow
which the dominant lesion is noninvasive but in as solid cords extending from in situ area; further-
which there are one or more foci of infiltration, more the unequivocal influence of the plane
none of which measures more than 1 mm (about of section on the detection of continuity between
2 high power fields) in maximum diameter. the in situ and invasive component render
Small invasive carcinomas without an in situ the requirement “clearly separate foci” invalid;
component are classified as invasive.” In the moreover the “infiltration of nonspecialized
second edition of the Pathology Reporting in interlobular stroma” has been considered a
Breast Cancer Screening published in 1995, it requirement untenable since vascular invasion
is proposed that “only when unequivocal inva- can occur even within the lobular stroma due to
sion is seen outside the specialized lobular the presence of vascular channels both within
stroma, namely into the non-specialized the specialized lobular stroma and immediately
interlobular stroma, should MIC be diagnosed. surrounding the basement membrane that invests
If there is sufficient doubt about the presence of ductules.
invasion, the case should be classified as in situ Considering the difficulty to ascertain exten-
carcinoma.” sion of malignant cells beyond the specialized
In the 2003 edition of WHO Classification of lobular stroma, the current WHO Classification
Tumours of the Breast and Female Genital of Tumours of the Breast (Pinder et al. 2012)
Organs, in spite of the pT1mic category officially reports that MIC is diagnosed when convincing
being recognized by the fifth edition of the AJCC histological features are present, despite malig-
Cancer Staging Manual, MIC was still considered nant cells not being clearly beyond the specialized
an evolving concept as there was no generally lobular stroma.
Clinical Features low-volume metastases and consequently a

low risk of additional metastases in axillary
There are no specific clinical or radiologic fea- lymph nodes, therefore complete axillary
tures associated with MIC. lymph node dissection is not recommended.
In cases where MIC arises in association with in A recent meta-analysis of nearly 1000
situ lesions (prevalently high nuclear grade DCIS, patients with MIC who underwent SLNB
other types of DCIS and, more rarely, classic or showed that the SLN-positivity rate for macro-
pleomorphic LCIS (▶ Lobular In Situ Neoplasia) metastasis was, even in the worst-case
the clinical presentation is dictated by the in situ scenario, acceptably low (5.6%); similar
carcinoma (mammographically detected micro- low positivity rates were observed for micro-
calcifications, or less commonly a mass, asymme- metastases or ITC, concluding that the
try, architectural distorsion). indication for SLNB in patients with MIC
should be probably individualized. Conse-
• Incidence quently, an accurate preoperative diagnosis
Uncommon; the incidence rate of MIC ranges distinguishing MIC from frankly invasive car-
from 0.7% to 2.4% (mean less than 1% of all cinoma on percutaneous needle core biopsy
breast cancers). (NCB) or vacuum-assisted needle core biopsy
• Age (VANCB) should be made because size of
MIC occurs throughout the age range of breast invasive carcinoma could impact on surgical
carcinoma. decisions.
• Sex Only few studies have evaluated the role
Female patients, rarely in male patients. of systemic adjuvant therapy in patients with
• Site MIC. Further studies with prolonged follow-up
No specific sites in breast. of large cohorts are necessary to assess the
• Treatment significance of systemic treatment in MIC.
The majority of patients, reported in literature • Outcome
with MIC, were treated with mastectomy. Considering the variety of definitions that have
However, breast-conserving surgery has been been used to report MIC and that some lesions
described as effective as mastectomy in several categorized as MIC based on limited tissue
reports. The presence of MIC probably has sampling could actually represent frankly inva-
little independent impact on the effectiveness sive carcinomas not submitted for histological
of local control in the breast. The characteris- examination or not represented on the slides
tics of in situ lesion that is associated with MIC because the cancer was deeper in the blocks,
are crucial determinants for the type of surgical robust data on the clinical behavior of MIC are
treatment (mastectomy versus breast conserv- not available. Moreover the paucity and the
ing therapy). nonuniformity of the clinical outcome data
Although most clinicians have abandoned have led to uncertainty regarding the separa-
the routine use of sentinel lymph node biopsy tion of MIC from in situ carcinomas and from
(SLNB) in patients with in situ carcinoma small invasive carcinomas.
(DCIS and pleomorphic LCIS), many still The prevailing view is that MIC has an excel-
believe that there is a subset of patients with lent prognosis with a low risk of associated
in situ carcinoma at high risk for MIC and axillary lymph node metastasis. The reported
subsequent axillary metastases who may ben- incidence of axillary lymph node metastases in
efit from the SLNB. At present SLNB is a patients given the diagnosis of MIC ranges from
common clinical practice in treatment of 0% to 28% (mean 9.4%) This wide range may
patients with DCIS and MIC due to the possi- be explained by both the different histopatho-
bility of axillary lymph node metastases. How- logical criteria used to define MIC and the var-
ever, most MICs with a positive SLN have iable degree of breast tissue sampling, but it also
depends on the different techniques utilized to a smooth border surrounded by a circumferential

examine axillary lymph nodes (only H&E or layer of myoepithelial cells and stroma or a thick-
H&E plus immunohistochemistry (IHC) for ened basement membrane.
cytokeratins), especially after the introduc- At sites of microinvasive focus, tumor cells are
tion of SLNB. Moreover, the relatively high distributed singly or as small groups having irreg-
frequency of axillary lymph node metastasis ular shapes reminiscent of conventional invasive
reported is due to considering as positive also carcinoma with no particular orientation (Hoda
lymph nodes with isolated tumor cells. It is 2014).
likely that when current AJCC definitions for When microinvasion occurs, especially in
microinvasion and lymph node status are cases associated with in situ lesions, it is likely
used [“isolated tumor cells” have been to be multifocal. It is therefore appropriate to
down-staged as pN0(i+)], the true frequency search carefully for additional small foci and to
of axillary lymph node involvement will be confirm that the size of each focus does not exceed
quite low. Clinical outcome of MIC associ- 1 mm in greatest dimension, the number of foci
ated to in situ lesion is reported to be more and the range of their sizes, including the largest,
similar to in situ lesion than small invasive should be reported. The sum of the sizes should
carcinoma pT1a (>1 mm and less than or not be used to determine pathological T factor.
equal to 5 mm.) When reporting the number of multiple foci is
Data on clinical behavior of MIC not asso- difficult, it is recommended that an estimate of
ciated to an in situ lesion are not available; the number be provided or, alternatively, a note
presumably, it will likely be more similar to that the number of microinvasive foci is too
DCIS than small invasive carcinoma pT1a. numerous to quantify but that no identified focus
The number of microinvasive foci does not is larger than 1 mm.
have an impact on prognosis. Absence of basement membrane components
(laminin and type IV collagen) around nests
M
of tumor cells and of myoepithelial cells are useful
Macroscopy
to define invasion. However, immunohistochem-
istry (IHC) for laminin and type IV collagen is
MIC cannot, by definition, be identified on
reported to be technically problematic in formalin-
gross pathologic examination, and it is typically
fixed paraffin-embedded tissue. Moreover, in situ
detected during microscopic examination of
lesions may show variable basement membrane
breast specimens containing benign lesions or in
loss and cells of invasive cancer can still synthe-
situ carcinoma.
size some components of basement membrane
around invasive nests; therefore the use of
basement membrane markers for the detection of
Microscopy stromal invasion is not formally recommended
and, when performed, should be interpreted with
The tumor focus/foci must usually invade into caution.
the mammary stroma (specialized lobular, IHC for myoepithelial markers is
interlobular or periductal stroma). recommended in cases of doubt about the
The cells deemed to be invasive must be dis- presence or absence of microinvasion, moreover
tributed in a non-organoid pattern that does not the use of IHC results in marked improvement of
represent tangential sectioning of a duct or a lob- the diagnostic consistency in identifying MIC
ular structure involved by in situ carcinoma. (Cserni et al. 2016). However, myoepithelial cell
Tangentially sectioned foci of in situ carcinoma markers vary in their sensitivity and specificity,
that simulate microinvasion are within the special- and the use of a panel (e.g., p63, calponin, smooth
ized lobular and periductal stroma and usually muscle myosin heavy chain) is advised (Hilson
occur as compact groups of tumor cells that have et al. 2009).
Smooth-muscle myosin heavy chain (SMM-HC) Molecular Features

and calponin are the most common antibodies used
to identify myoepithelial cells. SMM-HC is slightly Two possible explanations have been proposed
less sensitive than calponin. Actin antibodies (such for higher rate of HER2 positivity reported in
as 1A4 and HHF-35 clones) are the least specific MIC: first, that HER2-positive in situ
reacting also with myofibroblasts. Antibodies to cancers are likely to be detected at mammographic
p63, a member of the p53 gene family, offer better screening because they have large comedo micro-
sensitivity and specificity for myoepithelial cells calcifications; second, that due to its strong immu-
than SSM-HC and calponin. However, p63 anti- nogenicity, HER2 causes increased accumulation
bodies have some limitations as well: (1) they occa- of tumor-infiltrating lymphocytes (TILs) espe-
sionally demonstrate an apparently discontinuous cially CD8+ cytotoxic T lymphocytes already
myoepithelial layer around nests of in situ lesions in the in situ stage and that a disruption of
and (2) they react with a small but significant subset myoepithelial cells and basement membrane
of breast carcinomas, especially of basal phenotype occurs during the stage of healing, so that cancer
although this aberrant reactivity rarely causes diag- cells are exposed in the stroma as cluster-like
nostic difficulties. invasion that leads to formation of MIC.
Detecting MIC can be difficult when there is a Most MIC are reported to develop from high
marked periductal fibrosis or inflammation; in grade DCIS; however, MIC has been found to be
these cases, IHC for cytokeratin may be of partic- associated also with low- and intermediate grade
ular value in confirming the presence of separate DCIS; on this basis, the presence of two different
foci of neoplastic cells embedded in periductal progressive pathways, “low grade luminal” path-
fibrosis or inflammation. MIC is typically associ- way and “high grade HER2” pathway, has been
ated with an inflammatory cell reaction, mainly of proposed based on genomic analysis (Morita
lymphocytes. et al. 2016).
The diagnosis of MIC still remains problem- MIC is the first step in the development of
atic, even with the use of ancillary techniques. invasive carcinoma, and the lesion is positioned
If there is sufficient doubt about the presence of between in situ and frankly invasive carcinoma.
microinvasion (i.e., in cases with marked fibrosis Genetic analysis of in situ and invasive carcino-
or inflammation), the case should be classified as mas has demonstrated that both entities display
in situ carcinoma with possible microinvasion. remarkably similar genetic profiles when matched
by morphology and immunophenotype. However,
these molecular studies have failed to reveal spe-
Immunophenotype cific genetic alterations in in situ cancers associ-
ated with an invasive component and hence
There are only few studies reporting biomarkers driving progression from the in situ to the invasive
of MIC. Results of Estrogen (ER) and Progester- stage. These results support the hypothesis that
one (PR) receptors, Ki-67 expression, and HER2 the progression from in situ to invasive carcinoma
status are usually concordant between MIC and may not be necessarily determined by specific
the associated in situ lesion. If MIC is no longer genetic alterations or their consequences on gene
present on the slides recut for biomarkers, IHC expression profile.
results of the associated in situ lesion should be
reported and used as a surrogate for the
immunophenotype of MIC. Differential Diagnosis
HER2 positive status has been found signifi-
cantly higher (49%) in MIC compared with both According to Fisher, MIC “represents one of, if
invasive carcinoma >1 mm (10–15%) and DCIS not the most, commonly overdiagnosed events in
(20%); although HER2 positivity in MIC is not the pathology of breast carcinoma.” Over-
associated with nodal metastases or recurrence. diagnosing a MIC as a frankly invasive carcinoma
can be particularly harmful because it may lead to needling procedure. In cases with a history
overtreatment. of a prior needling procedure for preoperative
The differential diagnosis of MIC includes diagnosis (FNA, NCB or VANCB), the
pure in situ disease and, conversely, invasive diagnosis of MIC should be made with cau-
breast carcinoma measuring >1 mm; the size of tion because artifactual disruption of the
the focus should be carefully measured with an epithelial-stromal junction of glandular struc-
ocular micrometer to exclude frankly invasive tures involved by in situ carcinoma is not
breast carcinoma. infrequently encountered in subsequent exci-
A variety of patterns in DCIS (▶ Ductal sion biopsy or therapeutic specimen. Granu-
Carcinoma In Situ) and, more rarely, in LCIS lation tissue, old or recent hemorrhage (iron-
(▶ Lobular In Situ Neoplasia) may be mis- laden macrophages, cholesterol crystals,
interpreted as stromal invasion (Schnitt and reactive fibrosis, hemosiderin deposition), tis-
Collins 2013). Lesions and artifacts commonly sue tears, and a degenerative appearance of
mistaken for MIC include: the dislodged tumor cells can help in
distinguishing pseudo-invasion from true
1. DCIS involving lobules (“lobular invasion.
cancerization”) 8. DCIS or LCIS involving benign complex scle-
2. Chronic inflammatory reaction present in rosing lesions such as radial scar (▶ Radial
association with, and obscuring, involved Scar), sclerosing papilloma (▶ Intraductal
ducts and acini Papilloma), ductal adenoma (▶ Ductal Ade-
3. Branching of involved ducts noma), and sclerosing adenosis (▶ Sclerosing
4. Distorsion or entrapment of involved ducts or Adenosis) (Fig. 4, Ductal carcinoma in situ
acini by fibrosis (sometime due to prior nee- involving sclerosing adenosis. (a) H&E.
dling procedure) (b) Calponin immunostain).
5. Crush artifacts
M
6. Cautery effects Additional H&E-stained sections may help to
7. Artifactual displacement of DCIS or LCIS define the nature of the process in problematic
cells into the surrounding stroma or adipose cases. In many cases, IHC for myoepithelial
tissue due to tissue manipulation or a prior cells markers is of greater value for distinguishing
Microinvasive Carcinoma of the Breast, Fig. 4 Ductal the suspicion of microinvasive carcinoma.
carcinoma in situ involving sclerosing adenosis. (b) (Immunohistochemistry): Calponin immunostain dem-
(a) (H&E): Solid nests and glands composed onstrates a myoepithelial cell layer around nests and glands
of neoplastic cells in a desmoplastic stroma raising supporting the diagnosis of ductal carcinoma in situ
300 Mucocele-like Lesion
true MIC from its mimics (see “Microscopy” Low-grade luminal pathway and high grade HER2
section). pathway based on high tumor-infiltrating lymphocytes.
When there is doubt about the diagnosis of Pinder, S. E., Ellis, I. O., Schnitt, S. J., et al. (2012).
MIC or the suspicious area is no longer seen on Microinvasive carcinoma. In S. R. Lakhani, I. O.
any further sections or IHC, it is recommended Ellis, S. J. Schnitt, et al. (Eds.), WHO classification of
that the case should be diagnosed as in situ lesion tumours of the breast (pp. 96–97). Lyon: International
Agency for Research on Cancer.
with no definite evidence of MIC. Schnitt, S. J., & Collins, L. C. (Eds.). (2013). Biopsy
As reported above, MIC can be not only over- interpretation of the breast (2nd ed.pp. 267–281).
diagnosed but also underdiagnosed. MIC cannot Philadelphia: Lippincott Williams & Wilkins.
be reliably excluded unless all tissue is serially
sectioned, completely embedded, and submitted
for histological examination. This method is
now recommended in clinical guidelines Mucocele-like Lesion
as well in breast screening programs.
However it is well-known that even with a Janina Kulka
large number of paraffin blocks, only a part of 2nd Department of Pathology, Semmelweis
the tissue is examined microscopically, and University, Budapest, Hungary
pathologists can never be absolutely certain that
MIC is really absent.
Serial sections supported by IHC usually Synonyms
provide the best evidence of MIC. Care should
be taken to obtain IHC early in the evaluation Mucocele-like tumor
of suspected MIC, before the sample has been
sectioned excessively, first to confirm MIC and
second to exclude the possibility of larger Definition
invasive foci.
Rosen, who first described these lesions in 1986,
gave the following definition: “mucin containing
cysts lined by flat or low cubical epithelium with
or without extravasated mucin” (Rosen 1986).
Amin, M. B., Edge, S. B., Greene, F. L., et al. (Eds.).
(2017). AJCC cancer staging manual (8th ed.
pp. 589–628). New York: Springer. Clinical Features
Bianchi, S., & Vezzosi V. (2008). Microinvasive Carci-
noma of the Breast. Pathology and Oncology Research,
14, 105–111. • Incidence
Cserni, G., Wells, C. A., Kaia, H., et al. (2016). Since the first description by Rosen in 1986,
Consistency in recognizing microinvasion in breast single case reports or relatively small series
carcinomas is improved by immunohistochemistry for have been published. With the introduction of
myoepithelial markers. Virchows Archive, 468,
473–481. screening programs, the incidence increased
Hilson, J. B., Schnitt, S. J., & Collins, L. C. (2009). due to the associated microcalcifications. The
Phenotypic alterations in ductal carcinoma in situ- incidence of MCLLs is very low, ranging from
associated myoepithelial cells: Biologic and diagnostic 0.25% (Jaffer et al. 2011) to <1% (102 MCLL
implications. The American Journal Surgical Pathol-
ogy, 33, 227–232. cases in a population of 13,412 women with
Hoda, S. A. (2014). Ductal carcinoma in situ. biopsy proven benign breast disease) (Meares
In S. A. Hoda, E. Brogi, F. C. Koerner, & P. P. Rosen et al. 2016).
(Eds.), Rosen’s breast pathology (4th ed., pp. 331–411). • Age
Philadelphia: Lippincott Williams & Wilkins.
Morita, M., Yamaguchi, R., Tanaka, M., et al. (2016). Two Since MCLLs are very often associated with
progressive pathways of microinvasive carcinoma: microcalcifications and are discovered mainly
Mucocele-like Lesion 301
on screening mammograms, the mean age atypical ductal hyperplasia (▶ Atypical Ductal
reported is 53–55 years. Hyperplasia) or DCIS (▶ Ductal Carcinoma In
• Sex Situ), even if VACB has been the diagnostic
No MCLLs have been described in male method, further surgical excision seems the
patients to date. right treatment.
• Site • Outcome
No specific site in the breast has been According to the few large series (Jaffer et al.
described. 2011; Meares et al. 2016; Dash et al. 2017), the
• Imaging upgrade rate of MCLLs devoid of atypia diag-
The majority of these lesions are nonpalpable, nosed on VACB specimens is very low. Very
detected on screening mammograms due to close radio-pathological correlation is necessary
associated indetermined, suspicious clustered, and surgical excision can be avoided only if the
coarse or pleomorphic microcalcifications lesion had been removed entirely. In the Not-
(Davies et al. 1995) (Fig. 1). Some MCLLs tingham series (Rakha et al. 2013), 2/54 MCLL
present as a well-circumscribed mass. On ultra- without atypia on core biopsy were upgraded to
sound, cysts, cyst with calcification or a hypo- DCIS in the surgical excision specimen (4%
echoic lesion may be present. upgrade rate). However, altogether in published
• Treatment series until 2013 among all MCLLs with atypi-
The appropriate treatment of MCLL is cal hyperplasia diagnosed on either 14G needle
debated. By definition, these lesions belong to biopsies or VACB the upgrade rate is 21%. In an
the B3 category of core biopsy diagnoses, and Australian series of 117 MCLLs, the upgrade
earlier publications concluded that further sur- rate to DCIS – all low to intermediate grade –
gical excision is necessary. However, in recent was 5% (Dash et al. 2017).
years, studies documented successful removal The question of MCLL as a risk factor was
of MCLLs by vacuum-assisted core biopsy recently analyzed in one of the largest MCLL
M
(VACB), a more conservative approach that series to date (Meares et al. 2016). Thirteen out
appears to be the appropriate treatment in of 102 patients developed in situ or invasive
MCLLs without associated atypical epithelial breast cancer during the follow-up period, the
proliferation. In MCLLs associated with median time to cancer was 11.8 years. It is
Mucocele-like Lesion,
Fig. 1 Specimen
mammogram of a MCLL
detected in screening due to
the presence of coarse,
clustered
microcalcifications
noteworthy that almost half of the cancers numerous authors as part of the spectrum of
developed in the contralateral breast. With mucinous breast lesions, representing the first
14.8 years median follow-up, it was found step along the line leading to invasive mucinous
that in women younger than 45, MCLL caused carcinoma through MCLL with atypia and mucin-
only a nonsignificant increase in cancer risk ous DCIS with mucocele-like features. MCLL
compared to the general population. In may have completely bland, flattened, cuboidal,
women above that age, the cancer risk incre- or low columnar epithelium, but some cases are
ment is low – equals that of proliferative breast associated with papillary projections, epithelial
disease. atypia, or frank DCIS (mucinous type, with crib-
riform, solid, papillary, or micropapillary archi-
tecture) and association with mucinous carcinoma
Macroscopy
(▶ Invasive Mucinous Carcinoma) or no special
type invasive breast carcinoma (▶ Invasive Car-
Since MCLLs are usually less than 1 cm, non-
cinoma NST) was also reported. MCLLs associ-
palpable lesions, description of their macroscopic
ated with DCIS (▶ Ductal Carcinoma In Situ)
appearance is missing from most case reports and
may be extensive (Fig. 3, H&E: Low grade
is not emphasized either in larger case series. In
DCIS associated with MCLL). The mucin filling
the original description by Rosen, the gross
the ducts and extravasated in the stroma is PAS,
appearances were described as follows: “irregular,
mucicarmin, and also Alcian blue positive at
gelatinous, shiny area” or “ill-defined mucinous
pH 2.5, suggesting the presence of neutral to
mass,” or “multicystic colloid nodule.”
acidic mucin in these lesions. An important clue
to the diagnosis is the lack of epithelial cell clus-
ters in the extravasated mucin pools. However, the
Microscopy epithelial cells can detach from the cyst walls and
superficially may be reminiscent to the floating
MCLLs of the breast are localized lesions, affect- epithelial cell clusters so characteristic in mucin-
ing the terminal duct-lobular unit. The main fea- ous carcinomas. It is of utmost importance that in
ture is the dilatation and partial rupture of the such cases the epithelial cell clusters be thor-
mucin filled- and cystically dilated ductules and oughly analyzed: those in MCLLs are linear in
as a consequence, mucin leakage into the adjacent most of the cases, as they represent a cohesive
stroma. (Fig. 2). MCLL has been described by fragment of the lining epithelium of a mucin filled
Fig. 2 Subgross
appearance of a MCLL:
cystic, distended ductules in
a TDLU. Arrows point to
the extravasated mucin
Mucocele-like Lesion 303
Fig. 3 H&E: Low-grade
DCIS associated
with MCLL
and/or ruptured cyst. In some cases, a complete showed mainly luminal/apical or luminal/apical
arborizing papillary structure may detach from the and cytoplasmic expression. MUC2 was only
cyst wall and be present in the extravasated expressed in MCLLs associated with atypia or
mucin. Lack of cellular atypia and presence of DCIS and was positive in almost every mucinous
M
myoepithelial cells are the key for the correct carcinoma studied.
diagnosis (Tan et al. 2008). A common feature
in MCLLs leading to their identification on
screening mammograms are (indeterminate – or Molecular Features
suspicious, coarse, and polymorphic) micro-
calcifications. Calcifications are common in the To date, no molecular studies have been
mucin pools in MCLL (Fig. 4, H&E). In some performed on MCLL series.
cases, a heavy stromal lymphoid cell infiltrate is
also present around the areas of extravasated
mucin (Fig. 5). Differential Diagnosis
The most important differential diagnosis is

Immunophenotype mucinous carcinoma (▶ Invasive Mucinous Car-
cinoma). In MCLL, in the extravasated mucin, no
The epithelium in MCLL is two layered, as it is in epithelial cells are present as seen in cases of
normal breast epithelium. Demonstration of the mucinous carcinoma. However, in some cases of
presence of myoepitheial cells by p63, calponin, MCLL, the epithelial lining of the cysts can be
smooth muscle actin, or other myoepithelial detached, raising suspicion of mucinous carci-
markers may solve diagnostic dilemmas, if exist. noma. In such dubious cases, the correct diagnosis
The MUC profile of MCLLs was investigated (Kim may be assisted by the following features: in
et al. 2012) and compared to that of mucinous MCLL, the epithelial cell clusters tend to be lin-
carcinomas. MCLLs and mucinous carcinomas ear, and p63 immunohistochemistry shows the
type A showed similar MUC profile: MUC1 presence of myopithelial cells. In contrast,
Fig. 4 H&E: MCLL with
microcalcification
Fig. 5 H&E: Foci of
lymphoid cell infiltrate in
the vicinity of acellular
mucin pools
mucinous carcinomas’ cell clusters are more MCLLs. Cytology diagnosis of MCLL requires
abundant and are formed by uniformly atypical great caution, since the presence of mucinous
cells. When a MCLL is associated with atypia or material on the smears may lead to erroneous
DCIS, the correct diagnosis requires even greater conclusion. It is also important to keep in mind
caution. that mucinous carcinomas occur mostly in older
The diagnostic dilemma is even more diffi- women than do MCLLs. The difficulty is even
cult in core biopsies, when only fragments of the greater when MCLL is associated with atypia or
lesion can be evaluated. A helpful feature is the frank DCIS. In such cases, fragments of the
presence of totally acellular mucin in cases of atypical epithelium may detach and float in the
MCLL and lack of atypia of the epithelial cells, extravasated mucin. The linear appearance of
if present. Multiple levels may help to confirm these epithelial fragments may help not to over-
the lack of epithelium in the mucin pools. In diagnose the case as mucinous carcinoma
mucinous carcinoma the areas of extracellular (Fig. 3). Nevertheless, in some cases, it is
mucin often contain small vessels embedded in impossible to unequivocally differentiate a
thin fibrous bands, which is not a feature in MCLL from a mucinous carcinoma on core
Mucoepidermoid Carcinoma of the Breast 305
Mucocele-like Lesion, Table 1 Differential diagnosis of MCLL and mucinous carcinoma (Based on Torous et al. 2017)
MCLL Mucinous carcinoma
Clinical presentation Most often incidentally detected on Usually presents as a mass (palpable or
(screening) mammography due to radiologically detected)
microcalcifications
Microscopy
Extracellular mucin Acellular; may contain detached linear Tumor cell clusters floating in the mucin;
fragments of epithelium evidence of neovascularization
Epithelium Most often low cuboidal to columnar Low to intermediate grade nuclear atypia of
without atypia, proliferative changes and the tumor cells that form small clusters in
papillarization may be present; usual type- the mucin pools; myoepithelial cells are not
or atypical ductal hyperplasia and DCIS seen
may be associated; myoepithelial cells are
present
Immunohistochemistry Myoepithelial markers stain the No myoepithelial cells can be identified
myoepithelial cells, but staining may be
absent in associated ADH or DCIS
biopsy and these doubts have to be stated in the & Visscher, D. W. (2016). Mucocele-like lesions of the
report (Table 1). breast: A cliniical outcome and histologic analysis of
102 cases. Human Pathology, 49, 33–38.
Cystic hypersecretory breast lesions may Rakha, E. A., Shaaban, A. M., Asma Haider, S., Jankins, J.,
superficially resemble to MCLL at low power. Menon, S., Johnson, C., Yamaguchi, R., Murphy, A.,
However, in cystic hypersecretory breast lesions Liston, J., Cornford, E., Hamilton, L., James, J., Ellis,
(hyperplasias and DCIS), the secretion that fills I. O., & Lee, A. H. S. (2013). Histopathology, 62,
894–898.
the cystic spaces is deeply eosinophilic and Rosen, P. P. (1986). Mucocele-like tumors of the
resembles thyroid colloid. breast. American Journal of Surgical Pathology, 10, M
An extremely rare breast tumor, mucinous 464–469.
cystadenocarcinoma may also possess extrava- Tan, P. H., Tse, G. M. K., & By, B. H. (2008). Mucinous
breast lesions: Diagnostic challenges. Journal of Clin-
sated mucin pools, but myoepithelial cells are ical Pathology, 6, 11–19.
not present, the epithelial cells are tall columnar Torous, V. F., Schnitt, S. J., & Collins, L. C. (2017). Benign
cells and contain intracellular mucin, both fea- breast lesions that mimic malignancy. Pathology, 49,
tures lacking in MCLL. 181–196.

Mucoepidermoid Carcinoma
Dash, I., Dessauvagie, B., Hardie, M., Saunders, C., & of the Breast
Wilie, E. (2017). Mucocele-like lesions: Is surgical
excision still necessary. Clinical Radiology, 72, 992. Maria P. Foschini and Luca Morandi
e1–992.e6.
Davies, J. D., Kutt, E., Kulka, J., Farndon, J. R., & Webb,
Department of Biomedical and Neuromotor
A. J. (1995). Mucocoele-like lesions detected by the Sciences, University of Bologna, Unit of
mammographic presence of suspicious clustered Anatomic Pathology at Bellaria Hospital,
microcalcifications. The Breast, 5, 135–140. Bologna, Italy
Jaffer, S. J., Bleiweiss, I. J., & Nagi, C. S. (2011). Benign
mucocele-like lesions of the breast: Revisited. Modern
Pathology, 24, 683–687.
Kim, D., Jung, W.-H., & Koo, J. S. (2012). Expression Definition
of MUC1, MUC2, MUC5AC and MUC5B in
mucinous lesions of the breast. Pathobiology, 79,
144–153.
Mucoepidermoid carcinoma (MEC) of the breast
Meares, A. L., Frank, R. D., Degnim, A. C., Vierkant, is a tumor composed of mucous-secreting inter-
R. A., Frost, M. H., Hartmann, L. C., Winham, S. J., mediate and epidermoid cells. It can present a
306 Mucoepidermoid Carcinoma of the Breast
great variety of architectural patterns, ranging Macroscopy

from cystic to solid. Its features are similar to
MEC arising in the major and minor salivary Breast MEC presents as nodule, ranging from a
glands (Foschini et al. 2017; Foschini and Krausz few millimeters to 11 cm. Nodules can be solid or
2010). cystic.
Clinical Features Microscopy
• Incidence Histology is characterized by the presence of

Breast MEC is an extremely rare type of tumor. mucous-secreting intermediate and epidermoid
Its incidence is not exactly known, as only cells. Their features vary according to the tumor
single case or small series are reported grade (Di Tommaso et al. 2004; Foschini
(Basburg 2011; Foschini 2017). et al. 2017).
• Age
MEC affects mainly adult patients, aged from
29 to 80 years.
• Sex
At present breast MEC has been described in
female patients only.
• Site
MEC can arise in all breast quadrants. When it
affects the retro-areolar region, it can present
with nipple discharge.
• Treatment
Radical surgical resection is the treatment of
choice. Axillary lymph node dissection and
chemotherapy have been added in high-
grade MEC.
• Outcome Mucoepidermoid Carcinoma of the Breast,
Outcome mainly depends on MEC grading. Fig. 1 Low-grade MEC with predominant cystic component
MEC, according to breast or salivary gland (H&E)
grading systems, can be of low, intermediate,
or high grade. None of the patients with low or
intermediate grade tumors died of disease
(Basburg et al. 2011; Foschini and Krausz
2010; Foschini et al. 2017). One case only of
MEC low grade recurred as high grade, but the
patient, after receiving radical surgical exci-
sion, remained alive and well 156 months
after surgery (Tjalma et al. 2002).
On the contrary 5/11 patients affected by
high-grade MEC developed distant metastases
and died of the disease. All these cases had Mucoepidermoid Carcinoma of the Breast,
axillary metastases at presentation (Basburg Fig. 2 Low-grade MEC composed of different cell
types: basaloid cells (indicated by “B”) are located at the
et al. 2011). These features underline the
periphery of the neoplastic nests, while epidermoid cells
importance of correct grading and staging in (indicated by “E”) are located in the central part of the
this type of tumor. neoplastic nests (H&E)
Mucoepidermoid Carcinoma of the Breast 307
Low-grade MEC are characterized by mixture seen. In situ component having the same cell
of basaloid, intermediate, epidermoid, and population can be present, associated with inva-
mucous-secreting cells arranged mainly in cystic sive MEC.
and solid nests (Figs. 1 and 2 H&E). Basaloid High-grade MEC share the same cell features
cells are usually located at the periphery of the of low-grade MEC but show a higher degree of
neoplastic nodules, while the center of the nod- cellular atypia and higher mitotic count; necrosis
ule is mainly composed of intermediate and epi- can be encountered.
dermoid cells (Fig. 3 H&E). True keratinization One case only of MEC of intermediate malig-
is not a feature of MEC. Epidermoid and inter- nancy grade was reported by Di Tommaso et al.
mediate cells have wide and granular eosino- (2004). The same case showed solid architectural
philic, less frequently clear cytoplasm that pattern with prevalence of intermediate and epi-
can be enriched in mitochondria. Nuclei are dermoid cells and focal presence of mucous-
centrally located. Mucous cells usually line the secreting cells.
cystic areas (Fig. 3 H&E). Alcian Blue pH 2.5
and PAS after diastase digestion can evidence
the mucous-secreting cells. On rare occasions, Immunophenotype
mucous-secreting cells have a signet ring
appearance (Fig. 4a and b H&E). In low-grade Immunohistochemistry can be helpful in the
MEC, atypia is mild, atypical mitotic diagnosis of breast MEC, and each single cell
figures are extremely rare, and no necrosis is type has its peculiar immunohistochemical
pattern.
Basaloid, intermediate, and epidermoid cells
are mainly positive with high-molecular-weight
cytokeratins (CK) as CK 14 and with p63. These
same cells can be positive with anti-mitochondrial
M
antibody but to a lesser intensity than observed in
salivary gland counterpart.
On the contrary mucous-secreting cells are
positive with low-molecular-weight CK as CK7,
epithelial membrane antigen (EMA), and MUC 1,
MUC 5 AC, and MUC 6.
Mucoepidermoid Carcinoma of the Breast,
Estrogen, progesterone receptors, and HER2
Fig. 3 Low-grade MEC with cystic features; mucous-
secreting cells line the cystic component. Epidermoid are consistently negative in all the reported
cells, devoid of true keratinization, are present (H&E) cases.
Mucoepidermoid Carcinoma of the Breast, Fig. 4 (a and b) Low-grade (a) and intermediate-grade (b) MEC: single
mucous-secreting cells are indicated by arrows (H&E)
308 Myoepithelial Carcinoma of the Breast
Molecular Features Tjalma, W. A., Verslegers, I. O., De Loecker, P. A., & Van
Marck, E. A. (2002). Low and high grade
mucoepidermoid carcinomas of the breast. European
Salivary gland MEC is characterized by the Journal of Gynaecological Oncology, 23, 423–425.
MECT-MAML2 translocation. Similarly, Camelo-
Piragua et al. (2009) found the 11q21 deletion at
the site of MAML2 gene.
Myoepithelial Carcinoma of
the Breast
Horst Bürger
Low-grade MEC diagnosis can be difficult when Institute of Pathology Paderborn/Höxter,
clear cells or mitochondrion-rich cells are numer- Paderborn, Germany
ous, raising the suspicion of clear cell carcinoma
or of oncocytic carcinoma (▶ Invasive Oncocytic
Carcinoma). The differential diagnosis is mainly Synonyms
based on the detection of mucous-secreting cells
intermingled with the neoplastic population. Malignant myoepithelioma; Metaplastic carci-
Diagnosis is more difficult in high-grade MEC. noma; Spindle cell carcinoma
Differential diagnosis should be carried out
mainly with carcinomas showing adenosquamous Definition
features (▶ Low-Grade Adenosquamous Carci-
noma). These latter tumors usually show true A malignant lesion composed of myoepithelial
keratinization features that are usually lacking in cells with increased mitotic activity and expres-
both low- and high-grade MEC. sion of myoepithelial markers, such as high
molecular weight cytokeratins, p63, smooth mus-
cle actin, and others.
References
Basbug, M., Akbulut, S., Arikanoglu, Z., Sogutcu, N., Clinical Features
Firat, U., & Kucukoner, M. (2011). Mucoepidermoid
carcinoma in a breast affected by burn scars: Compre-
hensive literature review and case report. Breast Care • Incidence
(Basel), 6, 293–297. Myoepithelial carcinomas of the breast repre-
Camelo-Piragua, S. I., Habib, C., Kanumuri, P., Lago, sent an extremely rare and poorly understood
C. E., Mason, H. S., & Otis, C. N. (2009).
entity of invasive breast cancer. The exact inci-
Mucoepidermoid carcinoma of the breast shares cyto-
genetic abnormality with mucoepidermoid carcinoma dence of these tumors is unknown, partially due
of the salivary gland: A case report with molecular to the disputed definition. According to the
analysis and review of the literature. Human Pathology, actual WHO classification, myoepithelial carci-
40, 887–892.
nomas are a subgroup of metaplastic carcinoma
Di Tommaso, L., Foschini, M. P., Ragazzini, T., Magrini,
E., Fornelli, A., Ellis, I. O., & Eusebi, V. (2004). (Reis-Filho et al. 2012). Under these assump-
Mucoepidermoid carcinoma of the breast. Virchows tions, the incidence is probably significantly
Archives, 444, 13–19. lower than <1%.
Foschini, M. P., & Krausz, T. (2010). Salivary gland-type
• Age
tumors of the breast: A spectrum of benign and malig-
nant tumors including “triple negative carcinomas” of Myoepithelial carcinomas have been seen in all
low malignant potential. Seminar in Diagnostic Pathol- age groups from 25 to 81 years.
ogy, 27, 77–90. • Sex
Foschini, M. P., Morandi, L., Asioli, S., Giove, G.,
Rare cases of myoepithelial carcinoma of the
Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the breast have been described in women. The
breast. Pathology, 49, 215–227. incidence in male patients is not known.
Myoepithelial Carcinoma of the Breast 309
• Site
A predominant site within the breast has not
been described.
• Treatment
Recommendations concerning the treatment of
these lesions are differing. This is mainly due
to the unsharp definition of this tumor entity.
Since some regard atypical adenomyoe-
pithelioma as one end of a morphological spec-
trum and myoepithelial carcinoma as the other
end, the treatment of these former tumors sig-
nificantly differs from myoepithelial carci-
noma fulfilling the criteria of ▶ metaplastic
carcinoma. Myoepithelial Carcinoma of the Breast,
Fig. 1 Myoepithelial carcinoma of the breast (H&E)
Whereas atypical adenomyoepithelioma (200)
does not fulfil the criteria to justify a treatment
as invasive carcinoma, myoepithelial carcino-
mas are treated according to the respective supports the diagnosis of myoepithelial carci-
guidelines for metaplastic, hormone receptor- noma (Tan and Ellis 2013). Extensive sampling
negative cancers. of the tumor is required since in most cases an
• Outcome adenomyoepithelial component may give hints to
Reliable data concerning the outcome are rare. the myoepithelial differentiation of this tumor.
Limited follow-up data report an increased In-situ carcinoma can also be observed in a large
local recurrence rate and a rather low incidence subset of tumors, indicating the epithelial origin of
of regional lymph node metastasis. the malignant lesion.
M
Macroscopy
Immunophenotype
Myoepithelial carcinomas might present as round
The immunophenotype reflects the expression
to oval, well-demarcated nodules as well as
patterns observed in normal myoepithelial cells.
tumors with irregular borders and overt infiltrating
This includes the expression of keratins, mainly
growth pattern. Hemorrhage, cystic degenera-
high molecular weight cytokeratins (Ck5, 14, 17),
tions, and calcifications can be seen. In most
smooth muscle actin, vimentin, caldesmon,
cases, the tumors appear as white-grey tumors
calponin, S-100, CD10, GFAP, D2–40 (examples
with largely varying size (up to >20 cm diameter).
given in Fig. 2a–c) and the lack of expression of
estrogen receptor (ER), progesterone receptor (PR),
and negativity for HER2 (Schmitt et al. 2012).
Microscopy
Typically myoepithelial carcinoma presents as a Molecular Features

proliferation of spindle cells, sometimes
intermingled by epithelioid appearing cells Little is known about molecular features of “pure”
(Fig. 1). Typically, remnants of normal breast myoepithelial carcinomas. Since myoepithelial
parenchyma seem to be entrapped by the spindle carcinomas are nowadays regarded as a subgroup
cells. In some cases, the spindle cells adjacent to of metaplastic carcinoma, more information on
the normal breast remnants seem to originate from the genetic status of these tumors are available
normal myoepithelial cells. This finding strongly (Tavassoli and Eusebi 2009).
310 Myoepithelial Carcinoma of the Breast
Myoepithelial Carcinoma of the Breast, Fig. 2 (a) (c) Myoepithelial carcinoma of the breast with strong and
Myoepithelial carcinoma of the breast with focal positivity homogeneous positivity for D2–40 as a marker of
for p63 (200). (b) Myoepithelial carcinoma of the breast myoepithelial differentiation (200)
with focal expression of cytokeratin (200).
In general, these tumors reveal a high number exact classification of these tumors (Weidner and
of genetic alterations, indicating a high genetic Dabbs 2012; Schnitt and Collins 2009; Fine and
instability. Major hallmarks, however, only seen Kurdek 2016).
in rather small proportions are p53-alterations, Therefore, myoepithelial carcinomas should be
EGFR amplification, lack of HER2 expression, separated from all kind of spindle cell lesions of
and negativity for ER and PR. the breast, mainly spindle cell carcinomas and all
However, one series described a lower rate of forms of ▶ metaplastic carcinoma.
genetic alterations per case compared to invasive Since the morphological and immunohisto-
breast cancer no-special type. This discrepancy chemical differential diagnosis between these
seems to be a reflection of the controversial defi- tumors might be arbitrary, some authors regard
nitions of myoepithelial carcinoma. the distinction between these tumors rather as a
problem of semantics.
At the current state, it is not clear if this sub-
Differential Diagnosis grouping is supported by other hallmarks, e.g.,
molecular findings. Other authors argue that due
The differential diagnosis of these tumors is, to a very close morphological relationship
despite a clear immunophenotype, complicated between myoepithelial carcinomas and
and reflects the current discussion concerning the adenomyoepithelial tumors, these tumors might
Myoepithelial Carcinoma of the Breast 311
be seen as the extreme end of a morphological Reis-Filho, J. S., Lakhani, S. R., Gobbi, H., & Sneige,
continuum of tumors with a predominant N. (2012). Metaplastic carcinoma. In S. R. Lakhani,
I. O. Ellis, S. J. Schnitt, P. H. Tan, & M. J. van de Vijver
myoepithelial differentiation. (Eds.), WHO classification of tumours of the breast
Malignant ▶ phyllodes tumor can be a differ- (pp. 119–124). IACR: Lyon.
ential diagnosis. However, the lack of epithelial Schmitt, F., Tan, P. H., Dabbs, D., & Jones, L. (2012).
glands, expression of high molecular weight Myoepithelial and epithelial–myoepithelial lesions.
In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H.
cytokeratins, p63, and other markers of Tan, & M. J. van de Vijver (Eds.), WHO classifi-
myoepithelial differentiation allows a clear dis- cation of tumours of the breast (pp. 119–124).
tinction from myoepithelial carcinomas in the IACR: Lyon.
vast majority of the cases. Schnitt, S. J., & Collins, L. C. (2009). Spindle cell lesions.
In S. J. Schnitt (Ed.), Biopsy interpretation of the breast
Fibromatosis, a spindle cell proliferation (pp. 323–343). Philadelphia: Lippincott Williams &
rarely seen in the breast may also be considered. Wilkins.
Lack of p63 and high molecular weight Tan, P. H., & Ellis, I. O. (2013). Myoepithelial and
cytokeratin positivity in these lesions helps to epithelial–myoepithelial, mesenchymal and
fibroepithelial breast lesions: Updates from the WHO
make distinction from myoepthelial carcinoma. Classification of Tumours of the Breast 2012. Journal
of Clinical Pathology, 66, 465–470.
Tavassoli, F. A., & Eusebi, V. (2009). Myoepithelial
lesions. In F. A. Tavassoli & V. Eusebi (Eds.), Tumors
References and Further Reading of the mammary gland (pp. 249–262). Washington,
DC: Armed Forces Institute of Pathology.
Fine, M. A., & Kurdek, L. A. (2016). An approach to the Weidner, N., & Dabbs, J. D. (2012). Myoepithelial lesions
diagnosis of spindle cell lesions of the breast. Histopa- of the breast. In D. J. Dabbs (Ed.), Breast pathology
thology, 68, 33–44. (pp. 307–323). Philadelphia: Saunders.
M
P
Paget Disease of the Nipple is associated with an underlying in situ or inva-

sive breast carcinoma in 82–94% of cases
Janina Kulka1 and Anna Sapino2,3 (Wong et al. 2015). Wong et al. in their large
1
2nd Department of Pathology, Semmelweis American patient cohort described statistically
University, Budapest, Hungary significant decrease in the age-adjusted
2
Unit of Pathology, Candiolo Cancer Institute incidence of the disease from 2000 to 2011,
FPO-IRCCS, Candiolo, Italy mainly due to decreasing rates of PD with
3
Department of Medical Sciences, University of underlying carcinoma (Wong et al. 2015). PD
Turin, Turin, Italy without underlying malignant lesion is
considered pTis.
• Age
Synonyms PD most commonly affects middle-aged
women, occurring between 50 and 60 years
Mammary Paget disease; Paget disease of the of age, although it has been reported in young
breast; Paget disease of the nipple and areola patients in their late 20s.
• Sex
PD of the nipple almost exclusively affects
Definition women. However, there have been rare cases
described in men (Adams and Kanthan 2016).
Paget disease (PD) is characterized by the pres- • Site
ence of malignant glandular epithelial cells (Paget The nipple and adjacent areas are typical sites
cells) within the squamous epithelium of the nip- of this lesion. However, rarely, in advanced
ple that may extend into the areola and adjacent cases, PD may affect large areas of the
skin (Shousha et al. 2012). breast skin.
• Symptoms
The initial skin changes of PD often mimic
Clinical Features eczema or other inflammatory skin disease: a
crusted or scaly red or pale lesion involving the
• Incidence nipple, with itching, burning sensations, sore-
PD was first described by the British surgeon ness, or pain. For this reason, the diagnosis is
Sir James Paget in 1874. It is a rare disease; its often delayed up to 6 months or more. Most
exact incidence in unknown. It is estimated to women presenting with PD have an underlying
occur in 1–4% of all breast cancer patients. PD ductal carcinoma in situ (DCIS) (Fig. 1a) or
https://doi.org/10.1007/978-3-319-62539-3
314 Paget Disease of the Nipple
Paget Disease of the Nipple, Fig. 1 (a) Paget disease of highlighted by CK 7 positivity (CK7 IHC reaction). (d)
the nipple with underlying DCIS in large ducts (H&E). Paget cells are GATA3 positive (GATA3 IHC reaction). (e)
(b) Paget cells in the epidermis forming nests (H&E). In this case, Paget cells are strongly HER2 positive (HER2
(c) Massive intraepidermal spread of Paget cells is IHC reaction)
invasive carcinoma, which may be palpable in Macroscopy

about half of the cases. Three different clinical
patterns have been described: (1) changes in the In diagnostic excision specimens, an area of
nipple-areola complex with palpable mass, superficial skin erosion may be identified or no
(2) changes in the nipple-areola complex without macroscopic lesion is present.
palpable mass, and (3) subclinical PD found
incidentally in the surgical pathology specimen
of either a breast mass or prophylactic mastec- Microscopy
tomy (Sandoval-Leon et al. 2013).
• Treatment The cells of PD of the nipple are pleomorphic,
Where no underlying malignant tumor is pre- large, usually with nuclei showing irregular
sent, and the disease is confined to the nipple nuclear contours, and prominent nucleoli. The
and areola, conservative surgery is cytoplasm is eosinophilic or amphophilic, often
recommended with removal of the nipple and abundant and may contain mucin. Paget cells are
areola along with a safe layer of the underlying usually present singly or in small aggregates
breast tissue. In case a breast cancer (in situ or (Fig. 1b); they rarely form glands (Shousha
invasive) is found, the surgical or neoadjuvant 2007; Barnes et al. 2007). The atypical cells
oncology treatment is tailored to their may be scattered within the whole thickness of
characteristics. the epidermis. Rare reports of PD of the nipple
• Outcome have been attributed to intraepidermal spread of
The overall disease course depends upon the lobular carcinoma in situ (LCIS) (Sahoo
nature and size of the underlying malignancy. et al. 2002).
Paget Disease of the Nipple 315
Paget Disease of the Nipple, Fig. 2 Melanin pigment is Paget Disease of the Nipple, Fig. 3 Acantholysis in a
present in the cytoplasm of a Paget cell (H&E) case of PD (H&E)
Pigmented variant of PD is an increasingly

well-recognized mimic of melanoma not only his- a rare finding causing severe diagnostic dilemma
tologically but clinically and dermatoscopically as (Ozerdem et al. 2016). Paget cells are negative for
well. In this variant, the Paget cells have melanin high molecular weight cytokeratins. S100
pigment in their cytoplasm (Fig. 2), and immunostaining may be positive in PD of the nip-
melanophag cells are also present in the dermis. ple, but Paget cells are negative for other
In most such cases, immunohistochemical reac- melanocytic markers, e.g., HMB45, SOX10, and
tions are necessary to the correct diagnosis. Ana- Melan-A (Table 1). Other immunohistochemical
plastic PD was first described in 1992 (Rayne and markers that have been described in more than
Santa Cruz 1992) as a rare variant mimicking 75% of PD cases are p16, androgen receptor,
Bowen’s disease. Full thickness atypia of the epi- CK8/18, CK19, MUC3, Claudins 3 and 4,
dermis and acantholysis (Fig. 3) are the main NY-BR1 (Sandoval-Leon et al. 2013). In a recent
features of this variant. Dyskeratotic cells are not study focusing on surrogate subtypes of PD of the
present, and rare atypical cells with nipple-areola complex and the underlying breast
intracytoplasmic vacuoles can be found. Mucin carcinoma, the authors showed that in PD the
stains, and other usual immunohistochemical HER2 subtype predominates (cca. two third of the
markers of conventional PD (see below), may be cases) followed by Luminal B HER2 positive sub- P
negative. In this first series of six cases, three type. In the majority of the cases, PD and the under-
patients had underlying invasive carcinoma. Inva- lying invasive carcinoma share immunophenotype;
sive PD, i.e., invasion of the dermis by Paget however, discrepant cases are not uncommon (cca.
cells is extremely rare: only 15 patients have one quarter of the cases). The Ki67 labeling index is
been reported until 2014 (Lee et al. 2014). The above 20% (Wachter et al. 2019). Earlier studies
invasive foci show identical phenotype to the already showed that associated carcinomas are usu-
intraepidermal lesion. Patterns of invasion are ally high grade, and Paget cells are estrogen and
either single-cell infiltration or small, solid cell progesterone receptor (ER/PR) negative in the vast
clusters or gland-forming tumor cell clusters. majority of cases (Meissner et al. 1990; Wolber et al.
1991; Anderson et al. 2003; Bianco and Vasef
2006).
Immunophenotype
Paget cells are almost invariably positive for Molecular Features

cytokeratin 7 (Fig. 1c), Cam 5.2 and EMA, usually
positive for CEA, GATA3 (Fig. 1d), often positive In a recent study using whole exome sequencing
for HER2 (Fig. 1e) and rarely for GCDFP-15. technique, the most frequent recurrent mutations
Cytokeratin 7 negative PD have been described as occurred in the chromatin remodeling genes:
316 Paget Disease of the Nipple
Paget Disease of the Nipple, Table 1 Immunohistochemical characteristics of the main entities in the differential
diagnosis of Paget disease
Paget In situ squamous cell carcinoma/Bowen Malignant
disease Toker cells disease melanoma
Cytokeratin 7 + +
Cam 5.2 + +
EMA + +
CEA +
GATA3 + No reports
available
Cytokeratin +
5/6
p63 +
S100 + or + or +
Melan-A +
HMB45 +
SOX10 +
ER/PR Usually May be + or
HER2 Often +
Mucin May be + Not present Not present Not present
Major source: Jacobs, T.W. Clear Cells of Toker in the Nipple Epidermis, Case presentation, USCAP 2010 Annual
Meeting
KMT2C (MLL3, 39%) and ARID2 (22%), with glandular structures are absent. As opposed to
additional recurrent somatic mutations, such as PD, high molecular weight cytokeratins are
CDCC168 (34%), FSIP2 (29%), CASP8AP2 expressed by the atypical cells. Paget cells may
(29%), and BIRC6 (24%). Interestingly, in paired take up melanin pigment released by epidermal
mammary PD and underlying breast carcinoma cells or melanocytes (referred to as pigmented PD
samples, in 3 cases out of 20, distinct gene muta- in the literature), mimicking malignant mela-
tions were detected, suggesting independent noma: both PD and melanoma in situ may show
oncogenic events in the pathogenesis of these an intraepidermal population of epithelioid cells
lesions (Zhang et al. 2019). Mai et al. (2018) individually or arranged in small nests and the
described dysregulation of FOXA1 and the presence of atypical epithelioid cells in the supra-
nuclear receptor signaling pathway in both mam- basal layer. Both lesions may show melanin pig-
mary and extramammary PD. ment not only within tumor cells’ cytoplasm but
also in dermal melanophages and within dendritic
melanocytes between tumor cells (Solinas et al.
Differential Diagnosis 2018). HER2 staining if positive is particularly
useful (especially in the differential diagnosis
Differential diagnosis of PD includes those with melanoma, pagetoid Spitz nevus, in situ
lesions characterized by so-called intraepidermal squamous cell carcinoma/pagetoid Bowen disease
“pagetoid spread” of atypical cells: pagetoid and Toker cells (▶ Toker Cells of the Nipple),
Bowen’s disease, malignant melanoma, pagetoid which are all negative). The distinction between
Spitz nevus, Merkel cell carcinoma, mycosis LCIS involving the nipple skin in the form of PD
fungoides, Langerhans histiocytosis, and ductal versus Toker cells may be difficult since both have
eccrine carcinoma (Sandoval-Leon et al. 2013). bland appearing cells. However, Toker cells are
Paget cells are not to be mistaken with Toker cells E-cadherin positive as opposed to LCIS cells. The
(▶ Toker Cells of the Nipple). In Bowen’s disease, neoplastic T cells in mycosis fungoides have large
intracellular mucin, signet ring cells, and convoluted (cerebriform) nuclei, pale cytoplasm,
Paget Disease of the Nipple 317
and show CD3 positivity. Similar to occasional Mai, R., Zhou, S., Zhou, S., Zhong, W., Hong, L., Wang,
cases of PD, a clear halo is often seen around Y., Lu, S., Pan, J., Huang, Y., Su, M., Crawford, R.,
Zhou, Y., & Zhang, G. (2018). Transcriptome analyses
single neoplastic cells. Furthermore, Pautrier reveal FOXA1 dysregulation in mammary and extra-
microabscesses may resemble glandular struc- mammary Paget’s disease. Human Pathology, 77,
tures in PD. In various forms of histiocytoses, 152–158.
the nuclei of the atypical cells are large, bean Meissner, K., Riviere, A., Haupt, G., & Loning, T. (1990).
Study of neu-protein expression in mammary Paget’s
shaped, and the cytoplasm stains pale. If in disease with and without underlying breast carcinoma
doubt, CD1a, HLA-DR, and S100 immunohisto- and in extramammary Paget’s disease. American Jour-
chemical positivity of the atypical histiocytes is nal of Pathology, 137, 1305–1309.
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Cytokeratin 7-negative mammary Paget’s disease:
eccrine carcinoma arising in the nipple-areola A diagnostic pitfall. Pathology Research and Practice,
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As opposed to PD, eccrine adnexal tumors are p63 Park, B. W., Kim, S. I., Lee, K. S., & Yang, W. I. (2001).
Ductal eccrine carcinoma presenting as a Paget’s
positive. Merkel cell carcinomas may also have a disease-like lesion of the breast. The Breast Journal,
pagetoid intraepidermal component. The tumor 7, 358–362.
cells, however, are positive for neuroendocrine Rayne, S. C., & Santa Cruz, D. J. (1992). Anaplastic
immunohistochemical markers unlike Paget cells Paget’s disease. American Journal of Surgical Pathol-
ogy, 16, 1085–1091.
(Stanoszek et al. 2017). Satellite invasive breast Sahoo, S., Green, I., & Rosen, P. P. (2002). Bilateral Paget
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malignantpaget.html. Accessed 13 Jan 2019.
References and Further Reading Sandoval-Leon, A. C., Drews-Elger, K., Gomez-
Fernandez, C. R., Yepes, M. M., & Lippman, M. E.
Adams, S. J., & Kanthan, R. (2016). Paget’s disease of the (2013). Paget’s disease of the nipple. Breast Cancer
male breast in the 21st century: A systematic review. Research and Treatment, 141, 1–12.
The Breast, 29, 14–23. Shousha, S. (2007). Glandular Paget’s disease of the nip-
Anderson, J. M., Ariga, R., Govil, H., Bloom, K. J., ple. Histopathology, 50, 812–814.
Francescatti, D., Reddy, V. B., et al. (2003). Assess- Shousha, S., Eusebi, V., & Lester, S. (2012). Paget disease P
ment of Her-2/Neu status by immunohistochemistry of the nipple. In S. R. Lakhani, I. O. Ellis, S. J. Schnitt,
and fluorescence in situ hybridization in mammary P. H. Tan, & M. J. van de Vijver (Eds.), WHO classifi-
Paget disease and underlying carcinoma. Applied cation of tumours of the breast (4th ed., pp. 152–153).
Immunohistochemistry and Molecular Morphology, Lyon: IARC.
11, 120–124. Solinas, A., Mahar, A., Cooper, W. A., Thompson, J. F.,
Barnes, P. J., Dumont, R. J., & Higgins, H. G. (2007). Spillane, A. J., & Scolyer, R. A. (2018). Pigmented
Acinar pattern of mammary Paget’s disease: A case Paget’s disease of the nipple mistaken for melanoma
report. The Breast Journal, 13, 520–526. in situ: A diagnostic pitfall for the unwary. Pathology,
Bianco, M. K., & Vasef, M. A. (2006). HER-2 gene ampli- 50, 364–367.
fication in Paget disease of the nipple and extra- Stanoszek, L. M., Wang, G. Y., & Harms, P. W. (2017).
mammary site: A chromogenic in situ hybridization Archives of Pathology and Laboratory Medicine, 141,
study. Diagnostic Molecular Pathology, 15, 131–135. 1490–1502.
Jacobs, T. W. Clear cells of Toker in the Nipple Epidermis. Wachter, D. L., Wachter, P. W., Fasching, P. A.,
USCAP 2010 Annual Meeting, Specialty Conference, Beckmann, M. W., Hack, C. C., Riener, M. O.,
Breast Pathology, Case 2. http://uscapknowledgehub. Hartmann, A., & Strehl, J. D. (2019). Characterization
org/newindex.htm?99th/specbreah2.htm of molecular subtypes of Paget disease of the breast
Lee, H. W., Kim, T. E., Cho, S. Y., Kim, S. W., Kil, W. H., using immunohistochemistry and in situ hybridiza-
Lee, J. E., Nam, S. J., & Cho, E. Y. (2014). Invasive tion. Archives of Pathology and Laboratory Medicine,
Paget disease of the breast: 20 years of experience at a 143, 206–211.
single institution. Human Pathology, 45, 2480–2487. Wolber, R. A., Dupuis, B. A., & Wick, M. R. (1991).
Lloyd, J., & Flanagan, A. M. (2000). Mammary and extra- Expression of c-erbB-2 oncoprotein in mammary and
mammary Paget’s disease. Journal of Clinical Pathol- extramammary Paget’s disease. American Journal of
ogy, 53, 742–749. Clinical Pathology, 96, 243–247.
318 Phyllodes Tumor
Wong, S. M., Freedman, R. A., Stamell, E., Sagara, Y., its malignant potential became known when a
Brock, J. E., Desantis, S. D., & Golshan, M. (2015). metastatic case was reported by Lee and Pack.
Modern trends in the surgical management of Paget’s
disease. Annals of Surgical Oncology, 22, 3308–3316. Phyllodes tumors are classified as benign, border-
Zhang, G., Zhou, S., Zhong, W., Hong, L., Wang, Y., Lu, line, or malignant (Ellis et al. 2013).
S., Pan, J., Huang, Y., Su, M., Crawford, R., Zhou, Y., Usage of the original term of cystosarcoma
& Mai, R. (2019). Whole-exome sequencing reveals phyllodes is discouraged given that the majority
frequent mutations in chromatin remodeling genes in
mammary and Extramammary Paget’s diseases. Jour- of these neoplasms are benign. The preferred term
nal of Investigative Dermatology, 139, 789–795. as recommended by the World Health Organiza-
tion in 1981 is phyllodes tumor, with the benign,
borderline, or malignant prefix used as appropri-
ate (Tan et al. 2016).
Phyllodes Tumor
Clinical Features
Mark O’Loughlin1 and Grace Callagy1,2
1
Discipline of Pathology, NUI Galway, Galway,
• Incidence
Ireland
2 Phyllodes tumors are uncommon, representing
NUI Galway Clinical Science Institute, Galway,
approximately 1% of all breast neoplasms at
Ireland
most (0.2–1%) and only 2.5% of fibroepithelial
breast lesions. The exact incidence of tumors
that fall into the benign, borderline, and malig-
Synonyms
nant categories is uncertain. This is because the
rates reported for each category vary consider-
Benign phyllodes tumor; Benign phylloides
ably between studies due to the use of different
tumor; Borderline phyllodes tumor; Borderline
classification systems and to the well-
phylloides tumor; Cystosarcoma phyllodes;
recognized difficulty in distinguishing between
Cystosarcoma phylloides; Malignant phyllodes
tumors in the different categories. It is esti-
tumor; Malignant phylloides tumor; Phyllodes
mated that benign phyllodes tumors are likely
tumor; Phylloides tumor
to account for at least 70%, malignant tumors
for 10–20%, and borderline tumors for the
remainder of all these cases (Ellis et al. 2013;
Definition Tan et al. 2012, 2016).
Malignant phyllodes tumors are more com-
Phyllodes tumors are true fibroepithelial neo- mon among Hispanic populations than other
plasms characterized by a biphasic growth pattern ethnic groups, particularly those born in Cen-
which comprises an epithelial and a stromal com- tral and South America. Phyllodes tumors are
ponent and resembles an intracanalicular more common in nulliparous women (Tan
fibroadenoma. The epithelial component is dou- et al. 2012).
ble layered and arranged in clefts and is • Age
surrounded by the hypercellular stromal compo- These tumors are more common in perimeno-
nent. Together these give the appearance of leaf- pausal and postmenopausal women. The aver-
like structures. This appearance is the origin of the age age at presentation is usually 40–50 years,
name cystosarcoma phyllodes when they were with the median age being 45 years. Phyllodes
first described in 1838 by Müller (phyllos being tumors tend to develop a decade later than the
the Greek word for leaf, cysto- pertaining to the usual age for fibroadenomas and are relatively
cystic spaces identified, and sarcoma pertaining to rare below the age of 25. However, there have
the sarcomatous stroma). The lesion was initially been reports with ages ranging from younger
described as benign, and it was not until 1931 that than 10 years to older than 70. In Asian
Phyllodes Tumor 319
populations, age at diagnosis is lower than for retrospective reviews is contradictory with
other populations, approximately 25–30 years some recording no relationship between mar-
(Tan et al. 2012). gin width and recurrence rates, whereas others
• Sex found that recurrence increased with margins
It predominantly affects women though there <1 cm. Interpretation is compounded by the
have been a small number of cases described in fact that the rate of recurrence for
men, which is slightly more often found in fibroadenomas, the main differential diagnosis
those with preexisting gynecomastia (Tan for a benign phyllodes tumor, is in the order of
et al. 2012). 15%. Moreover, not all benign phyllodes
• Site tumors with a positive margin recur. In the
These neoplasms affect breast tissue and rarely absence of definitive evidence, many would
involve the skin, though they can stretch the consider the presence of tumor cells touching
skin if grown to a large size, giving a bluish ink or within 1 mm of the margin as a positive
discoloration and dilated veins. This margin. A benign phyllodes tumor with a pos-
stretching, nipple retraction, and potential itive margin can be managed conservatively;
pain can all occur with both benign and malig- however, most would advocate clear margins
nant phyllodes tumors. Ulceration onto the for recurrent, borderline, and malignant phyl-
skin surface is very rare and is far more likely lodes tumors (Tan et al. 2016).
to be observed with malignant phyllodes than Mastectomy may be considered in some
with benign or borderline tumors, although cases depending on the size of the tumor and
very large benign tumors can ulcerate the over- the malignancy status. Axillary node sampling
lying skin. Phyllodes tumors are typically uni- is not recommended given the low rate of nodal
lateral, with multifocal or bilateral lesions metastasis.
being regarded as rare (Ellis et al. 2013). The role of adjuvant radiotherapy in the treat-
• Clinical Presentation ment for malignant tumors is unclear. There are
The presentation is classically a clinically pal- some reports of reduced rates of local recurrence
pable mass in the breast parenchyma with an but no effect on overall survival. There is no
average size of 4–5 cm. This lump is usually, evidence to support the use of cytotoxic or
but not always, painless, well defined, and targeted chemotherapy (Tan et al. 2016).
mobile. It is not possible to distinguish a phyl- • Outcome P
lodes tumor from a fibroadenoma or other Phyllodes tumors of all grades have the potential
benign breast lesion at clinical presentation, for recurrence, although recurrence is rare when
although a phyllodes tumor is often rapidly the tumor is completely excised. Recurrence is
growing. Smaller tumors can present on rou- more common for malignant tumors (23–30%)
tine mammography as well-defined lesions or than for borderline (14–25%) or benign
as hypoechoic masses with hyperechoic stria- (10–17%) tumors. In the vast majority of cases,
tions on ultrasound imaging (Ellis et al. 2013). recurrence is local and usually occurs within
• Treatment 2–3 years of initial diagnosis. Recurrent disease
The currently accepted gold standard of treat- is typically of the same grade as the initial tumor,
ment for phyllodes tumors is surgical resection though progression to a higher-, or rarely a
with a margin of normal tissue. Unlike the case lower-, grade tumor can occur (Tan et al. 2012).
for invasive carcinoma, there is no consensus Metastatic rates vary from 1% to 22%, and
on what constitutes an adequate margin thick- metastasis is associated with a poor prognosis
ness, especially for benign tumors. Most data with death from disease most commonly ensu-
on margin status comes from retrospective ing within 5–8 years after diagnosis. Virtually
studies. Some advocate a margin of 1 cm all metastases occur following a diagnosis of
even for benign tumors, but robust evidence malignant phyllodes tumor. There are reports
for this is lacking. The data on recurrence from of metastases occurring following a diagnosis
320 Phyllodes Tumor
of borderline and, less commonly, benign phyl- more likely to be malignant. Phyllodes tumors in
lodes tumor, but these are considered excep- general have a faster growth rate than
tionally rare occurrences. Metastatic sites fibroadenomas (Ellis et al. 2013; Tan et al. 2012).
include the lungs, pleura, bone, and very rarely Phyllodes tumors are round to oval in shape,
the central nervous system. The metastases are with a well-circumscribed border and a firm tex-
frequently composed of the sarcomatous stro- ture. They vary between lobulated contours to hav-
mal component of the tumor without epithelial ing a multinodular surface. Benign phyllodes
elements. Spread to lymph nodes is rare, and tumors can be grossly indistinguishable from
hence nodal sampling is not routinely fibroadenomas. The cut surface shows a tan or
recommended in the management of phyllodes pink to gray-white whorled pattern that may have
tumors. In extremely rare cases, metabolic dis- a fleshy or mucoid consistency, though they are
turbances caused by paraneoplastic syndrome more frequently firm. They typically have cleft
can occur whereby phyllodes tumors secrete spaces, and larger tumors can have areas of cystic
insulin-like growth factor II, causing severe degeneration, hemorrhage, or necrosis. These fea-
(or occasionally fatal) hypoglycemia (Ellis tures are more common in malignant compared to
et al. 2013; Tan et al. 2012). benign phyllodes tumors. The borders of benign
• Factors Influencing Recurrence and tumors are usually well defined, whereas those of a
Behavior malignant phyllodes tumor may be grossly infiltra-
Margin status is one of the most important tive. Periductal stromal hyperplasia can occur adja-
factors determining the risk for recurrence. In cent to the phyllodes tumor and can make
many instances, recurrence is due to inade- assessment of the border difficult. In some
quate resection, and a further wide local exci- instances, a “pseudocapsule” composed of com-
sion can be curative. Conversely, positive pressed normal breast parenchyma can envelop
margins do not result in inevitable recurrence. the tumor (Ellis et al. 2013).
A review of factors associated with an
increased risk of adverse outcome identified
margin status as being the most important Microscopy
with atypia, mitoses, stromal overgrowth also
being important, but the evidence for this is Phyllodes tumors are derived from the specialized
weak. As yet, there are no validated prognostic lobular stroma of the breast, and the biphasic
features to identify those patients who will growth pattern is the characteristic feature of this
develop metastatic disease (Ellis et al. 2013). tumor. Phyllodes tumors are composed of a dou-
ble layer of glandular epithelium with
myoepithelial and luminal epithelial cells that
Macroscopy line cleft-like spaces. The clefts create the appear-
ance of large leaflike structures in which the
Tumor size is extremely variable with case reports stroma is cellular. The stroma is the dominant
documenting cases from 1 cm in diameter up to component of the tumor; the epithelium appears
greater than 40 cm. The average size at diagnosis benign. Tumors are classified as benign, border-
is usually 4 cm or 5 cm with the size range most line, or malignant based on the assessment of a
commonly being between 2 and 10 cm. Mammo- number of interrelated histological features, as
graphic screening has seen an increase in detec- outlined in the WHO Classification of Tumors of
tion of smaller tumors that are between 2 and the Breast (Tan et al. 2012).
3 cm. It is not possible to distinguish between
the different grades of phyllodes tumor by size Benign Phyllodes Tumor
because there is significant overlap in the sizes of These lesions characteristically have pushing,
benign, borderline, and malignant tumors. How- lobulated borders that are well circumscribed. In
ever, some reports suggest that larger tumors are benign phyllodes tumors, the biphasic growth
Phyllodes Tumor 321
patterns assume an exaggerated intracanalicular In most centers, a preoperative diagnosis

appearance and give rise to the impression of of benign phyllodes tumors is made on a
fronds or leaflike structures with clefts and needle core biopsy. This can be problematic
cystically dilated spaces (Fig. 1a H&E). The stro- because of the small amount of tissue which may
mal cellularity is at best regarded as mildly not be representative of the larger tumor and
increased and, in general, appears uniform because the morphological features of phyllodes
throughout the tumor (Fig. 1b H&E). tumor overlap with those of fibroadenomas and
A commonly observed feature is in accentuation other spindle cell lesions in the breast (see differ-
of cellularity around ducts, but there is no stromal ential diagnosis) (Jara-Lazaro et al. 2010).
overgrowth. The latter is defined so that low-
power views, achieved by the use a 4 objective Malignant Phyllodes Tumor
lens and a 10 eyepiece lens, only allow the The diagnosis of malignant phyllodes tumor is often
stroma to be visualized, in which epithelial ele- straightforward. These tumors have infiltrative bor-
ments are absent (Ellis et al. 2013). ders and are characterized by a uniform and marked
In benign phyllodes tumors, the spindle cells in increase in stromal cellularity, marked nuclear
the stroma will not display much, if any, pleomor- atypia, numerous mitoses (>10 per 10 hpf), and
phism. Mitotic figures are few, <5 per 10 high- overgrowth of the stromal component (Fig. 2a, b
power fields (hpf). Necrosis is rare but can be seen H&E). Stromal overgrowth can mean that the epi-
with edema and ulceration in benign tumors if they thelium is present focally and thorough sampling is
reach a very large size. Stromal giant cells can required to identify residual glandular elements.
occasionally be seen and should not be interpreted Occasionally, the stromal growth is not as pro-
as an indicator of either a borderline or malignant nounced as would be expected, and in this instance,
tumor. Adipose tissue can be seen within the the finding of nuclear pleomorphism of stromal cells
stroma, and if adipocytes are particularly promi- and atypical mitoses is relied upon to correctly
nent, the term lipophyllodes tumor can be utilized. characterize a lesion as malignant. The stroma
This can also be seen in fibroadenomas and should could be either monomorphic or pleomorphic
not be confused with malignant heterologous dif- with appearances similar to that of a fibrosarcoma
ferentiation in a malignant phyllodes tumor (Ellis and may have areas of malignant heterologous
et al. 2013; Tan et al. 2016). differentiation such as liposarcomatous or
P
Phyllodes Tumor, Fig. 1 (H&E) (a) Architecture of a without pleomorphism, mitotic activity or stromal over-
benign phyllodes tumour. The characteristic leaf-like pro- growth. In this case, the overall cellularity is not increased
cesses are seen throughout a benign phyllodes tumor. (b) illustrating the fact that all of the classic features of a
High power image of benign phyllodes tumour (the same tumour grade may not be present together
case as in Figure 2) shows a minimal increase in cellularity,
322 Phyllodes Tumor
Phyllodes Tumor, Fig. 2 (H&E) (a) Stromal overgrowth Heterologous elements present within a malignant phyl-
and increased cellularity in a malignant phyllodes tumor. lodes tumor. Liposarcomatous differentiation is seen at low
Note the absence of epithelial elements in this medium power (c). Pleopmorphic lipoblasts are seen at high power
power view. (b) Malignant phyllodes tumor shows hyper- (d)
cellular stroma infiltrating normal breast tissue. (c and d)
chondrosarcomatous differentiation with possible demonstrate a degree of stromal hypercellularity,

metaplastic cartilage or bone development which is similar to or slightly more than in benign
(Fig. 2c, d H&E). The latter can be present, albeit phyllodes tumors, and have a pronounced
rarely, without other features of malignancy and is intracanalicular growth pattern when compared
sufficient in itself for a diagnosis of malignant phyl- to benign phyllodes tumors (Fig. 3a, b H&E).
lodes tumor. These elements must be distinguished Mitotic figures are only slightly higher than in
from benign adipose and chondroid differentiation a benign phyllodes tumor, at 4–9 per 10 hpf. The
that can be seen in benign and borderline phyllodes tumor borders are predominately pushing and
tumors. Foci of ductal carcinoma in situ, lobular well circumscribed, but very focal infiltration
carcinoma in situ, or invasive carcinoma can be can be seen. These pushing margins with buds
seen in an otherwise typical phyllodes tumor, but projecting into surrounding stroma can be left
these are rare (Ellis et al. 2013; Tan et al. 2012). behind at surgical excision (Ellis et al. 2013; Tan
et al. 2012, 2016).
Borderline Phyllodes Tumor
Borderline phyllodes tumors are those which fall Grading of Phyllodes Tumors
in between the benign and malignant categories. Grading of phyllodes tumors is notoriously diffi-
These have highly variable morphologies but cult. Various grading systems exist to differentiate
Phyllodes Tumor 323
Phyllodes Tumor, Fig. 3 (H&E) (a and b) Leaf-like overgrowth and no infiltrative margin. A high power view
architecture within a borderline phyllodes tumor (a). The of the same case shows an accentuation of stromal hyper-
mitotic activity was low in this case. There was no stromal cellularity in the subepithelial zone (b)
Phyllodes Tumor, Table 1 Histological features of fibroadenoma, benign, borderline, and malignant phyllodes tumor
Fibroadenoma Benign PT Borderline PT Malignant PT
Stromal Hypocellular but Mild, can be diffuse or Moderate Marked and
hypercellularity can be cellular heterogeneous diffuse
Cellular Absent Mild Moderate Marked
pleomorphism
Mitoses Absent or low (<2 Few (<5 per 10 hpf) Frequent (5–9 per Numerous (10
per 10 hpf) 10 hpf) per 10 hpf)
Borders Well defined Well circumscribed, Well defined, can be Infiltrative
pushing focally infiltrative
Stromal overgrowth None None None or present focally Usually present
Malignant None Absent Absent Can be present
heterologous
differentiation
P
Adapted from WHO Classification of Tumors of the Breast (Tan et al. 2012)
the different grades of tumor and combine the cellularity and architectural abnormality (Tan
assessment of the same features: tumor border, et al. 2012).
stromal cellularity, stromal overgrowth, nuclear As a general guide, it is recommended that
pleomorphism, mitotic activity, and the presence tumors are graded as malignant when all the fea-
of heterologous elements. The WHO three-tier tures of malignancy are present and as borderline
system is the most widely used (Table 1) (Tan when only some are present. The presence of any
et al. 2012). malignant heterologous elements implies a diag-
Assessment and quantification of the histolog- nosis of malignancy (Fig. 2c, d H&E) (Tan
ical features are subjective, and the thresholds for et al. 2016).
each parameter that assign a tumor in one grade
over another are unclear. For example, a benign
phyllodes tumor may show an increase in cellu- Immunophenotype
larity with a focally infiltrative border but with
minimal mitotic activity and few leaflike struc- The diagnosis of phyllodes tumor is made on
tures. It is generally recommended that grading H&E staining; immunohistochemistry is not
should be based on the most florid area of required to make a diagnosis. Stromal cells
324 Phyllodes Tumor
express CD34 and b-catenin, and their expression upregulation of beta-catenin and cyclin D1
is inversely related to tumor grade. Expression of (among others), and the stroma promotes epithe-
proliferation markers, e.g., Ki-67 as well as c-kit lial proliferation via pathways such as IGF and
(CD117), p53, p16, pRb, VEGF, CD10, and IGFR1. The epithelial-stromal feedback is dimin-
EGFR, can be observed in the stromal cells with ished in malignant tumors where there is also
increasing levels of expression from benign to frequent loss of beta-catenin expression (Tan
borderline to malignant phyllodes tumors. et al. 2012).
Immunohistochemistry is required to distin- Detailed genomic analysis has revealed chro-
guish phyllodes tumors from other entities. mosomal changes in phyllodes tumors with the
CD34, p63, p40, and cytokeratins, e.g., aberrations being more frequent and more com-
MNF116, CK 5/6, 34be12, and AE1/3, are most plex in malignant and borderline phyllodes
useful in the distinction between phyllodes tumor tumors compared to benign tumors. Clonal
and metaplastic spindle cell carcinoma. Tradition- changes are detectable in both the epithelial and
ally, CD34 was reportedly positive in the stromal stromal component of phyllodes tumors. Specific
cells in all grades of phyllodes tumor and negative genomic aberrations include gains in chromo-
in carcinomas, whereas p63, p40, and some 1q, losses in chromosome 13, deletions of
cytokeratins were positive in carcinomas and neg- chromosomal 9p, and MYC amplification (Tan
ative in phyllodes tumors. Focal positivity for et al. 2012).
cytokeratin can be observed in malignant phyl-
lodes tumor but not in lower-grade phyllodes
tumors. While benign and borderline phyllodes Differential Diagnosis
tumors and fibroadenomas are negative for p63,
its isoform p40 and cytokeratin, malignant phyl- Benign Phyllodes Tumor
lodes tumors can express p63, p40, and The main differential diagnosis for a benign phyl-
cytokeratin in 57%, 29%, and 21% of cases, lodes tumor is a fibroadenoma (▶ Fibroadenoma).
respectively, and 43% of malignant phyllodes It can often be very challenging because many of
tumors can be negative for CD34. the features relied upon are subject to
interobserver disagreement, and it is important
not to rely on and overinterpret the significance
Molecular Features of any single criterion to distinguish between
these two entities (Tan et al. 2016).
Phyllodes tumors are considered to arise de novo. The distinction is particularly heightened for a
There are very obvious morphological similarities cellular fibroadenoma, a juvenile fibroadenoma,
between fibroadenomas and phyllodes tumors, and fibroadenomas occurring in children and ado-
but direct evidence supporting a precursor role lescents. Intracanalicular growth pattern and leaf-
for fibroadenomas has been lacking. Recent like structures can be seen in both entities. In a
work, however, identified mutations in the medi- phyllodes tumor, the latter structures are generally
ator complex subunit (MED) 12 gene, which is in present throughout the tumor and are hyper-
both fibroadenomas and phyllodes tumors, cellular, whereas they are present only focally
supporting a common molecular link between and are often hyaline and hypocellular in a
both lesions (Tan et al. 2016). fibroadenoma. If stromal fronds are not present
The biphasic appearance of a phyllodes tumor in a benign phyllodes tumor, then the long clefts
is characterized by benign-appearing epithelium may also be a clue to the diagnosis of phyllodes
and a dominant neoplastic stroma, particularly in a tumor (Fig. 4a H&E) (Tan et al. 2016).
periductal location. This feature is in keeping with It is recommended that fibroadenomas are
the hypothesis of an epithelial-stromal cross talk, assessed for features of phyllodes tumors on first
in which the epithelium induces stromal prolifer- viewing whenever there is an increase in stromal
ation via the Wnt signalling pathway and cellularity. A more uniform increase in cellularity
Phyllodes Tumor 325
Phyllodes Tumor, Fig. 4 (H&E) (a) Benign phyllodes lesion. This was classified as a fibroepithelial lesion with a
tumor in which the features overlap with those of a cellular comment that a benign phyllodes tumor could not be
fibroadenoma. In this low power view, leaf-like processes excluded. At low power, an obvious leaf-like architecture
are not seen; however, there are some cleft-like spaces. The is seen with only a minimal increase in stromal cellularity
stromal cellularity and mitotic activity were increased and and no mitotic activity. Fragmentation of the biopsy, as a
some stromal fronds were seen elsewhere in the lesion. result of the needle passing through the fronds, is a clue to
This illustrates the heterogeneity that can be seen within a the diagnosis of a benign phyllodes tumor. This lesion was
benign phyllodes tumor and the diagnostic difficulty in excised because it was large and a diagnosis of a benign
distinguishing benign phyllodes tumors from cellular phyllodes tumor was made based on the features in the
fibroadenomas. (b) Needle core biopsy of a fibroepithelial excised tumor
favors a fibroadenoma. Mitotic activity may not through the frond (Fig. 4b H&E). Mitotic activ-
be particularly helpful in distinguishing between ity is often unhelpful on a core biopsy (Jara-
these entities as it is low in both. Mitotic counts Lazaro et al. 2010).
above 2 per 10 hpf favor a phyllodes tumor how- In many cases, stating that the lesion is a
ever (Tan et al. 2012). fibroepithelial lesion and that a phyllodes
Caution is advised in diagnosing a benign tumor cannot be excluded is the best approach
phyllodes tumor in children and adolescents with the most appropriate management
where increased stromal cellularity and high decided upon through multidisciplinary P
mitotic activity (up to 7 mitoses per 10 hpf) can discussion. Clinical and radiological features
be observed. In this situation, other features of may aid in the decision with excision performed
benign phyllodes tumor, e.g., leaflike architec- if the lesion is growing to >3 cm in size (Jara-
ture, should also be seen to arrive at a diagnosis Lazaro et al. 2010).
of a phyllodes tumor (Tan et al. 2016). Pure stromal tumor is a rare entity in which a
The distinction between fibroadenoma and spindle cell proliferation surrounds open ducts.
benign phyllodes tumor can be especially chal- This entity lacks the architectural leaflike archi-
lenging on a needle core biopsy. Increased stro- tecture of phyllodes tumor, but some reports sug-
mal cellularity has been found to be the most gest that pure stromal tumor and phyllodes tumor
helpful distinguishing feature on core biopsy. may be part of the same disease spectrum (Tan
The threshold cellularity that favors a phyllodes et al. 2012).
tumor is unclear, and some have proposed that it
be present in over half of the core biopsy. The Malignant Phyllodes Tumors
presence of stroma without epithelial elements in Malignant phyllodes tumors need to be distin-
a 10 field, if seen, also favors a phyllodes guished from metaplastic carcinomas (▶ Inva-
tumor. Fragmentation of the biopsy is another sive Metaplastic Carcinoma) because the
clue to the diagnosis of a phyllodes tumor, management of both entities is different. Both
which is most likely due to the core being taken the malignant spindle cells and the heterologous
326 Pleomorphic Lobular Carcinoma
elements within a malignant phyllodes tumor breast core needle biopsies. American Journal of Sur-
can lead to the tumor being confused with the gical Pathology, 38, 1689–1696.
Ellis, I., Lee, A., Pinder, S., & Rakha, E. (2013). Tumors of
different morphological subtypes of a metaplas- the breast. In C. Fletcher (Ed.), Diagnostic histopathol-
tic carcinoma (Tan et al. 2016). ogy of tumors (4th ed., pp. 1064–1065). Philadelpia:
The key feature in this distinction is the dem- Elsevier.
onstration of epithelial differentiation in the Jara-Lazaro, A. R., Akhilesh, M., Thike, A. A., Lui, P. C.-
W., Tse, G. M.-K., & Tan, P. H. (2010). Predictors of
spindle cells to support a diagnosis of carcinoma phyllodes tumours on core biopsy specimens of
and the demonstration of benign admixed epi- fibroepithelial neoplasms. Histopathology, 57, 220–232.
thelium (i.e., biphasic growth) to support a diag- Tan, P. H., Tse, G., & Kee, A. (2012). Fibroepithelial
nosis of malignant phyllodes tumor. In phyllodes tumours. In S. Lakhani, I. Ellis, S. Schnitt, P. H. Tan,
& M. van de Vijver (Eds.), WHO classification of
tumors, epithelium is both morphologically tumours of the breast (4th ed., pp. 143–147). Geneva:
benign and distinct from the stromal elements, World Health Organisation.
and thorough sampling may be required to iden- Tan, B. Y., Acs, G., Apple, S. K., Badve, S., Bleiweiss, I. J.,
tify it. Demonstration of convincing epithelial Brogi, E., . . . Tan, P. H. (2016). Phyllodes tumours of
the breast: A consensus review. Histopathology, 68,
differentiation within the stromal compartment 5–21.
supports a diagnosis of carcinoma. Again, this
may require thorough sampling and the demon-
stration of cytokeratin positivity, bearing the
caveats outlined above in mind (see Pleomorphic Lobular
immunophenotype). The presence of ductal car- Carcinoma
cinoma in situ adjacent to malignant spindle cells
also favors a metaplastic carcinoma (Ellis et al. Sofia Asioli1 and Chiara Baldovini2
1
2013; Tan et al. 2016). In difficult cases, GATA3 Department of Biomedical and Neuromotor
and SOX10 can also be helpful. GATA3 is rarely Sciences (DIBINEM)-Surgical Pathology
expressed in malignant phyllodes tumors and is Section, Alma Mater Studiorum – University of
expressed in up to 50% of metaplastic carcino- Bologna, Bologna, Italy
2
mas; SOX10 is negative in malignant phyllodes Pathology Unit, Giannina Gaslini Institute,
tumors and is expressed in 40% of metaplastic Genoa, Italy
carcinomas. b-catenin is expressed in both
malignant phyllodes tumors and metaplastic car-
cinoma and is therefore unhelpful in Definition
distinguishing these entities (Cimino-Mathews
et al. 2014). Pleomorphic lobular carcinoma (PLC) is currently
Distinction between malignant phyllodes defined by the World Health Organization
tumor and the rare entity of pure stromal sarcoma (Lakhani et al. 2012) as a rare variant of invasive
is made by the finding of the epithelial elements lobular carcinoma (ILC), exhibiting marked
of a phyllodes tumor. These can be very focal if nuclear pleomorphism and cellular atypia. It may
the stromal overgrowth is particularly probe associated with pleomorphic lobular carcinoma
nounced and thorough sampling is required. in situ (PLCIS), which refers to a lobular carci-
However, the management of both is similar noma in situ (LCIS) with high-grade cytological
(Tan et al. 2016). features. PLC was first documented by Martinez
and Azzopardi (1979) then subsequently reported
by Dixon (Dixon et al. 1982) and formally
described by Page and Anderson (1987). Further
characterization was provided in 1992 by Eusebi
Cimino-Mathews, A., Sharma, R., Illei, P. B., Vang, R., & (Eusebi et al. 1992) and Weidner (Weidner and
Argani, P. (2014). A subset of malignant phyllodes Semple 1992), who emphasized its aggressive
tumors express p63 and p40: A diagnostic pitfall in behavior and poor clinical outcome.
Pleomorphic Lobular Carcinoma 327
Clinical Features epidermal growth factor receptor 2 (HER2),

respectively.
• Incidence • Outcome
The exact incidence of PLC is unknown In the first descriptions PLC was referred to as
because of its rare occurrence and the lack of an aggressive variant of ILC. However, since
large case studies addressing this issue. Based those studies were limited by small sample
on current literature, PLC represents approxi- size, other investigators attempted to better
mately 10–15% of ILC, thus accounting for define the prognosis of PLC based on larger
less than 1% of all mammary gland carcinomas case series. As expected, several studies found
(Al-Baimani et al. 2015). that PLC was associated with high-risk clini-
• Age copathological features when compared with
PLC usually presents at older age than classic ILC-C (larger tumor size, higher grade,
ILC (ILC-C). It commonly affects postmeno- increased nodal involvement, and higher
pausal women aged between 60 and 80. How- expression of HER2). Jung found no differ-
ever, it may also present earlier among patients ences in relapse-free survival (RFS) and dis-
carrying BRCA2 mutations (Butler and Rosa ease specific survival (DSS) when comparing
2013). PLC and invasive carcinoma no special type
• Sex (NST) (Jung et al. 2012). Another study indi-
In line with most variants of breast carcinoma, cated that both disease free survival (DFS) and
PLC predominantly affects females. Only a overall survival (OS) were similar between
minority of cases have been reported among PLC and ILC-C, and that survival correlated
males. with well-established prognostic factors such
• Site as tumor size, tumor stage, lymph node
There is no specific preferential site. Similar to involvement, and surgical treatment
ILC-C, PLC often arises bilaterally, showing (Narendra et al. 2015). Finally, Liu found that
multifocal distribution. PLC was initially associated with worse
• Treatment progression-free survival (PFS) when com-
Owing to the rarity of PLC, there is insuffi- pared with ILC-C, but such a result
cient data to develop specific guidelines for disappeared after adjustment for cancer stage.
management. As for most breast cancers, sur- There were no differences in OS (Liu et al. P
gery remains the treatment of choice. Avail- 2017). Taken together, these findings suggest
able data suggest that, compared with ILC-C, that PLC may not be associated with increased
PLC presents with larger tumors, increased mortality as originally described.
lymph node involvement, and higher inci-
dence of distant metastases. Although PLC
shares high rates of multifocality and multi- Macroscopy/Imaging Findings
centricity with ILC-C, it seems to require
mastectomy more often than ILC-C The gross appearance of PLC is usually described
(Al-Baimani et al. 2015). However, conserva- as an irregular fibrotic area, without notable dif-
tive surgery is favored for patients with local- ferences from ILC-C. Neither can PLC be differ-
ized disease. Despite the lack of evidence entiated from ILC-C based on imaging findings,
regarding the role of adjuvant therapy in although it may present more aggressive features
PLC, there is a tendency to administer adju- (Jung et al. 2012). The reported higher detection
vant chemotherapy, mainly based on PLC rate of PLC compared to ILC-C on mammogra-
adverse clinico-pathological characteristics. phy might reflect such findings (Al-Baimani et al.
Adjuvant endocrine therapy and trastuzumab 2015). Radiologically, most lesions consist of
may be of value for patients displaying posi- spiculated masses or architectural distortions,
tivity for hormone receptors and human with or without calcifications. Magnetic
328 Pleomorphic Lobular Carcinoma
resonance imaging (MRI) has become increas- (WHO 2012). Sometimes, neoplastic cells may
ingly important in the detection of multifocal, also show singular intracytoplasmic vacuoles giv-
multicentric or contralateral disease, especially ing them the appearance of signet-ring cells. Polyg-
for patients diagnosed with lobular carcinoma onal cells with eosinophilic cytoplasm reminiscent
including PLC. of rhabdomyoblasts are also occasionally found
(Fig. 3 H&E). In contrast with ILC-C, PLC often
displays evidence of vascular invasion and high
Microscopy mitotic index. Owing to the marked degree of
nuclear pleomorphism, PLCs are more likely to
The original morphologic criteria are still applied to be scored as G2, G3 within the Nottingham grading
identify PLC. Although some investigators found system, depending on mitotic activity.
that nonclassical growth patterns were more fre-
quent in tumors with marked nuclear pleomor-
phism, in most studies PLC did not display
significant differences from ILC in terms
of architecture. Similar to ILC-C, PLC displays
poorly circumscribed lesions, characterized by dis-
sociated neoplastic cells, which may delineate
“targetoid” patterns around ducts and acini (Fig. 1
H&E). Alveolar, solid, and mixed patterns of
growth may be seen as well. In contrast to ILC-C,
PLC nuclei are larger – approximately four times
the size of a lymphocyte (Weidner et al. 1992) –
indented and often eccentrically placed. Prominent
and multiple nucleoli are generally present (Fig. 2
H&E). The cytoplasm is abundant, pale to eosino-
Pleomorphic Lobular Carcinoma, Fig. 2 The neoplas-
philic, but varying degrees of granular to vacuo- tic nuclei of PLC are larger, indented and often eccentri-
lated cells have been described. Indeed, according cally placed with prominent and multiple nucleoli (H&E)
with the last WHO classification, PLC may dem-
onstrate apocrine or histiocytoid differentiation
Pleomorphic Lobular Carcinoma, Fig. 1 The neoplas-

tic cells of PLC surround and invade the stroma around Pleomorphic Lobular Carcinoma, Fig. 3 Polygonal
residual ducts and acini in a concentric “targetoid” patterns neoplastic cells with eosinophilic cytoplasm reminiscent
similar to ILC (H&E) of rhabdomyoblasts are also occasionally found (H&E)
Pleomorphic Lobular Carcinoma 329
Immunophenotype common origin. In addition, PLC may subsequently

acquire further alterations typical of high-grade NST
In contrast with invasive carcinoma NST, PLC cancers (8q+, 17q24 q25+,13q , amplification of
shares the loss of E-cadherin expression with 8q24, 12q14, 17q12, 20q13), which may explain its
other subtypes of lobular carcinoma, estimated higher grade and more aggressive biology (Simpson
to occur in 80–100% of cases (Al-Baimani et al. 2008). In line with these findings, inactivation
et al. 2015). Whereas, the expression of gross of E-cadherin and p53 resulted in the development
cystic disease fluid protein 15 (GCDFP-15), asso- of invasive mammary carcinomas with strong
ciated with apocrine differentiation, is signifi- resemblance with human PLC in mouse models
cantly higher in PLC than among ILC-C (Eusebi (Derksen et al. 2011).
et al. 1992). The relationship between BRCA1 and BRCA2
Other immunohistochemical differences be- status and PLC is still poorly understood.
tween PLC and ILC-C include the expression of Although BRCA1 loss of heterozygosity (LOH)
p53 tumor suppressor, which is rare in ILC-C and was found in approximately one third of PLC,
high in PLC. Since the expression of p53 is asso- another study demonstrated a high rate (40%) of
ciated with an aggressive clinical course, this find- BRCA2 mutations. Later studies corroborated
ing could partly explain the biological behavior of these data showing that BRCA2 mutation carriers
PLC. The higher proliferative index (as evaluated harbored significantly higher rates of PLC com-
with Ki67) in cases of PLC compared with ILC-C pared to BRCA1 mutation carriers (Al-Baimani
further supports the clinical observation of its et al. 2015).
aggressive nature.
Overexpression of HER2, which has been
documented in a wide range (40–80%) of PLC, Differential Diagnosis
probably contributes to this aggressive pheno-
type. However, when considering only IHC 3+ High-grade NST carcinoma (▶ Invasive Carci-
cases, the positivity rate is much lower (13%) noma NST) is often considered in the differential
(Butler and Rosa 2013). diagnosis of PLC. High-grade NST carcinoma is
There are conflicting data regarding the more likely to display solid patterns of growth
expression of hormone receptors throughout compared to PLC. Both tumors share marked
the literature: some investigators found a decreased cellular pleomorphism, but the former may also P
expression of both estrogen (ER) and progesterone display areas of spindled and squamoid differen-
receptors (PR) in PLC, but this was not tiation. In high-grade NST carcinoma necrosis is
confirmed in other series. Nevertheless, this extremely common as well as vascular invasion,
result could depend on methodological hetero- whereas these features are less frequent among
geneity across studies. PLC also expresses andro- PLC cases. Intraductal carcinoma is present in
gen receptor (AR). This finding is in line with up to 70% of NST tumors. In most cases immu-
the occasional apocrine features and frequent nohistochemistry allows a prompt differentiation,
GCDFP-15 expression mentioned above. with E-cadherin expression being preserved in
NST carcinomas and lost/reduced in PLC. In addi-
tion, ER, PR, and AR positivity favor a diagnosis
Molecular Features of PLC over NST cancer.
Both PLC and apocrine carcinoma (▶ Apo-
Molecular biology studies have shown an over- crine Carcinoma) possess similar cytological and
lapping developmental pathway between PLC and immunohistochemical features (GCDFP-15 and
ILC, compared to NST carcinomas. Indeed, compar- AR positivity). However, they can be distin-
ative analysis of aCGH data showed that PLC and guished mainly based on architectural features
ILC share some important molecular features (1q+, matched with E-cadherin immunostain. Indeed,
11q , 16p+, and 16q ), thus indicating a possible apocrine carcinoma usually retains the growth
330 Polymorphous Carcinoma
pattern typical of ductal carcinoma along with Derksen, P. W., Braumuller, T. M., et al. (2011). Mammary-
E-cadherin positivity. specific inactivation of E-cadherin and p53 impairs
functional gland development and leads to pleomorphic
invasive lobular carcinoma in mice. Disease Models &
Pleomorphic lobular carcinoma
Mechanisms, 4, 347–358.
Definition Dixon, J. M., Anderson, T. J., et al. (1982). Infiltrat-
– A rare variant of invasive lobular carcinoma (ILC), ing lobular carcinoma of the breast. Histopathology,
exhibiting marked nuclear pleomorphism 6, 149–161.
Age distribution Eusebi, V., Magalhaes, F., et al. (1992). Pleomorphic lob-
– Postmenopausal women aged between 60 and 80 ular carcinoma of the breast: An aggressive tumor
Clinical features showing apocrine differentiation. Human Pathology,
– Often arises bilaterally, showing multifocal 23, 655–662.
distribution Jung, S. P., Lee, S. K., et al. (2012). Invasive pleomorphic
Microscopic findings lobularcarcinoma of the breast: Clinicopathologic char-
– Dissociated neoplastic cells acteristics and prognosis compared with invasive duc-
– Nonspecific architectural pattern (classic, alveolar, tal carcinoma. Journal of Breast Cancer, 15, 313–319.
solid, mixed) Lakhani, S., Ellis, I., et al. (2012). WHO classification of
– Nuclei: Large, indented, lobulated, and eccentric Tumours of the breast (4th ed.). Lyon: IARC Press.
– Cytoplasm: Abundant, eosinophilic, granular, Liu, Y. L., Choi, C., et al. (2017). Invasive lobular breast
vacuolated (single or multiple vacuoles) carcinoma: Pleomorphic versus classical subtype, asso-
– Frequent vascular invasion and high mitotic activity ciations and prognosis. Clinical Breast Cancer,
– PLCIS 8209(16), 30558–30554.
Immunohistochemical findings Martinez, V., & Azzopardi, J. G. (1979). Invasive lobular
– E-cadherin: Negative carcinoma of the breast: Incidence and variants. Histo-
– Estrogen, progesterone, androgen receptors: pathology, 3, 467–488.
Frequently positive Narendra, S., Jenkins, S. M., et al. (2015). Clinical
– HER2: May be positive (2+/3+: 40–80%, 3+: 13%) outcome in pleomorphic lobular carcinoma: A case-
– P53: Frequently positive control study with comparison to classic invasive
– GCDFP-15: Frequently positive lobular carcinoma. Annals of Diagnostic Pathology,
19, 64–69.
Molecular findings
Page, D. L., & Anderson, T. J. (1987). Diagnostic his-
– Lobular histotype typical alterations: 1q+, 11q ,
topathology of the breast. Edinburgh: Churchill
16p+, and 16q
Livingstone.
– Ductal histotype typical alterations: Gains of HER2/
Simpson, P. T., Reis-Filho, J. S., et al. (2008). Molecular
neu, c-myc, p53 positivity, amplification of 8q24, 12q14,
profiling pleomorphic lobular carcinomas of the breast:
and 20q13
Evidence for a common molecular genetic pathway
– LOH BRCA2 40%
with classic lobular carcinomas. Journal of Pathology,
Differential diagnosis 215, 231–244.
– High-grade invasive carcinoma no special type Weidner, N., & Semple, J. P. (1992). Pleomorphic variant
(NST) of invasive lobular carcinoma of the breast. Human
– Apocrine carcinoma Pathology, 23, 1167–1171.
Prognosis and treatment
– Unfavorable prognostic factors
– Recent evidence of DFS and OS similar to ILC-C
– Mastectomy +/ adjuvant therapy (endocrine,
trastuzumab) Polymorphous Carcinoma
Sofia Asioli and Costantino Ricci

Department of Biomedical and Neuromotor
References and Further Reading Sciences (DIBINEM)-Surgical Pathology
Section, Alma Mater Studiorum – University of
Al-Baimani, K., Bazzarelli, A., et al. (2015). Invasive
pleomorphic lobular carcinoma of the breast: Patho- Bologna, Bologna, Italy
logic, clinical, and therapeutic considerations. Clinical
Breast Cancer, 15, 421–425.
Butler, D., & Rosa, M. (2013). Pleomorphic lobular carci-
Synonyms
noma of the breast: A morphologically and clinically
distinct variant of lobular carcinoma. Archives of
Pathology & Laboratory Medicine, 137, 1688–1692. Polymorphous low-grade adenocarcinoma
Polymorphous Carcinoma 331
Definition metastases can reach 50% of cases (Foschini

et al. 2017).
Polymorphous carcinoma is a very rare breast
carcinoma with epithelial cell differentiation
Macroscopy
showing morphological features similar to those
referred as polymorphous low-grade adenocarci-
Tumors are generally present as palpable and firm
noma in salivary glands.
nodules displaying indistinct borders. The size of
the lesion may be variable (range from 1.5 to
4 cm).
Clinical Features
• Incidence
Microscopy
Five cases of this special type of primary breast
carcinoma have been reported in literature with
Polymorphus carcinoma shows the same morpho-
morphological description.
logical features as that of minor salivary glands
• Age
counterpart.
Median age at presentation is 55 years, ranging
In particular, this neoplasm is non-encapsu-
from 37 to 74 years.
lated and is constituted of neoplastic cells show-
• Sex
ing a polymorphous structure that consists of
All the patients reported in literature are
central areas showing solid nests, surrounded at
female.
the periphery by alveolar and cribriform struc-
• Site
tures as well as trabeculae and “Indian file”
Breast without the prevalence of a specific
arranged cells. Combinations and transitions
mammary quadrant.
among all these patterns are frequent. The neo-
• Treatment
plastic cells are uniformly small, have round to
Wide excision with axillary lymph node dis-
ovoid nuclei with dispersed vesicular chromatin,
section is the choice of treatment of the cases
and have inconspicuous to small nucleoli.
reported in the literature, followed by radio-
Mitotic activity ranges from 10 to 12 per
therapy in two patients. Although no lymph
10 high-power fields; necrotic areas are not P
node metastases are found, polymorphous car-
seen. Altogether the histological grade,
cinoma seems to be an aggressive neoplasm
according to the Elston and Ellis grading system
and recommended treatment consists of wide
of breast cancer (Elston and Ellis 1991), is grade
excision with sentinel node biopsy and even-
2. Neither vascular nor perineural invasion has
tually axillary lymph node dissection.
been reported (Fig. 1).
• Outcome
Follow-up has been reported in three cases
(Asioli et al. 2006). In two out of these three
patients, the follow-up was very short. The Immunophenotype
other case had a very aggressive clinical course
with the patient developing liver metastases Estrogen and progesterone receptors, as well as
and dying of widespread disease 3 years after HER2, were consistently negative, so this entity is
the diagnosis. Therefore, it was suggested to considered as triple-negative breast carcinoma by
name the tumor in the breast as “polymorphous immunohistochemistry (Asioli et al. 2006). The
adenocarcinoma,” avoiding the term of “low neoplastic cells are faintly positive for cytokeratin
grade.” The same conclusion has led to rename 7, E-cadherin, and EGFR, and strongly stain for
the salivary gland counterpart as polymor- Bcl-2. On the contrary, EMA, cytokeratin
phous carcinoma, as at long-term follow-up 14, smooth muscle actin, and c-Kit are negative
the incidence of local recurrences and distant (Foschini et al. 2017; Reyes et al. 2013).
332 Polymorphous Carcinoma
Polymorphous Carcinoma, Fig. 1 Polymorphous car- magnification x100), trabeculae (c; H&E, Original magni-
cinoma shows different growth patterns including central fication x200) and “Indian file” infiltration pattern (d;
areas with solid nests (a; H&E, Original magnification H&E, Original magnification x40)
x40), alveolar and cribriform structures (b; H&E, Original
Molecular Features elements as well as c-kit renders these lesions

different from adenoid cystic carcinomas that,
No specific molecular alterations have been on the contrary, show by definition two types of
reported on breast polymorphous carcinoma. cells and smooth muscle actin positive elements
(Foschini et al. 2017). An “Indian file” pattern of
infiltration of neoplastic cells in some peripheral
Differential Diagnosis areas of polymorphous carcinoma can simulate
an invasive lobular carcinoma. The immunohis-
Differential diagnosis includes mainly invasive tochemical features help in the differential diag-
lobular carcinoma ▶ Invasive Lobular Carci- nosis. In polymorphous carcinoma, neoplastic
noma chapter and adenoid cystic carcinoma cells are E-cadherin positive and EMA, estro-
▶ Adenoid Cystic Carcinoma. The fact that the gen, and progesterone receptors negative, all
polymorphous carcinoma of the breast, as in features different from those seen in invasive
salivary glands, shows one type of cell only lobular carcinoma (Asioli et al. 2006; Foschini
and is devoid of smooth-muscle actin positive et al. 2017).
Pseudoangiomatous Stromal Hyperplasia 333
Polymorphous breast carcinoma – fact sheet Pseudoangiomatous Stromal

Definition
- Very rare breast carcinoma showing a triple-negative Hyperplasia
profile and morphological features similar to those
referred to as polymorphous low-grade adenocarcinoma Janina Kulka1 and Anna Sapino2,3
in salivary glands 1
2nd Department of Pathology, Semmelweis
Age distribution University, Budapest, Hungary
- Median age: 55 years (range 37–74 years) 2
Unit of Pathology, Candiolo Cancer Institute
Clinical features
- Palpable and firm nodules with indistinct borders FPO-IRCCS, Candiolo, Italy
3
Microscopic findings Department of Medical Sciences, University of
- Non-encapsulated lesion Turin, Turin, Italy
- Polymorphous structure: central areas showing solid
nests, surrounded at the periphery by alveolar and
cribriform structures as well as trabeculae and Indian file
arranged cells
Synonyms
- Grade 2 carcinoma according to the Elston & Ellis
grading system Nodular myofibroblastic stromal hyperplasia of
- Vascular and nerve invasions are uncommon the mammary gland (Leon et al. 2002).
Immunohistochemical findings
- Estrogen and progesterone receptors, and HER2:
negative
- Cytokeratin 7, E-cadherin, EGFR, and Bcl-2: variably Definition
positive
- EMA, cytokeratin 14, smooth muscle actin, and c-kit: Pseudoangiomatous hyperplasia of mammary
negative
stroma (PASH) is a benign proliferation of keloid-
Differential diagnosis
- Invasive lobular carcinoma like fibrosis, containing slit-like pseudovascular
- Adenoid cystic carcinomas spaces lined by spindle shaped cells without mitotic
Prognosis and treatment figures and atypia. (Ibrahim et al. 1989). PASH is
- Wide excision with axillary lymph node dissection considered a breast-specific myofibroblastic prolif-
- Not indolent clinical behavior
eration (Krings et al. 2017).
Clinical Features P
References
• Incidence
Asioli, S., Marucci, G., Ficarra, G., Stephens, M.,
Foschini, M. P., Ellis, I. O., & Eusebi, V. (2006).
PASH of the breast was first described by
Polymorphous adenocarcinoma of the breast. Report Vuitch et al. in 1986 (Vuitch et al. 1986). Its
of three cases. Virchows Archiv, 448, 29–34. incidence was later investigated in a series of
Elston, C. W., & Ellis, I. O. (1991). Pathological prognostic 200 consecutive breast biopsies and surgical
factors in breast cancer. 1. The value of histological
grade in breast cancer: Experience from a large study
specimens and was found to be an incidental
with long-term follow-up. Histopathology, 19, finding in breast biopsies in 23% of the cases
403–410. (Ibrahim et al. 1989). Incidental PASH can be
Foschini, M. P., Morandi, L., Asioli, S., Giove, G., found in fibroadenomas, gynecomastia, nor-
Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the
mal breast tissue, hamartomas, and sclerosing
breast. Pathology, 49, 215–227. lobular hyperplasia. It has also been described
Reyes, C., Jorda, M., & Gomez-Fernández, C. (2013). in surgical specimens of gigantomastia. Two
Salivary gland-like tumors of the breast express cases were described in immunosuppressed
basal-type immunohistochemical markers. Applied
Immunohistochemistry and Molecular Morphology,
patients (Seidman et al. 1993 and de Saint
21, 283–286. Aubain Somerhausen et al. 1997). In a case
334 Pseudoangiomatous Stromal Hyperplasia
series of 24 mass forming PASH, it was found appears as an oval, circumscribed, hypoechoic
that 40% of the female patients had family mass. On magnetic resonance imaging, PASH
history of breast cancer (Bowman et al. 2012). usually has progressive (Type 1) enhancement,
• Age and high-signal slit-like spaces may be seen on
PASH occurs in pre- or perimenopausal T2-weighted and short tau inversion recovery
patients and is often associated with fibrocystic (STIR) images (Raj et al. 2017). A case of
changes (Ibrahim et al. 1989). The mean age of PASH (confirmed in a subsequent core biopsy)
patients diagnosed with tumor forming was incidentally revealed due to focal
(nodular) PASH is 37 years (Powell et al. increased radiotracer uptake in the left breast
1995). However, PASH was also described in of a prostate cancer patient undergoing
postmenopausal women: among them more Ga-labeled prostate-specific membrane anti-
than half of those with tumor forming PASH gen ligand PET-CT (Malik et al. 2017).
were receiving hormone replacement therapy • Treatment
(Virk and Khan 2010). Rare cases of PASH The current recommendations are to excise
causing voluminous and rapidly growing lesions more than 2 cm and conservative man-
breast mass with severe breast asymmetry agement and watchful waiting with smaller
occurring in adolescents have been described lesions. Successful treatment of PASH with
(Pellini et al. 2018). Tamoxifen in a patient with PASH presenting
• Sex with breast enlargement, pain, and breast
PASH is mainly found in female breast tissue, masses was described (Pruthi et al. 2001).
but it is also common in male gynecomastia: • Outcome
according to one study, 23.8% of gynecomastia Sporadic cases of recurrent PASH have been
cases harbored PASH (Milanezi et al. 1998). described following incomplete excision. On
Occurrence of PASH in the breast of a trans- the other hand, spontaneous regression of
gender male patient has been described PASH is also documented in the literature.
(Bowman et al. 2012).
• Site
Macroscopy
No specific site in the breast has been
described. PASH was reported in axillary
Only PASH forming a nodular lesion in the breast
accessory breast tissue (Lee et al. 2005).
can be seen macroscopically: the typical appear-
• Symptoms
ance is a well-circumscribed firm or rubbery
PASH is found incidentally in most of the cases
tumor with a white-gray/tan cut surface (Powell
without any clinical symptoms. Fewer cases or
et al. 1995). The largest lesion described in the
case series are described in the literature with
literature measured 20 cm (Sasaki et al. 2008).
PASH occurring as palpable mass. Raj et al.
reported 44% of PASH presenting as palpable
breast lesion (Raj et al. 2017). A rare manifes-
tation is diffuse massive process with asymme- Microscopy
try of the breast (Shahi et al. 2015). PASH was
also described as a cause of gigantomastia Microscopically, a spectrum of pathological stro-
(Roy et al. 2015). In a published series of mal changes can be seen ranging from anastomos-
seven cases, the lesions were identified on ing slit-like spaces lined by flat, bland spindle
mammograms as noncalcified masses measur- cells (Figs. 1 and 2) to more proliferative lesions
ing 1.1–11 cm in largest diameter (Polger et al. composed of bundles of plump spindle cells that
1996). Mammographic and ultrasound appear- may obscure the underlying pseudoangiomatous
ance of nodular PASH is very similar to those architecture in the most florid lesions (Powell
of fibroadenomas: on ultrasound, PASH often et al. 1995).
English language literature. According to Rosen,

who mentioned two young girls’ cases with this
lesion in his famous Breast Pathology book, atyp-
ical PASH appears to be myofibroblastic sarcoma
(Rosen 2001). In the case published by Nassar
et al. (2010), atypical PASH occurred in the back-
ground of nodular PASH. The two lesions
described so far were rapidly growing breast
masses, showing atypia of the myofibroblasts lin-
Pseudoangiomatous Stromal Hyperplasia, Fig. 1 ing the pseudovascular spaces, with mitotic activ-
(H&E) Detail of a breast hamartoma showing PASH ity (Noda et al. 2019).
Most probably as a coincidence, invasive
breast carcinoma rarely may be associated with
PASH (Ferreira et al. 2008).
Recavarren and co-workers described a similar
stromal change (Recavarren et al. 2009) called
PASH-like stroma seen intimately associated
with columnar cell change of the duct epithelium
(the acronym they used was CCPLS). They sug-
gest an epithelial-stromal interaction as the back-
ground of this finding, which differed from PASH
in terms of immunophenotype.
Pseudoangiomatous Stromal Hyperplasia, Fig. 2

(H&E) High magnification of PASH: slit-like spaces in Immunophenotype
collagenous stroma lined by bland spindle cells
The spindle cells lining the slit-like spaces are
Nodular PASH (“tumorous” or “tumor forming” vimentin and CD34 positive but factor VIII and
PASH), as opposed to incidental PASH, is well CD31 are always negative. In more cellular fascic-
circumscribed microscopically and may be associ- ular lesions, the stromal cells may be positive for P
ated with florid ductal type epithelial hyperplasia. desmin and smooth muscle actin. The immunohis-
Diffuse PASH is rare, less than 20 cases were tochemical features are consistent with
reported in the literature. It may be the cause of myofibroblastic histogenesis of PASH. Progester-
rapidly developing gigantomastia during preg- one receptor (PR) positivity in stromal cell nuclei is
nancy (Krawczyk et al. 2016). usually more pronounced than estrogen receptor
PASH with stromal giant cells is an extremely (ER) positivity in these lesions. ER may be
rare variant, characterized by mostly multi- completely negative in the spindle cells (Powell
nucleated myofibroblasts lining the slit-like et al. 1995). Because of the consistent finding
spaces (Comunoğlu et al. 2007). Two cases asso- of PR positivity of the spindle cells lining the slit-
ciated with von Recklinghausen disease in males like spaces, it was suggested that hormonal factors
were described and as a conclusion the authors play a major role in the development of PASH.
warn that PASH with stromal giant cells should be
recognized as a feature of gynecomastia in von
Recklinghausen’s disease (Damiani and Eusebi Molecular Features
2001).
Atypical PASH has also been described. Only There are no literature data about the molecular
two formal case reports are available in the characteristics of PASH.
336 Pseudoangiomatous Stromal Hyperplasia
Differential Diagnosis Malik, D., Basher, R. K., Mittal, B. R., Jain, T. K., Bal, A.,
& Singh, S. K. (2017). 68Ga-PSMA expression in
Pseudoangiomatous stromal hyperplasia of the breast.
The most important differential diagnosis is well Clinical Nuclear Medicine, 42, 58–60.
differentiated angiosarcoma (▶ Angiosarcoma of Milanezi, M. F., Saggioro, F. P., Zanati, S. G., Bazan, R., &
the Breast). Schmitt, F. C. (1998). Pseudoangiomatous hyperplasia
of mammary stroma associated with gynaecomastia.
Nassar, H., Elieff, M. L., Kronz, J. D., & Argani, P. (2010).
References and Further Reading Pseudoangiomatous stromal hyperplasia (PASH) of the
breast with focal of morphologic malignancy: A case of
Bowman, E., Oprea, G., Okoli, J., Gundry, K., Rizzo, M., PASH with malignant transformation? International
Gabram-Mendola, S., Manne, U., Smith, Journal of Surgical Pathology, 18, 564–569.
G., Pambuccian, S., & Bumpers, H. L. (2012). Pseudo- Noda, Y., Nishimae, A., Sawai, Y., Inaji, H., & Yamasaki, M.
angiomatous stromal hyperplasia (PASH) of the breast: (2019). Atypical pseudoangiomatous stromal hyperpla-
A series of 24 patients. The Breast Journal, 18, sia showing rapid growth of the breast: Report of a case.
242–247. Pathology International. https://doi.org/10.1111/
Comunoğlu, N., Comunoğlu, C., Ilvan, S., Calay, Z., & pin.12786.
Müslümanoğlu, M. (2007). Mammary Pseudo- Pellini, D. F., Lorenzi, M., Gaudino, R., Accordini, B.,
angiomatous stromal hyperplasia composed of pre- Mirandola, S., Invento, A., & Pollini, P. D. (2018).
dominantly Giant cells: An unusual variant. The Pseudoangiomatous stromal hyperplasia (PASH) in
Breast Journal, 13, 568–570. adolescence: A systematic review. World Journal of
Damiani, S., & Eusebi, V. (2001). Gynecomastia in type-1 Surgery and Surgical Research, 1, 1058.
neurofibromatosis with features of pseudoangiomatous Polger, M. R., Denison, C. M., Lester, S., & Meyer, J. E.
stromal hyperplasia with giant cells. Report of two (1996). Pseudoangiomatous stromal hyperplasia:
cases. Virchows Archiv, 438, 513–516. Mammographic and sonographic appearances. Ameri-
de Saint Aubain Somerhausen, N., Larsimont, D., Cluydts, N., can Journal of Roentgenology, 166, 349–352.
Heymans, O., & Verhest, A. (1997). Pseudo- Powell, C. M., Cranor, M. L., & Rosen, P. P. (1995).
angiomatous hyperplasia of mammary stroma in an Pseudoangiomatous stromal hyperplasia (PASH):
HIV patient. General & Diagnostic Pathology, 143, A mammary stromal tumor with myofibroblastic dif-
251–254. ferentiation. American Journal of Surgical Pathology,
Ferreira, M., Albarracin, C. T., & Resetkova, E. (2008). 19, 270–277.
Pseudoangiomatous stromal hyperplasia tumor: Pruthi, S., Reynolds, C., Johnson, R. E., & Gisvold, J. J.
A clinical, radiologic and pathologic study of (2001). Tamoxifen in the management of Pseudo-
26 cases. Modern Pathology, 21, 201–207. angiomatous stromal hyperplasia. The Breast Journal,
Ibrahim, R. E., Sciotto, C. G., & Weidner, N. (1989). 7, 434–439.
Pseudoangiomatous hyperplasia of mammary stroma. Raj, S. D., Sahani, V. G., Adrada, B. E., Scoggins, M. E.,
Some observations regarding its clinicopathologic Albarracin, C. T., Woodtichartpreecha, P., Posleman
spectrum. Cancer, 63, 1154–1160. Monetto, F. E., & Whitman, G. J. (2017). Pseudo-
Krawczyk, N., Fehm, T., Ruckhäberle, E., Mohrmann, S., angiomatous stromal hyperplasia of the breast: Multi-
Riemer, J. Braunstein, S. Hoffmann, J. (2016) Bilateral modality review with pathologic correlation. Current
diffuse Pseudoangiomatous stromal hyperplasia Problems in Diagnostic Radiology, 46, 130–135.
(PASH) causing Gigantomastia in a 33-year-old preg- Recavarren R. A., Chivukula M., Carter G., Dabbs D. J.
nant woman: Case report. Breast Care, 11, 356–358. (2009). Columnar cell lesions and pseudoangiomatous
Krings, G., McIntire, P., & Shin, S. J. (2017). hyperplasia like stroma: is there an epithelial-stromal
Myofibroblastic, fibroblastic and myoid lesions of the interaction? International Journal of Clinical and
breast. Seminars in Diagnostic Pathology, 34, Experimental Pathology, 3, 87–97.
427–437. Rosen, P. P. (2001). Rosen’s breast pathology. Philadel-
Lee, J. S., Oh, H. S., & Min, K. W. (2005). Mammary phia: Lippincott Williams & Wilkins.
pseudoangiomatous stromal hyperplasia presenting as Roy, M., Lee, J., Aldekhayel, S., & Dionisopoulos, T.
an axillary mass. The Breast, 14, 61–64. (2015). Pseudoangiomatous stromal hyperplasia:
Leon, M. E., Leon, M. A., Ahuja, J., & Garcia, F. U. A rare cause of idiopathic Gigantomastia. Plastic and
(2002). Nodular myofibroblastic stromal hyper- Reconstructive Surgery. Global Open, 3, e501.
plasia of the mammary gland as an accurate name Sasaki, Y., Kamata, S., Saito, K., Nishikawa, Y., & Ogawa, J.
for pseudoangiomatous stromal hyperplasia of (2008). Pseudoangiomatous stromal hyperplasia (PASH)
the mammary gland. The Breast Journal, 8, of the mammary gland: Report of a case. Surgery Today,
290–293. 38, 340–343.
Seidman, J. D., Borkowski, A., Aisner, S. C., & Sun, A rare tumor of the breast. Journal of Cancer Research
C. C. (1993). Rapid growth of pseudoangiomatous and Therapy, 11, 1032.
hyperplasia of mammary stroma in axillary Virk, R. K., & Khan, A. (2010). Pseudoangiomatous stro-
gynecomastia in an immunosuppressed patient. mal hyperplasia. An overview. Archives of Pathology
Archives of Pathology and Laboratory Medicine, and Laboratory Medicine, 134, 1070–1074.
117, 736–738. Vuitch, M. F., Rosen, P. P., & Erlandson, R. A. (1986).
Shahi, K. S., Bhandari, G., Gupta, R. K., & Sawai, M. Pseudoangiomatous hyperplasia of mammary stroma.
(2015). Pseudoangiomatous stromal hyperplasia: Human Pathology, 17, 185–191.
P
R
Radial Scar Clinical Features
Janina Kulka • Incidence

2nd Department of Pathology, Semmelweis The incidence of radial scars increased with the
University, Budapest, Hungary introduction of mammographic screening, but
in the whole screened population it remains a
rare lesion. Assessing the incidence of radial
Synonyms scars in the Welsh Breast Screening Pro-
gramme, 764 radial scars (0.05%) were
Rosette-like lesion; Proliferation center; reported in a population of 1,285,716 women
Sclerosing adenosis with pseudo-infiltration; attending breast screening between 1989 and
Sclerosing papillary proliferation; Benign scle- 2007 (Osborn et al. 2011). In a study from the
rosing ductal proliferation; Nonencapsulated Gustave Roussy Institute from 1985 (D’Amore
sclerosing lesion; Centre de proliferation et al. 1985) studying surgical pathology mate-
d’Aschoff; Fibroadenosis with fibroelastic core; rial of 6544 women operated for benign breast
Lesioni focali sclero-elastotiche; Radial scleros- lesions between 1976 and 1981, the authors
ing lesion; Indurative mastopathy; Strahlige identified only 70 cases (1%) with radial
Narben scars. Later, in a smaller cohort of 1396
patients with benign breast biopsies from the
Nurses’ Health Study, radial scars occurred in
Definition 7.1%. In their historical study describing sub-
gross findings in 300 whole human breasts,
The definition of radial scars was given by Wellings and Alpers (1984) found much higher
Wellings as follows: a radial scar is a radially incidence (14%) in 83 noncancerous breasts
symmetric tissue formation up to about 1 cm in that were collected during autopsies. An inter-
diameter; it is composed of a fibroelastic esting finding of this study was that the
core that often entraps small epithelial 12 breasts (12/83, 14%) had a total of 92 radial
tubules and is always surrounded by radiating scars indicating an average of 7.7 lesions per
ducts and lobules showing variable degrees breast. On the other hand, in the 107 cancer-
of adenosis and epitheliosis (Wellings and associated (ipsilateral or contralateral breast
Alpers 1984). cancer) breasts, they found 434 radial scars,

https://doi.org/10.1007/978-3-319-62539-3
340 Radial Scar
on average 15.5 per breast. Linell who of the cases diagnosed as radial scar. In almost
performed a study of 555 mastectomy speci- 10% of the cases, the lesion is better visualized
mens found radial scars in 16%, but in the by ultrasound than mammography. On MRI,
group of breast cancer patients radial scars radial scars possess variable morphology and
were present in half of the specimens (Linell their kinetic features are also not uniform.
1985). These findings led to suggest that radial Since they can demonstrate false positive
scars may be precancerous lesions. enhancement, ill-defined borders, and irregular
• Age shape, not infrequently MRI findings mimic
In large studies, the age range of radial scars invasive carcinoma.
varies between 25 and 89 years. The median of • Treatment
this range is around the perimenopausal age Given that core biopsy diagnosis of radial scars
group. is coded as B3 according to present guidelines,
• Sex these lesions need further multidisciplinary
Radial scars are mainly found in female work-up. Until a few years ago, core biopsy
breasts, but in occasional rare cases it may diagnosis of a radial scar was an absolute indi-
occur in male breasts as well. cation for surgical excision, and in large series
• Site the upgrade rate for malignancy varied between
No specific site had been described as concerns 0% and 24%. More recently, with the wide-
laterality or quadrant of the breast. spread use of vacuum-assisted core biopsy
• Imaging (VACB), the indications for surgical excision
Many papers had been published describing became more restricted. In the latest update of
the imaging features of radial scars given that the UK Breast Screening Quality Assurance
the structure of these lesions may mimic small Guideline (2016 update), the management of
stellate carcinoma on mammography. Tabar radial scars differs if the lesion was incidental
and Dean (1983) have first described system- (not seen on mammography) or was identified
atically the mammographic features that enable as a mammographic abnormality. For those
the radiology diagnosis, as follows: radial scars detected only histologically on
(i) depending on the view, the appearance of core biopsy performed for other radiologically
the detected lesion is variable, (ii) in relation to identified benign lesion, no further intervention
the long and thin spicules, the central opacity is is needed. For those radial scars detected as
small, (iii) parallel to the spicules a very thin, mammographic abnormality, at least 12 VACB
radiolucent line can be seen, (iv) the center of cores is recommended as a second intervention.
the lesion is radiolucent, and (v) there is dis- Radial scars completely removed by VACB
cordance between the mammographic finding require surgical excision only if epithelial atypia
of a stellate lesion and the lack of a palpable is associated to the lesion.
lesion by physical examination. Digital mam- • Outcome
mography is more sensitive than analogue In one of the longest follow-up study of
mammography, and breast tomosynthesis 32 patients with radial scar, only one patient
apparently discovers even more stellate lesions developed ipsilateral breast cancer 16 years
than analogue or digital mammography, thus after the diagnosis of the radial scar
seems to increase slightly the recall rate in (Andersen and Gram 1984). The mean
screening programs. In the Malmo Breast follow-up period in this study was 19.5 years
Tomosynthesis Screening Trial, around 10% (range 15–24 years). Many studies in the eight-
of the false positive recalls were due to radial ies suggested an elevated cancer risk associ-
scars. Ultrasound detects up to two-third of ated to radial scars; however, large recent
radial scars, most commonly as a hypoechoic studies are less convincing especially
area or mass. Parenchymal distortion without a concerning radial scars devoid of atypical epi-
hypoechoic mass is present in about one-fifth thelial proliferation and assessed on VACB.
Radial Scar 341
A meta-analysis showed a 1.33-fold increased (UDH)), sclerosing adenosis (▶ Sclerosing

risk in pooled analysis of more than 2000 cases Adenosis), and complex fibroadenoma
and more than 20,000 controls, but this was not (▶ Fibroadenoma). The association of atypical
statistically significant (Mengmeng et al. ductal (▶ Atypical Ductal Hyperplasia) - or
2014). Epithelial proliferation associated to atypical lobular hyperplasia, in situ lobular
radial scars slightly increases the risk to 1.6- neoplasia (▶ Lobular In Situ Neoplasia), and
fold. This increase of relative risk is similar flat epithelial atypia (▶ Columnar Cell
to proliferative fibrocystic change (▶ Fibro- Lesions) result in elevated relative cancer risk
cystic Breast Changes), usual type ductal similar to the relative risk of these low grade
hyperplasia (▶ Usual Ductal Hyperplasia atypical epithelial lesions measured outside of
the context of radial scars.
Macroscopy
Radial scars are either visible or not during gross

examination. By definition, these lesions are small,
less than 10 mm in maximum diameter. When
visible, a slightly firm, or rubbery, scar-like lesion
with irregular contour can be identified in the spec-
imen. On specimen mammography, identification
of the lesion may be easier since it may reveal the
characteristic stellate soft tissue density (Fig. 1).
Microscopy
Radial scars have a very characteristic micro-

scopic appearance that can be appreciated
already with very low magnification. They pos-
Radial Scar, Fig. 1 Magnified mammographic appear-
ance of a radial scar. In this case microcalcifications were
sess a central, focally elastotic “scar” from which
associated. (By courtesy of Dr. Éva Ambrózay, MaMMa the epithelial structures showing various degree
Clinic Budapest) of proliferative changes radiate toward the
R
Radial Scar, Fig. 2 H&E: (a) Distorted small ducts lacking any organoid arrangement in the central part of a small radial
scar. (b) Radial scar associated with flat epithelial atypia
342 Radial Scar
periphery. Within the central scar, very often one In some lesions, lymphoid inflammatory infiltrate
finds entrapped and distorted or ramifying small is also found. Presence of small microcalcification
ducts lacking any organoid arrangement particles is not uncommon. Radial scars often
(Fig. 2a). The nuclei of the epithelial cells lying occur in the background of fibrocystic breast
the entrapped ducts are devoid of atypia and no parenchyma. The presence of atypical epithelial
mitotic figures are present. Occasionally, the proliferations (Fig. 2b), in situ carcinomas, or
central elastosis and the scar itself is so much invasive carcinomas in radial scars has been
reminiscent to the contour of a totally obliterated described in larger lesions of older women
larger duct, for in the past periductal mastitis was (Sloane and Mayers 1993). Association of inva-
supposed as an etiologic factor for these lesions. sive carcinoma has not been described in lesions
However, there are opponents to this theory who that are smaller than 5 mm.
believe that radial scars are per se proliferative
lesions of the breast.
The radiating projections contain epithelial Immunophenotype
structures: ducts with various degree of dilatation
(Fig. 3), often with usual type ductal hyperplasia. High molecular weight cytokeratins (cytokeratin
Sclerosing adenosis, small papillomas, adenosis, 5/6, 14) and myoepithelial markers (p63, p40,
and columnar cell change are also common fea- calponin, CD10, etc.) can help to identify the
tures. Apocrine changes may also be associated. benign nature of the epithelial proliferation asso-
ciated with a radial scar or may help to identify an
associated in situ or invasive cancer (Fig. 4).
Molecular Features
Very few molecular studies of radial scars have

been published to date. More than 20 years ago
Ruiz-Sauri compared radial scars and tubular car-
cinomas by image cytometry and flow cytometry
analysis (Ruiz-Saurí et al. 1995). The case num-
bers were small (17 radial scars and 6 small tubu-
lar carcinomas), and only image cytometry could
Radial Scar, Fig. 3 Subgross appearance of the periphery identify ploidy differences between the two types
of a radial scar (Mayer’s hematoxylin) of breast lesions: most radial scars were diploid, as
Radial Scar, Fig. 4 (a) p63 immunohistochemistry highlights the myoepithelial cells and (b) CK14 immunohistochem-
ical reaction shows the heterogeneous epithelial cell population in entrapped small ducts in the center of a radial scar
Radial Scar 343
opposed to only 50% of tubular carcinomas that The differential diagnosis may be more diffi-
showed diploidy. However, using flow cytometry, cult in 14G needle core biopsies. However, in
both radial scars and tubular carcinomas proved close cooperation with the radiologist, the diag-
diploid. In the early 2000s, stromal mRNA nosis of a radial scar can be made with confi-
expression pattern of radial scars and invasive dence even in such specimens. Tissue fragments
cancers was compared using small number of showing the central elastotic scar with entrapped
cases and normal controls. Findings suggested small ducts with normal two layered epithelial
that expression of mRNAs encoding proteins lining (or usual type hyperplasia) are features
involved in the vascular stroma shows similarities that help to identify RSs even in fragmented
between radial scars and invasive breast cancers specimens.
(Jacobs et al. 2002). Chromosomal alterations
have also been described in radial scars, namely,
allelic imbalance of chromosome 16q and 8p.
This finding suggested that some areas of radial
scars are clonal and may be neoplastic (Iqbal et al. Andersen, J. A., & Gram, J. B. (1984). Radial scar in the
2002). More recently a few studies using next female breast. A long-term follow-up study of 32 cases.
generation sequencing (NGS) detected PIK3CA Cancer, 53, 2557–2560.
D’Amore, E., Montes, E., Le, M. G., Lacombe, M. J.,
mutations in radial scars with higher frequency
Bertin, F., Castaigne, D., & Contesso, G. (1985).
compared to the 25–30% PIK3CA mutation fre- Aschoff’s center of proliferation. Experience of the
quency detected in series of invasive breast carci- Gustave Roussy Institute. Annals of Pathology, 5,
nomas (Wilsher et al. 2017). 173–182.
Hamperl, H. (1975). Strahlige Narben und obliterierende
Mastopathie. Virchows Archiv (Pathological Anatomy),
369, 55.
Differential Diagnosis Iqbal, M., Shoker, B. S., Foster, C. S., Jarvis, C.,
Sibson, D. R., & Davies, M. P. (2002). Molecular and
genetic abnormalities in radial scar. Human Pathology,
Radial scars may be misdiagnosed by the
33, 715–722.
unexperienced pathologist as invasive breast car- Jacobs, T. W., Byrne, C., Colditz, G., Connolly, J. L.,
cinoma NST (▶ Invasive Carcinoma NST) or & Schnitt, S. J. (1999). Radial scars in benign
tubular carcinoma (▶ Tubular Carcinoma). It is breast-biopsy specimens and the risk of breast can-
cer. New England Journal of Medicine, 340(6),
noteworthy to mention that the irregular, haphaz-
430.
ardly arranged, compressed tubular structures in Jacobs, T. W., Schnitt, S. J., Tan, X., & Brown, L. F. (2002).
radial scars are exclusively seen in the central Radial scars of the breast and breast carcinomas have
elastotic nidus. In invasive cancers, the neoplastic similar alterations in expression of factors involved in
vascular stroma formation. Human Pathology, 33, R
tubules often invade the fat tissue which is not
29–38.
a feature in radial scars. Furthermore, in the rela- Lång, K., Nergården, M., Andersson, I., Rosso, A., &
tively wide radiating arms, there are ducts and/or Zackrisson, S. (2016). False positives in breast cancer
lobules showing various degree of the screening with one-view breast tomosynthesis: An
analysis of findings leading to recall, work-up and
abovementioned proliferative epithelial changes.
biopsy rates in the Malmö Breast Tomosynthesis
As opposed to this, in small grade 1 carcinomas or Screening Trial. European Radiology, 26(389),
tubular carcinomas, the neoplastic tubules build 9–3907.
up the whole lesion and most of their stellate Linell, F. (1985). Radial scars of the breast and their sig-
nificance for diagnosis and prognosis. Verhandlungen
peripheral projections are devoid of preexisting
der Deutschen Gesellschaft für Pathologie, 69,
ducts or lobules. In equivocal cases, immunohis- 108–118.
tochemical markers for myoepithelial cells can Mengmeng, L. V., Xingya, Z., Shanliang, Z., et al. (2014).
assist to exclude malignancy. In case of uncer- Radial scars and subsequent breast Cancer risk: A meta
analysis. PLoS One, 9, e102503.
tainty, high molecular weight cytokeratins are
NHS Breast Screening Programme Clinical guidance for
useful to characterize the associated intraductal breast cancer screening assessment. (2016). NHSBSP
proliferations. publication number 49, 4th ed.
344 Radial Scar
Osborn, G., Wilton, F., Stevens, G., Vaughan-Williams, E., sclerosing lesions: Importance of lesion size and patient
& Gower-Thomas, K. (2011). A review of needle core age. Histopathology, 23, 225–231.
biopsy diagnosed radial scars in the Welsh Breast Tabar, L., & Dean, P. B. (1983). Teaching atlas of mammog-
Screening Programme. Annals of Royal College of raphy (pp. 95–96). Stuttgart: Georg Thieme Verlag.
Surgeons England, 93, 123–126. Wellings, S. R., & Alpers, C. E. (1984). Subgross patho-
Ruiz-Saurí, A., Almenar-Medina, S., Callaghan, R. C., logic features and incidence of radial scars in the breast.
Calderon, J., & Llombart-Bosch, A. (1995). Radial Human Pathology, 15, 475–479.
scar versus tubular carcinoma of the breast. Wilsher, M. J., Owens, T. W., & Allcock, R. J. (2017).
A comparative study with quantitative techniques Next generation sequencing of the nidus of early
(morphometry, image- and flow cytometry). Pathology (adenosquamous proliferation rich) radial sclerosing
Research and Practice, 191, 547–554. lesions of the breast reveals evidence for a neoplastic
Sloane, J. P., & Mayers, M. M. (1993). Carcinoma and precursor lesion. Journal of Pathology: Clinical
atypical hyperplasia in radial scars and complex Research, 3, 115–122.
S
Sclerosing Adenosis 28.3% of older women and 21.6% of women

less than 45.
Gyula Pekar • Sex
Division for Laboratory Medicine, Department of SA is predominant in women and
Pathology, Lund University, Lund, Sweden more common in obese and in women using
hormone replacement therapy and with a
higher fibroglandular breast tissue density at
Synonyms mammography (>25%). Because of increased
estrogen receptor (ER) expression observed
Sclerosing adenosis (SA) compared with normal glandular breast tissue,
it is assumed that hormone imbalance and
dysregulation of ER may play a role in devel-
Definition opment of SA.
• Presentation
SA is a lobulocentric proliferation of distorted – Clinical appearance
acini around a central duct with preservation of Patients with a clinically palpable mass, termed
myoepithelial cells, accompanied with varying as nodular SA or adenosis tumor (▶ Adenosis,
degrees of epithelial atrophy and stromal fibrosis. Other Types), are generally younger, often in
their pre- or perimenopausal age. The lesion is
usually solitary, although multiple and bilateral
Clinical Features nodular SAwere reported. It may be ill-defined
and can be somewhat fixed within the breast
• Incidence parenchyma.
SA is often an incidental finding in breast tis- – Mammography
sue removed for other reasons. In autopsy stud- The main features of SA are multiple, punc-
ies performed on patients with no history of tuate microcalcifications (i.e., powdery, cot-
breast disease, the incidence of SA was in a ton ball-like, “skipping stone-like”) (Fig. 1a).
range of 7–20%. The lesion is present in Thick-section images demonstrate that the
12–28% of breast biopsies without cancer and radiologically detected microcalcifications
in 5–7% of malignant biopsies. can have “onion ring” like psammomatous
• Age appearance (Fig. 1b), and they are localized
Most patients are in their forties and fifties with within enlarged and distorted lobules
a peak in the 45–55 age group (34%), versus (Fig. 1c, d). Rarely mammographic
https://doi.org/10.1007/978-3-319-62539-3
346 Sclerosing Adenosis
Sclerosing Adenosis, Fig. 1 SA associated with micro- appearance (b), and localized within enlarged and distorted
calcifications. Specimen mammography shows clusters of lobules (c, d). The single black arrows on pictures d
cotton ball-like, powdery calcifications (a). Thick-section represent the two expanded foci of SA comparing to an
images demonstrate that the radio dense phosphate calcifi- intermingled normal lobule depicted with double black
cations can have “onion ring” like psammomatous- arrows
calcifications may be amorphous and pleo- and the distinction from infiltrating carci-
morphic and in such cases indistinguishable noma is impossible.
from non-comedo DCIS. SA is less com- – Magnetic resonance imaging (MRI)
monly detected as a mass lesion, which is Typical SA lesions are indistinguishable
generally circumscribed or lobulated and from breast parenchyma, but the enhance-
may be associated with microcalcifications. ment may increase moderately or rapidly
In rare cases, SA presents as an architectural over time making it difficult to distinguish
distortion. nodular SA from malignant lesions.
– Ultrasound • Treatment
Nodular SA often appears as a circum- Some evidence suggests that SA may regress
scribed, hypoechoic solid lesion. In cases after the menopause. When SA is associated
with asymmetrical density on mammogra- with non-proliferative lesions as a part of fibro-
phy, the typical ultrasound feature is focal cystic change, further excision is not
acoustic shadowing without a mass config- recommended. If SA is diagnosed in a core nee-
uration. Mass-like lesions with irregular dle biopsy (CNB), surgical excision of
contour in association with marked poste- the lesional area is recommended to rule out
rior acoustic shadowing are also observed, carcinoma, particularly in cases associated with
Sclerosing Adenosis 347
radiographically suspicious calcifications, a nodular mass. However the diagnostic clue is

spiculated contour, or combined with radial scle- swirling cluster of tubules or acini often around
rosing lesions, or atypical epithelial hyperplasia. central duct(s) with a whorled appearance
In the absence of the foregoing features, clinical (Fig. 2a) usually referred to as lobulocentric in the
follow-up is recommended. literature (Urban and Adair 1949). Further diagnos-
• Outcome tic criteria of SA are its size which is approximately
There is still disagreement as to whether SA is a twice the size of adjacent “normal” lobules, and at
risk factor for subsequent breast carcinoma. least 50% of the acini of individual TDLU must be
When only a small area of SA is present, there involved by the sclerosing process (Jensen et al.
may be no evidence that risk is elevated beyond 1989). However, the lobules can vary greatly in
that of other non-proliferative lesions size within the same breast; this criterion seems
(no increased breast cancer risk, 4% lifetime difficult to be applied. The range of SA varies
risk) such as usual ductal hyperplasia. The com- from highly cellular lesions to sclerotic/hyalinized
bination of SA with atypical ductal hyperplasia areas, depending on the amount of epithelial and
(ADH) (▶ Atypical Ductal Hyperplasia) or atyp- myoepithelial cells (Fig. 2b p63 and Fig. 2d CK14
ical lobular hyperplasia (ALH) increases the risk immunostaining of myoepithelial cells) and the
of cancer development (4.8–6.7). The associa- thickness of basement membranes (Fig. 2c). The
tion with lobular neoplasia (▶ Lobular In Situ acini are distorted and elongated and predominance
Neoplasia) is found to occur almost three times of myoepithelial cells is common. Intraluminal
more commonly than would be expected by microcalcifications may be prominent justifying
chance. In addition, positive family history of the radiological abnormality. Both intraluminal
breast cancer (2.85 risk), patient age (2.24 and stromal microcalcifications become progres-
risk in 45–55 years old group), and other risk sively more numerous with increasing sclerosis.
factors such as the degree of lobular involution SA may be associated with (i) nonproliferative
(2.67 risk in non-involutionary breast) and changes (i.e., apocrine metaplasia, mild epithelial
higher Ki-67 expression in SA and/or adjacent hyperplasia) (8%); (ii) fibroadenoma, papilloma,
normal breast can increase the risk of subsequent complex sclerosing lesions, columnar cell changes
invasive carcinoma (Nassar et al. 2015). (62.4%); and (iii) proliferative disease with atypia
(ADH and ALH equally distributed in 55.1%)
(Visscher et al. 2014). When SA is not limited to
Macroscopy a single lobule, the proliferating benign glands can
display a pseudo-infiltrative pattern. Spread to peri-
There are no distinctive gross appearances, the neural spaces is observed in 2–10% of the SA
breast tissue either appearing normal or showing cases, without impact on the biological behavior.
features of associated fibrocystic change. In cases
with nodular SA firm, lobulated but often ill-
Rarely SA is involved by atypical epithelial pro- S
liferations. Atypical apocrine cells, so-called atyp-
defined rubbery mass can be seen varying in size ical apocrine adenosis, DCIS, or lobular carcinoma
up to 5 cm. A nodular and whorled appearance in situ (LCIS) may be seen in SA (Fig. 3).
may be appreciated on the cut surface.
Immunophenotype
Microscopy
Due to its origin, SA maintains the immuno-
At low power three main forms of SA could phenotype of normal lobules (i.e., CK7, CK 8/18,
be observed: tiny foci in an otherwise normal breast p63, p40, smooth muscle actin, calponin, and high-
tissue, especially in perimenopausal women, larger molecular weight cytokeratins (CK5/6, CK14)).
but still microscopic lesions as part of the spectrum Using of more than one myoepithelial marker or
of fibrocystic change, and lesions that may form a “cocktail” of markers can be helpful (Pavlakis et al.
348 Sclerosing Adenosis
Sclerosing Adenosis, Fig. 2 Histology of SA. Enlarged partly obscured lumens on higher magnification (c, H&E
lobule with dilated glands (a, H&E 20) and retained 100) and the outer layer of myoepithelial cells being
myoepithelial cell layer which is highlighted with the p63 positive with CK14 IHC (d)
immunostain (b). Array of microtubular structures with
2006). Basement-membrane material is immunore- Invasive Carcinoma

active for collagen IV and laminin. The features favoring SA against invasive carci-
noma are the following: lobulocentric architec-
ture, myoepithelial cells on hematoxylin and
Molecular Features eosin (HE) slides or by immunohistochemistry
(IHC), and dense rather than desmoplastic
A recent gene expression profile study revealed stroma.
overexpression of DLK2, EXOC6, KIT, RGS12, SA can mimic tubular carcinoma (TC)
and SORBS2 in SA at risk of cancer development (▶ Tubular Carcinoma). TC does not recapitu-
(Winham et al. 2017). late the lobulocentric architecture and shows
haphazardly infiltrating growth pattern, edges
are irregular rather than circumscribed or lobu-
Differential Diagnosis lated, and the tubules are more widely spaced. In
addition, TC shows angulated tubules with open
Normal Breast Versus SA lumens and no myoepithelial cells. Invasive apo-
(1) Adenosis: lobules are enlarged; the number crine carcinoma (▶ Apocrine Carcinoma) can be
of acini is increased. It occurs in normal misdiagnosed in cases of atypical apocrine
circumstances such as pregnancy (▶ Adenosis, adenosis. However, in atypical apocrine
Other Types). (2) Lobules involution: involuting adenosis, the organoid appearance is obvious
lobules appear more eosinophilic than SA, being and specific IHC markers can demonstrate
dominated by luminal cells with plump blue nuclei. myoepithelial cells.
Sclerosing Adenosis 349
Sclerosing Adenosis, Fig. 3 SA harboring LCIS. The cytoplasmic membrane positivity and mixed with focally
part of SA shows irregularly distributed acini expanded by remaining normal glandular cells with continuous and
atypical cells of lobular type (a, H&E 80). E-cadherin intensive membrane staining (b). The myoepithelial cells
IHC shows that the cells of LCIS are completely lacking are intact as indicated by p63 IHC (c)
Microglandular Adenosis (MGA) A nested case-control study from the Mayo Benign
MGA (▶ Microglandular Adenosis) is composed Breast Disease Cohort. Breast Cancer Research and
Treatment, 151, 89–97.
of small round tubules scattered around normal Pavlakis, K., Zoubouli, C., Liakakos, T., Messini, I.,
breast structures. Luminal spaces are opened with Keramopoullos, A., Athanassiadou, S., Kafousi, M.,
round contours and eosinophilic secretions with- & Stathopoulos, E. N. (2006). Myoepithelial cell cock-
out obvious stromal response. MGA can be dis- tail (P63+SMA) for the evaluation of sclerosing breast
lesions. Breast, 15, 705–712.
tinguished from SA by lacking myoepithelial Urban, J. A., & Adair, F. E. (1949). Sclerosing adenosis. S
cells, ER negativity, and S100 strong positivity Cancer, 2, 625–634.
with IHC. Visscher, D. W., Nassar, A., Degnim, A. C., Frost, M. H.,
Vierkant, R. A., Frank, R. D., Tarabishy, Y.,
Radisky, D. C., & Hartmann, L. C. (2014). Sclerosing
adenosis and risk of breast cancer. Breast Cancer
References and Further Reading Research and Treatment, 144, 205–212.
Winham, S. J., Mehner, C., Heinzen, E. P.,
Jensen, R. A., Page, D. L., Dupont, W. D., & Rogers, Broderick, B. T., Stallings-Mann, M., Nassar, A.,
L. W. (1989). Invasive breast cancer risk in Vierkant, R. A., Hoskin, T. L., Frank, R. D.,
women with sclerosing adenosis. Cancer, 64, Wang, C., Denison, L. A., Vachon, C. M.,
1977–1983. Frost, M. H., Hartmann, L. C., Aubrey Thompson,
Nassar, A., Hoskin, T. L., Stallings-Mann, M. L., E., Sherman, M. E., Visscher, D. W., Degnim, A. C.,
Degnim, A. C., Radisky, D. C., Frost, M. H., & Radisky, D. C. (2017). NanoString-based breast
Vierkant, R. A., Hartmann, L. C., & Visscher, D. W. cancer risk prediction for women with sclerosing
(2015). Ki-67 expression in sclerosing adenosis and adenosis. Breast Cancer Research and Treatment,
adjacent normal breast terminal ductal lobular units: 166, 641–650.
350 Sebaceous Carcinoma of the Breast
Norris 1986; van Bogaert and Maldague

Sebaceous Carcinoma of the 1977).
Breast • Age
Based on the available literature data, seba-
Zsuzsanna Varga and Linda Moskovszky ceous breast carcinoma presents a wide range
Institute of Pathology and Molecular Pathology, of age, between 25 and 84 years at initial diag-
University Hospital Zurich, Zurich, Switzerland nosis with a mean age of 59.16 years, with
most patients being postmenopausal
(Murakami et al. 2009; Hisaoka et al. 2006;
Synonyms Varga et al. 2000).
• Sex
Carcinomas with sebaceous differentiation; Car- Almost exclusively female patients were
cinomas with skin adnexal differentiation reported in the literature so far. In one earlier
paper, a male patient with a large sebaceous
carcinoma in the breast area was described;
Definition however this tumor as described in this paper
represents a skin adnexal tumor rather than a
Infiltrative carcinomas of the breast exhibiting primary breast carcinoma (Acosta et al. 2018;
sebaceous cell differentiation in at least 50% of Maia and Amendoeira 2018; Murakami et al.
the invasive tumor cells. In order to classify a 2009; Hisaoka et al. 2006; Varga et al. 2000;
breast tumor as such, an extramammary tumor Ascari-Raccagni et al. 2011).
especially carcinomas arising from the skin • Site
adnexal structures must be excluded clinically or There is no site-specific predilection for this
immunohistochemically (Acosta et al. 2018; Maia tumor type. Both breasts are equally involved
and Amendoeira 2018; Martin et al. 2017). (Acosta et al. 2018; Maia and Amendoeira
2018; Martin et al. 2017).
• Treatment
Clinical Features Depending on the pathological stage and grade
of the tumor under consideration of the pres-
• Incidence ence or absence of the predictive markers as
This type of breast tumor is exceedingly rare, estrogen and progesterone receptors and HER2
accounting less than 1% of all breast carcino- status, the current recommendation to surgery
mas. Until now, 18 cases were reported in the and chemo- and radiotherapy is analogous to
literature, most of them fulfilling the complete breast cancer independently from the subtype
criteria for a sebaceous breast carcinoma, and (Murakami et al. 2009; Hisaoka et al. 2006;
some were described as invasive breast cancer Varga et al. 2000).
with sebaceous differentiation. Difficulties in • Outcome
recognizing this entity requires precise knowl- Follow-up is available in most reported cases.
edge and recognition of the specialized addi- Based on this information and on the limited
tional cell type within the infiltrating tumor number of cases, sebaceous breast carcinoma
cells (Acosta et al. 2018; Maia and tends to present with metastatic disease
Amendoeira 2018; Sakai et al. 2018; Martin (as skin, eyelid, and disseminated bone metas-
et al. 2017; Yamamoto et al. 2017; Švajdler tases) in about a third of the cases (Maia and
et al. 2015; Wachter et al. 2014; Carlucci Amendoeira 2018; Martin et al. 2017; Švajdler
et al. 2012; Müller et al. 2011; Murakami et al. 2015; Carlucci et al. 2012; Müller et al.
et al. 2009; Hisaoka et al. 2006; Varga et al. 2011; Varga et al. 2000). Death due to meta-
2000; Propeck et al. 2000; Tavassoli and static disease has been described in four
Sebaceous Carcinoma of the Breast 351
patients. Seven of eighteen patients presented

with positive nodal status at initial diagnosis
(Maia and Amendoeira 2018; Švajdler et al.
2015; Müller et al. 2011; Murakami et al.
2009; Hisaoka et al. 2006). Tumor stage is
variable, and reported tumor sizes vary
between 12 and 120 mm (mean size
35.9 mm) (Acosta et al. 2018; Maia and
Amendoeira 2018; Sakai et al. 2018; Martin
et al. 2017; Yamamoto et al. 2017; Švajdler
et al. 2015; Wachter et al. 2014; Carlucci
et al. 2012; Müller et al. 2011; Murakami
et al. 2009; Hisaoka et al. 2006; Varga et al.
2000; Propeck et al. 2000; Tavassoli and Sebaceous Carcinoma of the Breast, Fig. 1 Low-
power appearance of a sebaceous carcinoma. The tumor
Norris 1986; van Bogaert and Maldague exhibits several large cells with pale cytoplasm with coarse
1977). and bubbly vacuolated tumor cells (H&E stain, low
magnification)
Macroscopy
Sebaceous carcinomas usually present with a pal-

pable mass in the breast, as noted above in a third
of the cases with nodular lesions within the met-
astatic site. It has been reported that sebaceous
carcinomas exhibit a yellowish whitish cut surface
and a multilobulated tumor contour with sharp
borders (Acosta et al. 2018; Maia and
Amendoeira 2018; Sakai et al. 2018; Martin
et al. 2017; Yamamoto et al. 2017; Švajdler et al.
2015; Wachter et al. 2014; Carlucci et al. 2012;
Müller et al. 2011; Murakami et al. 2009; Hisaoka
et al. 2006; Varga et al. 2000; Propeck et al. 2000;
Tavassoli and Norris 1986; van Bogaert and Sebaceous Carcinoma of the Breast, Fig. 2 High-
power appearance of a sebaceous carcinoma, large tumor
Maldague 1977). cells with pale, coarse, and bubbly vacuolated cytoplasm
(H&E stain, high magnification)
S
Microscopy (Figs. 1–3) (Acosta et al. 2018; Maia and
Amendoeira 2018). These cells may show vari-
Tumor with sebaceous differentiation often has a able stain with fat stains (as Sudan black or Oil
background of an infiltrating carcinoma NST, Red O) and usually remain negative at the PAS
which exhibits sharp borders toward the tumor stain. Intermingled among the sebaceous cells,
periphery. According to the 2012 WHO classifi- there are usually other cell components found
cation of breast tumors, it was defined that at least (as of spindle, squamous, or ovoid morphology).
50% of the whole tumor mass containing large A few studies conducted electron microscopy
tumor cells with coarse or bubbly vacuolated showing non-membrane-bound empty vacuoles
cytoplasm resembling sebaceous cells of the skin corresponding to lipid droplets of different sizes
appendage need to be present for this diagnosis (Sakai et al. 2018; Varga et al., 2000). Grading in
352 Sebaceous Carcinoma of the Breast
2014; Carlucci et al. 2012; Müller et al. 2011;

Murakami et al. 2009; Hisaoka et al. 2006;
Varga et al. 2000; Propeck et al. 2000).
Molecular Features
No established molecular features are known cur-

rently. One reported case had a BRCA2 germ line
mutation; one additional case occurred within the
scope of the Muir-Torre syndrome, an autosomal
dominant inherited disease with variable pene-
trance and exhibiting at least one sebaceous gland
Sebaceous Carcinoma of the Breast, Fig. 3 High- tumor and one additional malignancy (Acosta et al.
power appearance of a sebaceous carcinoma, large tumor
cells with pale, coarse, and bubbly vacuolated cytoplasm 2018; Propeck et al. 2000) (Figs. 1, 2, and 3).
(H&E stain, high magnification)
the reported cases is G2 or G3; until now there is
no case reported with well differentiated The main differential diagnosis encompasses a
(G1) morphology (Acosta et al. 2018; Maia and primary skin adnexal tumor with sebaceous mor-
Amendoeira 2018; Sakai et al. 2018; Martin et al. phology. The presence of in situ components
2017; Yamamoto et al. 2017; Švajdler et al. 2015; (DCIS, LN) in the tumor and the lack of connec-
Wachter et al. 2014; Carlucci et al. 2012; Müller tion to the skin of the breast are useful features,
et al. 2011; Murakami et al. 2009; Hisaoka et al. which favor a primary sebaceous breast carci-
2006; Varga et al. 2000; Propeck et al. 2000). noma. Additionally, the use of immunohisto-
chemistry (especially a positive AR reaction and
the negativity for S100 and GCDFP-15 can sup-
Immunophenotype port breast origin) (Table 1).
Further differential diagnosis is the different
Most studies confirm that sebaceous cells are usu- types of breast cancers; especially the spectrum
ally strongly positive for keratins, EMA, and of primary clear cell carcinomas needs to be
adipophilin. Recent case reports could addition- excluded. Apocrine breast carcinoma (▶ Apo-
ally show GATA 3 and AR positivity in the seba- crine Carcinoma), lipid-rich breast carcinoma,
ceous cells. Three cases analyzed mismatch repair and glycogen-rich breast carcinoma (▶ Glyco-
proteins showing preserved epitopes without any gen-Rich Clear Cell Carcinoma) are in the differ-
selective loss. Interestingly, GCDFP-15 and S100 ential diagnosis. Morphology (large lipid
are consequently negative in the sebaceous cells. droplets, water-clear cytoplasm, or eosinophilic
One case was shown to exhibit neuroendocrine cytoplasm) and positive special stains (granular
differentiation by synaptophysin positivity PAS stain and large fatty droplets with Sudan
(Hisaoka et al. 2006). Black and Oil Red O) favor another type of clear
Predictive markers were tested in a large subset cell breast carcinoma. Expansive growth in a lob-
of reported cases; most cases are hormone recep- ular pattern and the presence of a dual neoplastic
tor positive and HER2 negative, and three cases cell population of larger sebaceous cells and
were triple negative and two cases HER2 positive smaller cells of different type are suggestive of a
(Acosta et al. 2018; Maia and Amendoeira 2018; sebaceous carcinoma (Acosta et al. 2018; Maia
Sakai et al. 2018; Martin et al. 2017; Yamamoto and Amendoeira 2018; Murakami et al. 2009;
et al. 2017; Švajdler et al. 2015; Wachter et al. Hisaoka et al. 2006; Varga et al. 2000).
Sebaceous Carcinoma of the Breast, Table 1 Summary of reported cases
Tumor
Number Age size Nodal Histological ER/
Publication of cases (years) (in mm) status grade PR HER2 IHC positive IHC negative other Follow-up
Acosta 1 51 20 mm pNO 2 +/+ Neg AR BRCA2+ NA
(2018) MMRP
Maia 2(1) 65 70 mm pN1(1/2) NA Neg/ Neg AR Died 9 months after
(2018) neg MMRP initial diagnosis
Sebaceous Carcinoma of the Breast
GATA 3
Maia 2 71 37 mm pNO NA +/ Neg GATA3 AR 100 months uneventful
(2018) neg MMRP
Sakai 2018 1 74 23 mm NA G2 +/+ Neg AR Mammoglobin NA
GATA3
Adipophylin
Martin 1 59 NA NA G2 +/+ Neg EMA Eyelid metastasis
2017 CK7 2 years after initial
CAM2 diagnosis
Yamamoto 1 80 35 mm NA NA Neg/ Neg EMA AR NA
2017 neg BerEp4
Adipophylin
Svajdler 4(1) 65 16 mm pN1(1/1) G3 +/+ Neg EMA S100 27 months uneventful
2015
Svajdler (2) 61 17 mm pN1(2/5) G3 Neg/ Neg EMA Died after 28 months
2015 neg
Svajdler 3 66 30 mm pN1(1/10) G2 +/+ Neg GCDFP-15 70 months uneventful
2015 EMA
S100
Svajdler 4 25 NA NA G3 +/+ Neg EMA GCDFP-15 75 months uneventful
2015 S100
Wachter 1 53 12 mm pNO G3 +/+ Neg GATA3 NA
2014 MMRP
(continued)
353
S
354
Sebaceous Carcinoma of the Breast, Table 1 (continued)

Tumor
Number Age size Nodal Histological ER/
Publication of cases (years) (in mm) status grade PR HER2 IHC positive IHC negative other Follow-up
Carlucci 1 84 120 NA NA Neg/ IHC EMA GCDFP-15 Metastases 10 years
2012 mm neg score S100 after initial diagnosis
3+ AR
Müller 1 61 NA pN3(18/19) G2 +/+ Neg EMA CEA Skin metastases 5 years
2011 Adipophylin after initial diagnosis
Muakami 1 50 24 mm pN1 NA Neg/ IHC AR GCDFP-15 NA
2009 neg score EMA S100
3+ Adipophylin
Hisaoka 1 63 20 mm pN1(1/9) NA +/+ Neg EMA GCDFP-15 NA
2006 Synaptophysin Vimentin
Lipid stains AR
P63
SMA
S100
Varga 2000 1 45 25 mm NA G2 +/+ Neg EMA + S100 Skin and disseminated
Vimentin bone métastases 8 years
CEA after initial diagnosis
Propeck 1 46 15 mm NA NA NA NA Muir- 6 months uneventful
1999 Torre
syndrome
Tawassoli 1 46 75 mm NA NA NA NA NA
1986
Van 3 NA NA NA NA NA NA NA
Bogaert
1977
Abbreviations: ER estrogen receptors, PR progesterone receptors, HER2 epidermal growth factor 2 receptors, AR androgen receptors, EMA epithelial membrane antigen, MMRP
mismatch repair protein, IHC immunohistochemistry, BRCA breast cancer, CEA carcinoembryonic antigen, GCDFP-15 gross cystic disease fluid protein 15, SMA smooth muscle
actin, NA not available
Sebaceous Carcinoma of the Breast
Sentinel Node 355
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variants of lipid-secreting carcinoma of the breast.
Acosta, A. M., Al Rasheed, M. R. H., Xu, H., Salibay, C., Virchows Archiv. A, Pathological Anatomy and Histol-
& Pins, M. R. (2018). Sebaceous carcinoma of the ogy, 375, 345–353.
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(886delGT) mutation – focus on histopathologic and R. (2000). Sebaceous carcinoma of the breast. Pathol-
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C., Righini, M. G., & Trevisan, G. (2011). A case of Beckmann, M. W., & Hartmann, A. (2014). Sebaceous
giant sebaceous carcinoma localized in the breast area breast carcinoma: report of a rare histological special
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Gambarotti, M., Giardina, C., & Bisceglia, M. (2012). noma of the breast: a case report. Surgical Case
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Lymph nodes are not identical, and those, which
carcinoma of the breast: Histological, cytological, and are directly connected to the primary tumor site
ultrastructural features. The Breast Journal, 24, by means of their afferent lymphatic vessels, are
656–657. the ones called sentinel nodes. The remaining
Švajdler, M., Baník, P., Poliaková, K., Straka, L.,
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356 Sentinel Node
regional lymph nodes as emboli via lymphatics pN1(sn), or pN2(sn) TNM categories denote path-
reach the sentinel node(s) (first echelon nodes) ological nodal stage categories established with
first and nonsentinel nodes (second or further sentinel node biopsy.
echelon nodes) only after. This explains why the Nodal staging of clinically node-negative
sentinel nodes are the most likely site of nodal (cN0) early breast cancer patients with sentinel
metastasis, and also suggests that if they are not node biopsy followed a stepwise evolution
involved by metastatic disease, the rest of the reflected in the surgical consequences of finding
lymph nodes can also be considered free of metas- metastases in sentinel nodes. The concept of sen-
tases. Therefore the sentinel nodes “guard” the tinel nodes was validated in different clinical tri-
regional nodal basin, what explains their name. als, where lymphatic mapping was followed by
The kinetics of tumor cell migration from complete axillary lymph node dissection. These
the primary site to the sentinel nodes also apply studies proved that the sentinel nodes are really
to tracer molecules which travel via lymphatics, more likely to harbor metastasis than nonsentinel
and first accumulate in the sentinel lymph nodes. nodes. As sentinel nodes were often more thor-
Vital dyes (such as patent blue, isosulfan blue, or oughly analyzed than the remaining of the lymph
isocyanine green), 99-meta-technecium labeled nodes, a few validation studies have also sub-
sulfur or albumin colloids, or super paramagnetic jected nonsentinel nodes to the same scrutiny as
iron oxide nanoparticles all use the same path, the sentinel nodes, and these studies also rein-
i.e. the lymphatic vessels to reach and selectively forced the theory that sentinel nodes are more
label the sentinel nodes. Depending on the tracers often involved by metastases (Turner et al. 1997;
used, the sentinel nodes can be selectively Weaver et al. 2000). Following these initial vali-
removed after being detected by their color, dation studies and early learning periods (all com-
(probe-detected) radioactivity or magnetism. pleted with axillary nodal dissection), the scenario
Identification of the sentinel nodes with such of performing axillary lymph node dissection (as
tracers is called lymphatic mapping, and their a surgical treatment of the axilla) only in patients
removal sentinel (lymph) node biopsy or sentinel with positive (i.e., metastatic) sentinel lymph
lymphadenectomy. nodes became the rule. Patients with negative
Lymphatic mapping studies have revealed sentinel nodes are spared from axillary clearance
that most sentinel nodes are located in the lower and its potential morbidity (lymphedema, motor
axilla, but some can be located at higher levels of dysfunction, sensory loss), although it must be
the axilla or at extra-axillary sites like the sub- admitted that sentinel node biopsy can also have
clavicular or supraclavicular regions, the breast complications, but less frequently and to a lesser
itself (intramammary sentinel nodes), or along degree. This new era of axillary nodal staging has
the internal mammary artery (internal mammary also initiated a novel approach to teaching sentinel
or parasternal sentinel nodes). The theoretical def- node biopsy: supervision by surgeons already
inition of the sentinel node given at the beginning trained in the procedure has become general
of the present description can be complemented and no complete axillary dissection was mandated
with a second practical one: the sentinel nodes are any more to prove proficiency in removing the
the ones that are identified as such during lym- proper lymph nodes. As the decision to clear the
phatic mapping. Their number is highly variable, axilla or not was dependent on the status of the
but is generally 1–3. If the number of sentinel sentinel nodes, intraoperative assessment has
nodes is consistently higher than this, one must gained emphasis similarly to preoperative staging
doubt about the adequacy of lymphatic mapping; by axillary ultrasound. Patients with negative axil-
the American Joint Committee on Cancer has lary palpation and axillary ultrasound findings
adopted a rule of allowing the (sn) classifier in (cN0 patients) are offered lymphatic mapping
the Tumor Node Metastasis (TNM) classification and sentinel node biopsy, whereas those with sus-
only for breast cancers where the number of picious findings have ultrasound-guided sampling
sentinel nodes does not exceed 6. The pN0(sn), (mostly fine needle aspiration, but sometimes core
Sentinel Node 357
needle biopsy) of the suspicious nodes or the most comparable with that of sentinel
suspicious one. The microscopic evidence of lymphadenectomy of cN0 patient not requiring
nodal involvement excludes patients from lym- neoadjuvant treatment (Geng et al. 2016). It is
phatic mapping, as the procedure is advocated therefore common to perform sentinel node
for cN0 patients. Later, a few studies explored biopsy after the completion of primary systemic
the idea that once nodal positivity was proven treatment, but the procedure has also been
by means of sentinel node biopsy, there was no performed before. For patients with initially
more need for axillary lymph node dissection in node-positive disease, the false-negative rates
the majority of patients. The American College have been found to be somewhat higher, but
of Surgeons Oncology Group (ACOSOG) trial with at least two sentinel nodes identified, and
Z-0011 concluded that patients with limited nodal adequate patient selection, post-neoadjuvant ther-
involvement (up to two metastatic lymph nodes apy sentinel node biopsy has also been found
independently of the size of the metastasis) under- reliable enough (El Hage Chehade et al. 2016;
going breast conserving surgery complemented van Nijnatten et al. 2015).
with whole breast irradiation needed no axillary Most surgeons remove only axillary sentinel
nodal dissection (Giuliano et al. 2017). The 6-year nodes and do not search for extra-axillary ones.
results of the European Organization for Research The latter, to be known about, require lympho-
and Treatment of Cancer (EORTC) After Map- scintigraphy, which visualizes them. Even if they
ping of the Axilla: Radiotherapy Or Surgery? are evidenced by lymphoscintigraphy, internal
(AMAROS) trial (Donker et al. 2014) and the mammary sentinel nodes are rarely removed by
8-year results of the Hungarian National Institute surgeons, despite the fact that reports indicate that
of Oncology Optimal Treatment of the Axilla: metastatic involvement of a parasternal sentinel
Surgery Or Radiotherapy (OTOASOR) trial node may impact on the planning of radiotherapy
(Sávolt et al. 2017) both concluded that axillary and the indication of systemic therapy. As a rule,
irradiation was as effective as axillary lymph node internal mammary sentinel nodes are smaller than
dissection in preventing regional recurrences in axillary ones, often less than 5 mm in size, and
patients with metastatic sentinel nodes. These commonly they are identified by gamma-probes
results have also led to a change in policy: at only on the basis of their radioactivity, and do not
present many patients with positive sentinel label with dyes.
nodes do not have an axillary lymph node dissec- Pathological assessment of sentinel nodes
tion (Lyman et al. 2016). This change had obvi- can be divided into two broad categories: the
ously resulted in a decrease in intraoperative intraoperative and the postoperative setting. As
examinations of the sentinel nodes, as the result concerns the intraoperative assessment, imprint
had no impact on subsequent surgery. (or scrape) cytology, frozen section histology,
Another setting of applying sentinel node and molecular analysis of sentinel nodes have all S
biopsy as a staging procedure with lower morbidity been in use to assess metastatic involvement of the
is its use after primary systemic (neoadjuvant) sentinel nodes. Imprint cytology is based on the
treatment of locally advanced breast cancer. Neo- exfoliation of tumor cells from the lymph node
adjuvant therapy is used for both clinically node- freshly cut surface to the glass slides. This spon-
negative and node-positive patients. In the second taneous detachment can be enhanced by scraping
set, it is widely accepted that sentinel node biopsy the cut surface and smearing the cells on the
should be offered only to patients who become slides. Different stains have been described and
clinically node-negative after systemic treatment used (Figs. 1 and 2).
(ycN0). The false-negative rate (the proportion The advantages of intraoperative cytology
of cases without sentinel node involvement but specimens include fast preparation, relatively
with metastasis in nonsentinel nodes) of sentinel low costs, lack of tissue loss during the procedure,
lymphadenectomy after neoadjuvant treatment of and a microscopic verification of malignant cell
initially cN0 patients has been found to be morphology. Its disadvantages include the
358 Sentinel Node
size, and many pathologists are more familiar with

the method. However, frozen section morphology
is still suboptimal when compared to the gold
standard of formalin-fixed and paraffin-embedded
tissue histology. The tissues undergo artifacts,
which may prevent ideal interpretation of the
cells and structures seen. Some tissue is lost dur-
ing assessment. It also takes longer time to prepare
the sections. The costs are higher than those
of imprints. Frozen sections are also not perfect,
false negative cases do occur. The use of fast
immunohistochemistry and/or the investigation
of step sections improve the accuracy of the eval-
Sentinel Node, Fig. 1 Metastatic cells on imprint cytol- uation. Some centers have used the painstaking
ogy (H&E, original magnification 400)
approach to investigate the whole sentinel nodes
by frozen step sections to allow the most precise
intraoperative microscopic sampling, but most
have found the costs and workload of this
approach prohibitive. Meta-analyses have assessed
the accuracy of imprint cytology and frozen sec-
tion evaluation, and it is suggested that the latter
has a pooled sensitivity about 10% higher than the
former for detecting macrometastases (those
greater than 2 mm) intraoperatively. The choice
of which morphologic intraoperative method to
use depends on many factors, including personal
preference and experience of the pathologist in
charge (Cserni et al. 2003).
Molecular intraoperative examinations sub-
Sentinel Node, Fig. 2 Metastatic cells on imprint cytol- stantially differ from imprint cytology and frozen
ogy (Giemsa, original magnification 400) section analysis, as they do not use microscopy
for detection. In contrast, they destroy the tissue
inability to measure the size of the metastasis, a structures and cells to allow the extraction of
higher false negative rate (metastases detected messenger ribonucleic acid (mRNA) of proteins
only after the histological examination of the sen- thought to represent metastatic tumor cells pro-
tinel node), a few false positive reports, and the portionally to their amount. Different amplifica-
need for training in cytopathology. The false neg- tion systems have been used, most often one step
ative rate can be diminished by increasing the nucleic acid amplification (OSNA) of cytokeratin
surface sampled (i.e., several cut surfaces). Fast 19 mRNA or reverse transcription polymerase
immunohistochemistry for the detection of epithe- chain reaction (RT-PCR) of cytokeratin 19 and
lial cells can also be combined with intraoperative mammaglobin mRNAs. These methods are more
cytology; this increases the accuracy, the time sensitive than classical microscopic examinations,
required for reporting, and the costs of the but obviously are rather epithelium than metasta-
examination. sis specific. Validation studies have been biased
Frozen sections have also often been used for by the fact that microscopic evaluation and molec-
the intraoperative examination of sentinel lymph ular analyses cannot be performed on the same
nodes. They allow a better morphological evalua- tissue parts, therefore different parts of the same
tion of metastases including the measurement of sentinel lymph nodes were investigated by the
Sentinel Node 359
different methods. It is accepted that different detecting these metastases (Giuliano et al. 1995;
parts of the sentinel nodes have different risks of Cserni et al. 2003). As a consequence, the average
being involved by the metastatic process, i.e., the size of nodal tumor deposits became also smaller.
areas at the junction of the tumor draining afferent Micrometastases (earlier defined by an upper
lymphatic vessels are involved at a much higher inclusive size limit of 2 mm) were identified at
frequency than areas away from this point. This is much higher rates than before the era of lymphatic
why, the best comparisons were made when alter- mapping. This led to a phenomenon called stage
nating slices of the lymph nodes were subjected to migration: the same patients who were classified
molecular and microscopic examinations. The as having node-negative disease after a conven-
comparison of larger series suggests that molecu- tional nodal examination following axillary
lar methods are substantially more sensitive in lymph node dissection could be identified as
detecting micrometastatic involvement of the sen- being node-positive by detecting tiny foci of met-
tinel nodes than either frozen sections or imprint astatic disease in the better investigated sentinel
cytology, but when it comes to macrometastases, nodes that the conventional evaluation had no
frozen sections are nearly as sensitive as molecu- chance to visualize. To limit stage migration, stag-
lar methods (Cserni 2012). To allow a nearly ing authorities have introduced a lower non-
complete assessment, many laboratories using a inclusive limit of 0.2 mm (and later an additional
molecular intraoperative assay use most if not all cell count limit of 200 for discohesive lobular
nodal tissue to adequately sample the sentinel carcinoma cells) to the definition of micro-
nodes, and this leaves no tissue for a morpholog- metastasis and have considered anything smaller
ical evaluation. A common recommendation pro- than that as isolated tumors cells or clusters (ITC)
poses to use at least one slice of tissue (generally to be staged as part of the node-negative set of
the central one) for histology and use only the patients (Figs. 3 and 4).
remaining parts of the sentinel node for the molec- At the beginning, the definitions of isolated
ular assay. Recommendations are in agreement tumor cells were not straight forward and uniform,
that intraoperative assessment of any type should and this has limited the proper prognostic evalua-
be restricted to cases where it has immediate tion of this subcategory, and its discrimination
influence on the intervention to follow (Wells from micrometastasis. At present, it seems that
et al. 2012). neither isolated tumor cells or clusters nor micro-
The traditional evaluation of sentinel nodes, metastases have major impact on breast cancer
which has been used as a gold standard for com-
parison with intraoperative examinations, is his-
topathological assessment. As the most likely
sites of nodal involvement, sentinel nodes have
been given more scrutiny: gross slicing, serial S
sectioning at equidistant steps (including step sec-
tioning till the extinction of the tissue blocks), and
immunohistochemistry have been used, often in
combination. This approach led to detection of
metastatic nodal involvement at a higher rate
than the previous conventional approach of
assessing one hematoxylin and eosin stained
slide of each lymph node or of each slice of larger
lymph nodes divided into pieces. Increased detec-
tion was partly due to the fact that sentinel nodes
Sentinel Node, Fig. 3 Isolated tumor cells of lobular
really harbor metastases more often than other
carcinoma detected by cytokeratin immunohistochemistry
lymph nodes of the same nodal basin, but also (Cytokeratin AE1/AE3 immunohistochemistry, original
due to the use of more sensitive techniques of magnification 400)
360 Sentinel Node
patients and therefore should not initiate any epithelial can lead to erroneous interpretation in
therapeutic intervention on their own. This clari- any intraoperative test.
fication of the prognostic impact of low-volume Endosalpingiosis of axillary sentinel nodes has
tumor deposits in sentinel nodes discovered by also been reported. Epithelial cells or structures
enhanced pathological evaluation has resulted like glands may be lodged artifactually during
in recommendations proposing not to search for tissue processing into holes without tissue
micrometastases and smaller volume involvement, (cracks) on the sections (Fig. 7).
but to devise assessment protocols that identify Similarly, epithelial displacement by needling
virtually all macrometastases (Cserni 2012). procedures (e.g., core needle biopsy, wire locali-
It must be kept in mind that sentinel nodes zation of the primary tumor, or intratumoral injec-
(as any other lymph nodes) may harbor a number tion of the tracer) or massage used to help tracer
of other changes or diseases than metastasis from migration during lymphatic mapping can lead to
breast cancer. This has often been an argument the misdiagnosis of displaced epithelium as a real
against the use of all nodal tissue for molecular metastasis. Papillary lesions have been reported to
analysis. Capsular nevi are a relatively common be especially prone for misplacement: most
finding, and generally do not pose a major differ-
ential diagnostic problem. Often they do not show
melanin content (Fig. 5).
On occasions they may involve the trabeculae
and even the nodal parenchyma when the differ-
ential diagnostic concern may be greater. Being
completely different in nature, they can easily
be clarified by their positivity for melanocytic
markers of nevi and their negativity for epithelial
markers. Involvement by other neoplastic (com-
monly chronic lymphoid leukemia, less commonly
other lymphomas or metastatic melanoma, etc.)
or infectious diseases (e.g., cat scratch disease
or toxoplasmosis) can also be encountered. Epi-
thelial inclusions (often of mammary type) Sentinel Node, Fig. 5 Capsular nevus without
(Fig. 6) are not very common, but by being melanin content. (H&E, original magnification 400)
Sentinel Node, Fig. 6 Apocrine glandular inclusion

Sentinel Node, Fig. 4 Isolated tumor cell cluster in an axillary sentinel lymph node. Note the outer
detected by conventional staining (H&E, original myoepithelial and inner epithelial cell layers (H&E, origi-
magnification 400) nal magnification 400)
Sentinel Node 361
nodes in breast cancer. Review of current data to be

considered for the formulation of guidelines. European
Journal of Cancer, 39, 1654–1667.
Donker, M., van Tienhoven, G., Straver, M. E., Meijnen, P.,
van de Velde, C. J., Mansel, R. E., Cataliotti, L.,
Westenberg, A. H., Klinkenbijl, J. H., Orzalesi, L.,
Bouma, W. H., van der Mijle, H. C., Nieuwenhuijzen,
G. A., Veltkamp, S. C., Slaets, L., Duez, N. J., de Graaf,
P. W., van Dalen, T., Marinelli, A., Rijna, H., Snoj, M.,
Bundred, N. J., Merkus, J. W., Belkacemi, Y., Petignat,
P., Schinagl, D. A., Coens, C., Messina, C. G.,
Bogaerts, J., & Rutgers, E. J. (2014). Radiotherapy
or surgery of the axilla after a positive sentinel node in
breast cancer (EORTC 10981-22023 AMAROS):
A randomised, multicentre, open-label, phase
3 non-inferiority trial. The Lancet Oncology, 15,
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(orientation marker of the tissue block) in a tissue crack El Hage Chehade, H., Headon, H., El Tokhy, O.,
of the sentinel node (H&E, original magnification 100) Heeney, J., Kasem, A., & Mokbel, K. (2016). Is senti-
nel lymph node biopsy a viable alternative to complete
axillary dissection following neoadjuvant chemother-
misplaced epithelial tissue reported to date was apy in women with node-positive breast cancer at diag-
related to papillary lesions. These may differ from nosis? An updated meta-analysis involving 3,398
patients. American Journal of Surgery, 212, 969–981.
metastatic cells or fragments by location (in the Geng, C., Chen, X., Pan, X., & Li, J. (2016). The feasibility
sinuses rather than the parenchyma of the sentinel and accuracy of sentinel lymph node biopsy in initially
node), morphology, and/or immunophenotype; clinically node-negative breast cancer after neo-
and not uncommonly the primary site has also adjuvant chemotherapy: A systematic review and
meta-analysis. PLoS One, 11, e0162605.
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fronds in lymphatics in an area of traumatized (1995). Improved axillary staging of breast cancer
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metastasis, misdiagnosing them as metastatic in Hansen, N. M., Whitworth, P. W., Blumencranz, P. W.,
nature should imply no erroneous indication of Leitch, A. M., Saha, S., Hunt, K. K., & Morrow, M.
surgical or systemic treatment or radiotherapy. (2017). Effect of axillary dissection vs no axillary dis-
section on 10-year overall survival among women with
Trials have been organized for identifying sub- invasive breast cancer and sentinel node metastasis:
sets of breast cancer patients who might not The ACOSOG Z0011 (Alliance) randomized clinical
require sentinel node biopsy either. trial. JAMA, 318, 918–926.
Lyman, G. H., Somerfield, M. R., Bosserman, L. D.,
Perkins, C. L., Weaver, D. L., & Giuliano, A. E. S
(2016). Sentinel lymph node biopsy for patients with
References early-stage breast cancer: American Society of Clinical
Oncology clinical practice guideline update. Journal of
Cserni, G. (2012). How much is enough? Pathologic eval- Clinical Oncology, 35, 561–564.
uation of sentinel lymph nodes. Current Breast Cancer Sávolt, Á., Péley, G., Polgár, C., Udvarhelyi, N.,
Reports, 4, 89–95. Rubovszky, G., Kovács, E., Győrffy, B., Kásler, M.,
Cserni, G., Amendoeira, I., Apostolikas, N., Bellocq, J. P., & Mátrai, Z. (2017). Eight-year follow up result of the
Bianchi, S., Bussolati, G., Boecker, W., Borisch, B., OTOASOR trial: The optimal treatment of the axilla –
Connolly, C. E., Decker, T., Dervan, P., Surgery or radiotherapy after positive sentinel lymph
Drijkoningen, M., Ellis, I. O., Elston, C. W., node biopsy in early-stage breast cancer: A random-
Eusebi, V., Faverly, D., Heikkila, P., Holland, R., Kerner, ized, single centre, phase III, non-inferiority trial.
H., Kulka, J., Jacquemier, J., Lacerda, M., Martinez- European Journal of Surgical Oncology, 43, 672–679.
Penuela, J., De Miguel, C., Peterse, J. L., Rank, F., Turner, R. R., Ollila, D. W., Krasne, D. L., &
Regitnig, P., Reiner, A., Sapino, A., Sigal-Zafrani, B., Giuliano, A. E. (1997). Histopathologic validation of
Tanous, A. M., Thorstenson, S., Zozaya, E., & Wells, the sentinel lymph node hypothesis for breast carci-
C. A. (2003). Pathological work-up of sentinel lymph noma. Annals of Surgery, 226, 271–276.
362 Solid Papillary Carcinoma
van Nijnatten, T. J., Schipper, R. J., Lobbes, M. B., solid nodules of neoplastic cells arranged around
Nelemans, P. J., Beets-Tan, R. G., & Smidt, M. L. multiple fibrovascular spaces. Despite the lack of
(2015). The diagnostic performance of sentinel lymph
node biopsy in pathologically confirmed node positive the external myoepithelial layer, these lesions are
breast cancer patients after neoadjuvant systemic ther- currently considered as noninvasive (Lakhani et al.
apy: A systematic review and meta-analysis. European 2012). However, cases of true invasive SPC exist.
Journal of Surgical Oncology, 41, 1278–1287.
Weaver, D. L., Krag, D. N., Ashikaga, T., Harlow, S. P., &
O’Connell, M. (2000). Pathologic analysis of sentinel
and nonsentinel lymph nodes in breast carcinoma: a Clinical Features
multicenter study. Cancer, 88, 1099–1107.
Wells, C. A., Amendoeira, I., Bellocq, J. P., Bianchi, S., • Incidence
Boecker, W., Borisch, B., Bruun Rasmussen, B., Callagy,
G. M., Chmielik, E., Cordoba, A., Cserni, G., Decker, T., SPC is a rare entity, accounting for 1–2% of
DeGaetano, J., Drijkoningen, M., Ellis, I. O., Faverly, breast carcinomas (BCs) (Otsuki et al. 2007).
D. R., Foschini, M. P., Frković-Grazio, S., Grabau, D., • Age
Heikkilä, P., Iacovou, E., Jacquemier, J., Kaya, H., Kulka, It usually affects women in the seventh decade,
J., Lacerda, M., Liepniece-Karele, I., Martinez-Penuela,-
J., Quinn, C. M., Rank, F., Regitnig, P., Reiner-Concin, with a mean age of 73.2 years (Maluf and
A., Sapino, A., Tot, T., Van Diest, P. J., Varga, Z., Koerner 1995).
Wesseling, J., Zolota, V., & Zozaya-Alvarez, E. (2012). • Sex
S2: Pathology update. Quality assurance guidelines for It is more frequently observed in female
pathology. In N. Perry, M. Broeders, C. de Wolf,
S. Törnberg, R. Holland, & L. von Karsa (Eds.), patients, but it has been sporadically described
European guidelines for quality assurance in breast can- in men (Nassar et al. 2006).
cer screening and diagnosis. Fourth edition, supplements • Side
(pp. 73–120). Luxembourg: European Commission, SPC is typically unifocal and localized in the
Office for Official Publications of the European Union.
central region of the breast (Guo et al. 2016),
although a single case of bilateral synchronous
SPC has been reported in the literature
(Yoshimura et al. 2013).
Solid Papillary Carcinoma • Clinical presentation
The clinical presentation does not differ from
Elena Vissio2, Caterina Marchiò1,2,3 and Anna the other BC histological types, being usually
Sapino1,2 diagnosed after the detection of a mammo-
1
Unit of Pathology, Candiolo Cancer Institute graphic density or a palpable mass. In
FPO-IRCCS, Candiolo, Italy 20–25% of cases, a bloody nipple discharge
2
Department of Medical Sciences, University of may occur (Lakhani et al. 2012).
Turin, Turin, Italy • Treatment
3
Institut Curie, Paris, France Mastectomy or conservative surgery represents
the usual treatment for these tumors. However,
since the risk of recurrence is not related to the
Synonyms surgical technique, mastectomy, as well as
lymph node excision, seems to represent an
Solid Papillary Neuroendocrine Breast Carcinoma overtreatment for small tumors with no signs
of invasion (Guo et al. 2016). There is no
agreement on the necessity of sentinel lymph
Definition node biopsy for these patients. Regarding adju-
vant treatment, the benefit of radiation and
Solid papillary carcinoma (SPC) is described in the hormone therapy is still debated.
2012 WHO classification within the group of the • Outcome
intraductal papillary lesions and is defined as a var- SPCs present an excellent prognosis. Lymph
iant of papillary carcinoma characterized by multiple node and distant metastasis are rare. Local
Solid Papillary Carcinoma 363
Solid Papillary Carcinoma, Fig. 1 (a) Solid (b) calponin immunohistochemical reaction shows focal
papillary carcinoma is characterized by a dense neoplastic lack of myoepithelial peripheral cell layer
proliferation featuring well-defined borders (H&E);
recurrences have been reported, even if appear well defined, the myoepithelial peripheral
uncommon, and death for SPC should be con- layer is frequently absent at immunohistochemi-
sidered exceptional (Guo et al. 2016). cal analyses (Fig. 1a, b). To date, it is still debated
Recently, the 21-gene recurrence score if SPC should be considered as a low-grade inva-
(RS) multigene assay was performed in sive carcinoma or a variant of ductal carcinoma in
5 cases of SPC, and the RS resulted low in situ (▶ Ductal Carcinoma In Situ). Nonetheless,
3 cases and intermediate in the remaining because of their generally favorable clinical
2 cases, confirming the good prognosis of this course, the current WHO classification recom-
histological type. The only woman who pre- mends to consider SPCs as in situ lesions
sented a local recurrence showed a RS of (Lakhani et al. 2012). By contrast, irregular mar-
25 (Turashvili et al. 2017). gins and multiple small nests arranged in a jigsaw
When SPCs are associated to an invasive car- pattern represent typical features that suggest
cinoma, the outcome is related to the features invasive growth (Lakhani et al. 2012).
of the infiltrative component (Lakhani et al. Inside the nodules, neoplastic cells are densely
2012; Tan et al. 2016). organized. They may form typical peripheral
palisading around delicate fibrovascular struc-
tures (Fig. 2a). Cells usually present small dimen-
Macroscopy sions, hyperchromatic nuclei, granular S
cytoplasmic pattern, and occasionally spindle
cell features (Lakhani et al. 2012). They are gen-
At macroscopic examination, SPC usually
erally low- or intermediate-grade lesions, with
appears as a well-circumscribed lobulated mass,
low mitotic activity (Guo et al. 2016). SPC may
characterized by a whitish-gray or yellowish-
produce extracellular and/or intracellular mucin
brown color (Lakhani et al. 2012). The size may
(Wei 2016), and neuroendocrine differentiation
be variable, with a reported average diameter of
is reported in about half of cases (Fig. 2b)
2.5 cm (Guo et al. 2016).
(Otsuki et al. 2007).
SPCs may present foci of invasive carcinoma,
Microscopy frequently characterized by neuroendocrine or
mucinous features (Nassar et al. 2006; Otsuki
At low magnification, SPC is characterized by et al. 2007), even if other histotypes have
multiple cellular nodules. Although its borders been described. Invasive mucinous carcinomas
364 Solid Papillary Carcinoma
Solid Papillary Carcinoma, Fig. 2 (a) Densely (b) SPCs may show neuroendocrine differentiation
organized neoplastic cells form a peripheral palisading (immunohistochemical reaction with anti-synaptophysin
layer around delicate fibrovascular structures (H&E). antibody)
associated with SPCs are usually classified as weight CKs, such as CK8 and CK18, are fre-
type B, characterized by high cellularity, lower quently positive (Lakhani et al. 2012).
mucin production, and neuroendocrine differenti- Synaptophysin (Fig. 2b) and/or chromogranin,
ation (Nassar et al. 2006) (▶ Invasive Mucinous considered typical neuroendocrine markers, is
Carcinoma). expressed in more than 50% of cases (Guo et al.
Mixed cases, where SPC and encapsulated 2016; Lakhani et al. 2012; Otsuki et al. 2007).
papillary carcinoma (EPC) (▶ Encapsulated Pap-
illary Carcinoma) coexist, have been reported,
hypothesizing a common carcinogenetic process Molecular Features
for the two tumors (Cui and Wei 2015; Duprez
et al. 2012). Copy number aberration patterns are similar
between papillary carcinomas (PCs) and ER+
invasive carcinomas of no special type of
Immunophenotype similar grade (Duprez et al. 2012). However,
gene expression analysis showed a down-
Similarly to other papillary tumors, SPC is com- regulation of genes related to cell migration, pro-
monly classified as Luminal A type, showing an liferation, assembly, and organization in PCs,
intensely positive expression of estrogen receptor whereas genes involved in cellular homeostasis
(ER) and progesterone receptor (PR), lack of and angiogenesis were upregulated (Piscuoglio
HER2 protein overexpression, and a low prolifer- et al. 2014).
ation activity (Guo et al. 2016; Otsuki et al. 2007), Among the main types of PCs (SPC, EPC, and
and a similar immunohistochemical pattern is fre- invasive papillary carcinoma), no differences in
quently reported also for the possibly associated copy number aberrations were noted (Piscuoglio
invasive component (Nassar et al. 2006). et al. 2014). On the other hand, SPC, when com-
Nonetheless, the PAM50 gene signature pared with EPC, presents a higher expression of
applied on four cases of SPCs assigned them to neuroendocrine-related genes (e.g., RET, ASCL1,
the Luminal B subtype (Piscuoglio et al. 2014). and DOK7), whereas EPC shows down-
Myoepithelial markers, like p63 and high regulation of genes involved in cell migration,
molecular weight cytokeratins (CK), may show possibly explaining the histological differences
positive or negative result by immunohistochem- between these two entities (Piscuoglio
ical staining (Ni and Tse 2016). Low molecular et al. 2014).
Syringomatous Tumor of the Nipple 365
Differential Diagnosis Otsuki, Y., Yamada, M., Shimizu, S., Suwa, K.,
Yoshida, M., Tanioka, F., Ogawa, H., et al. (2007).
Solid-papillary carcinoma of the breast: Clinicopatho-
Intraductal papilloma (▶ Intraductal Papilloma) logical study of 20 cases. Pathology International, 57,
and florid usual ductal hyperplasia (▶ Usual Duc- 421–429.
tal Hyperplasia (UDH)) may present similar fea- Piscuoglio, S., Ng, C. K. Y., Martelotto, L. G., Eberle,
tures with SPC, but they usually present no C. A., Cowell, C. F., Natrajan, R., Bidard, F. C., et al.
(2014). Integrative genomic and transcriptomic charac-
mitoses and do not show neuroendocrine or terization of papillary carcinomas of the breast. Molec-
mucinous differentiation. Furthermore, in benign ular Oncology, 8, 1588–1602.
lesions, CK5/6 is usually intensely positive; there- Rabban, J. T., Koerner, F. C., & Lerwill, M. F. (2006). Solid
fore, its evaluation may be helpful in challenging papillary ductal carcinoma in situ versus usual ductal
hyperplasia in the breast: A potentially difficult distinc-
cases (Lakhani et al. 2012; Rabban et al. 2006). tion resolved by cytokeratin 5/6. Human Pathology,
In case ER and/or PR expression are unusually 37, 787–793.
weak or absent, metastatic neuroendocrine tumors Tan, B. Y., Thike, A. A., Ellis, I. O., & Tan, P. H. (2016).
to the breast should be taken into account, and the Clinicopathologic characteristics of solid papillary car-
cinoma of the breast. American Journal of Surgical
clinical history of the patient should be accurately Pathology, 40, 1334–1342.
reviewed in order to identify the primary malig- Turashvili, G., Brogi, E., Morrow, M., Hudis, C.,
nancy (Burt et al. 2016). Dickler, M., Norton, L., & Wen, H. Y. (2017). The
21-gene recurrence score in special histologic subtypes
of breast cancer with favorable prognosis. Breast
Cancer Research and Treatment, 165, 65–76.
References and Further Reading Wei, S. (2016). Papillary lesions of the breast: An
update. Archives of Pathology & Laboratory Medicine,
Burt, M., Madan, R., & Fan, F. (2016). Metastatic 140, 628–643.
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M. B., MacKay, A., A’Hern, R., Gauthier, A., et al.
(2012). Immunophenotypic and genomic characteriza-
tion of papillary carcinomas of the breast. The Journal Syringomatous Tumor of the
of Pathology, 226, 427–441.
Guo, S., Wang, Y., Rohr, J., Fan, C., Li, Q., Li, X., &
Nipple
Wang, Z. (2016). Solid papillary carcinoma of the
breast: A special entity needs to be distinguished from Zsuzsanna Varga and Linda Moskovszky
conventional invasive carcinoma avoiding over- Institute of Pathology and Molecular Pathology,
treatment. The Breast, 26, 67–72.
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Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H.,
van de Vijver, M. J. (2012). WHO classification S
of tumours of the breast. World Health Organization
classification of tumours. Lyon, IARC press. ISBN-10: Synonyms
9283224337.
Maluf, H. M., & Koerner, F. C. (1995). Solid papillary
carcinoma of the breast. A form of intraductal carci- Infiltrating syringomatous adenoma of the nipple;
noma with endocrine differentiation frequently associ- Syringomatous adenoma of the nipple
ated with mucinous carcinoma. The American Journal
of Surgical Pathology, 19, 1237–1244.
Nassar, H., Qureshi, H., Adsay, N. V., Volkanadsay, N., &
Visscher, D. (2006). Clinicopathologic analysis of solid Definition
papillary carcinoma of the breast and associated inva-
sive carcinomas. The American Journal of Surgical Syringomatous tumor of the nipple/areola region
Pathology, 30, 501–507.
(SAN) is a benign rare condition, which is typi-
Ni, Y. B., & Tse, G. M. (2016). Pathological criteria and
practical issues in papillary lesions of the breast – cally observed in the dermal/subcutaneous region
A review. Histopathology, 68, 22–32. of the nipple area and which exhibits sweat gland
366 Syringomatous Tumor of the Nipple
differentiation (Ishikawa et al. 2015; Montgomery (Ishikawa et al. 2015; Montgomery et al. 2014;
et al. 2014; Boecker et al. 2014). These tumors Oo and Xiao 2009; Page et al. 2009).
have no metastastic potential but can recur if • Treatment
removed incompletely (Ishikawa et al. 2015; Therapy is surgical excision with clear mar-
Montgomery et al. 2014; Boecker et al. 2014). gins. If the tumor is close to the nipple and a
complete excision is therefore not possible, in
such cases, a thorough postoperative follow-up
Clinical Features with imaging is recommended (Ishikawa et al.
2015; Oo and Xiao 2009).
• Incidence • Outcome
This type of nipple tumor is very rare, account- Prognosis is favorable in all cases; until now, no
ing less than 1% of all tumors arising in the metastastic lesions and no death due to tumor
breast. Until now, 39 cases were reported in the progression were reported. However, local
English literature, mostly in form of case tumor recurrence in a small subset of patients
reports. Thirty seven patients were female, in the literature was reported mainly due to
and two were males (Ishikawa et al. 2015; incomplete resection (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009; Montgomery et al. 2014; Boecker et al. 2014;
Page et al. 2009; Jones et al. 1989; Carter and Oo and Xiao 2009; Page et al. 2009; Jones et al.
Dyess 2004; Rosen 1983). The original 1989; Carter and Dyess 2004).
description of nipple syringomatous adenoma
was published by PP Rosen in 1983. Since this
Macroscopy
description, this entity has been occasionally
addressed in reviews on diagnostic challenges
Syringomatous tumor usually presents as a solid
and immunohistochemical phenotypes as well
mass or ill-defined tumor in the dermis of the
as reported in the above mentioned case report
nipple. Rarely the lesion is detected due to
series in different journals (Ishikawa et al.
mammographic calcifications in the surrounding
2015; Montgomery et al. 2014; Boecker et al.
breast. Size of the lesion is variable, generally
2014; Oo and Xiao 2009; Page et al. 2009;
between 5 mm and 50 mm in diameter, with an
Jones et al. 1989; Carter and Dyess 2004).
average size of 17.7 mm in largest diameter
• Age
(Ishikawa et al. 2015; Montgomery et al. 2014;
Patients are mostly peri-/postmenopausal at the
Oo and Xiao 2009).
time of the diagnosis; however, one case was
described in a young prepubertal 11-year-old
girl occurring in a supernumerary nipple, and
one elderly patient of 87 years was reported Microscopy
with this entity (Oo and Xiao 2009; Page
et al. 2009). Syringomatous tumor of the nipple has an appar-
• Sex ent infiltrative growth in most cases arising in
Thirty-seven patients were female, and two a recognizable lobular growth pattern with nests
patients were males (Ishikawa et al. 2015; and branching cords of inconspicuous epithelial
Montgomery et al. 2014; Oo and Xiao 2009). cells situated in the dermis and in the subcutis of
• Site the nipple or areola (Ishikawa et al. 2015) (Fig. 1).
Both sides are equally affected and most The tumor cells typically show an infiltrative
lesions are unifocal. Two papers reported growth between the stroma and the smooth mus-
a syringomatous tumor arising in a supernu- cle cells of the dermis and subcutis (Fig. 2)
merary breast, each in one patient; two further (Ishikawa et al. 2015; Montgomery et al. 2014).
papers, each of them described one female Typically, there is no relationship between the
patient with bilateral syringomatous adenoma tumor and the overlying skin or the nipple
Syringomatous Tumor of the Nipple, Fig. 1 Low Syringomatous Tumor of the Nipple, Fig. 3 High
power appearance of a syringomatous tumor containing power appearance of a syringomatous tumor showing infil-
infiltrative bland solid epithelial formations in the dermis trative bland small epithelial formations surrounded by
of the skin in the vicinity of thin epithelial cysts (H&E, low smooth muscles and vessels of the dermal-subcutaneous
magnification) junction without any significant stromal desmoplasia
(H&E, high magnification)
2014). The epithelial structures are tubular and

solid, which are compressed or exhibit irregular
contours and show characteristic teardrop- or
comma-shaped formations. Usually there is
a deep infiltration into the severely fibrous under-
lying stroma (Ishikawa et al. 2015; Montgomery
et al. 2014; Oo and Xiao 2009; Rosen 1983).
Tumor cell nuclei are bland and lack any signifi-
cant atypia, the cytoplasm is rather pale or slightly
eosinophilic. Tumor cell formations consist
of a bilayered structure with an inner luminal
epithelial layer with cuboidal or flat cells, and an
Syringomatous Tumor of the Nipple, Fig. 2 Low outer layer of cells of similar appearance of pre-
power appearance of a syringomatous tumor containing
infiltrative bland solid epithelial formations in the dermis
sumably myoepithelial differentiation (Ishikawa
of the skin surrounded by smooth muscle bundles (H&E, et al. 2015; Montgomery et al. 2014; Boecker
low magnification) et al. 2014; Oo and Xiao 2009). Mitotic figures S
or necrosis are absent. The stroma around the
epidermis and usually no ulceration is observed epithelial cells is fibrotic and can contain spindle-
(Ishikawa et al. 2015; Montgomery et al. 2014; shaped mesenchymal cells (Ishikawa et al. 2015;
Oo and Xiao 2009; Rosen 1983). Tumor cells can Montgomery et al. 2014; Oo and Xiao 2009; Page
invade the perineural region and smooth muscles et al. 2009; Jones et al. 1989; Carter and Dyess
and can surround small keratinous cysts extending 2004; Rosen 1983).
from the epidermis into the dermis (Fig. 3)
(Ishikawa et al. 2015; Montgomery et al. 2014;
Oo and Xiao 2009; Rosen 1983). The margin of Immunophenotype
the lesion is not sharply defined due to infiltrative
growth and can be visualized more precisely Luminal epithelial cells are uniformly positive for
by immunohistochemical stains (Ishikawa et al. high molecular weight cytokeratins as 34betaE12
2015; Montgomery et al. 2014; Boecker et al. and for basal cytokeratins as CK5/6 and in a large
368 Syringomatous Tumor of the Nipple
subset with squamoid differentiation, also for p63. negative in both components. Ki67 index is usually
The outer layer is consequently positive for very low (<5%) (Ishikawa et al. 2015; Montgomery
myoepithelial markers as p63 (Fig. 4), CK5/6 et al. 2014; Boecker et al. 2014).
(Fig. 5), or smooth muscle myosin heavy chain
and also for high molecular weight cytokeratins as
34betaE12. Hormone receptors and HER2 are Molecular Features
There are no molecular data available based on

current literature on syringomatous tumors of the
nipple. The triple negative intrinsic phenotype and
the low Ki-67 index seems to be the most charac-
teristic surrogate molecular marker (Ishikawa et al.
2015; Boecker et al. 2014; Oo and Xiao 2009).
The differential diagnosis includes low-grade

adenosquamous carcinoma, tubular carcinoma,
classical nipple adenoma and also inflamed cases
Syringomatous Tumor of the Nipple, Fig. 4 P63 of epithelial hyperplasia, squamous metaplasia, or
immunohistochemistry decorates consequently the outer highly differentiated invasive squamous carci-
myoepithelial layer and in some glands also the inner
epithelial layer (p63 immunohistochemistry, clone 4A4, noma (Ishikawa et al. 2015; Montgomery et al.
low magnification) 2014; Boecker et al. 2014; Oo and Xiao 2009).
Syringomatous Tumor of the Nipple, note also the vicinity of the cystic protruding epidermal
Fig. 5 Cytokeratin 5/6 immunohistochemistry decorates structures (cytokeratin 5/6 immunohistochemistry, clone
both the inner epithelial and the outer myoepithelial layer, D5/16B4, high magnification)
The low-grade adenosquamous carcinoma squamous epithelium (Ishikawa et al. 2015;

(▶ Low-Grade Adenosquamous Carcinoma) of Montgomery et al. 2014; Oo and Xiao 2009).
the breast shares overlapping histological Highly differentiated squamous carcinoma can
and immunohistochemical characteristics with a pose a diagnostic challenge if nuclear morphology
syringomatous nipple tumor. Both lesions have is completely bland. However, a desmoplastic
a bland cytological appearance and are mostly stromal reaction and a lack of lobular growth
triple negative and exhibit very similar expression are usually present in squamous cell carcinomas
of basal cytokeratins and myoepithelial markers. (Ishikawa et al. 2015; Montgomery et al. 2014;
However, at difference from a syringomatous Oo and Xiao 2009).
adenoma a low-grade adenosquamous carcinoma
shows a clear deep infiltrative growth with
desmoplastic stromal reactions into the deeper
breast structures. A careful examination of the References and Further Reading
whole histological and immunophenotypical con-
Boecker, W., Stenman, G., Loening, T., Andersson, M. K.,
text is necessary to differentiate a syringomatous
Sinn, H. P., Barth, P., Oberhellmann, F., Bos, I.,
tumor from low-grade adenosquamous carcinoma Berg, T., Marusic, Z., Samoilova, V., & Buchwalow,
(Ishikawa et al. 2015; Montgomery et al. 2014; I. (2014). Differentiation and histogenesis of
Boecker et al. 2014; Oo and Xiao 2009). syringomatous tumour of the nipple and low-grade
adenosquamous carcinoma: Evidence for a common
A tubular carcinoma (▶ Tubular Carcinoma)
origin. Histopathology, 65, 9–23.
can imitate the histological picture of Carter, E., & Dyess, D. L. (2004). Infiltrating
syringomatous adenoma especially if angular syringomatous adenoma of the nipple: A case report
and pointed structures are compressed due to and 20-year retrospective review. The Breast Journal,
10, 443–447.
severe stromal sclerosis. Tubular carcinomas are
Ishikawa, S., Sako, H., Masuda, K., Tanaka, T.,
almost always hormone receptor positive and lack Akioka, K., Yamamoto, Y., Hosokawa, Y., &
myoepithelial cells, both morphologically and Manabe, T. (2015). Syringomatous adenoma of the
immunohistochemically, which can help in the nipple: A case report. Journal of Medical Case Reports,
13, 256.
differential diagnosis (Ishikawa et al. 2015;
Jones, M. W., Norris, H. J., & Snyder, R. C. (1989).
Montgomery et al. 2014; Oo and Xiao 2009; Infiltrating syringomatous adenoma of the nipple.
Page et al. 2009; Jones et al. 1989; Carter and A clinical and pathological study of 11 cases.
Dyess 2004; Rosen 1983). The American Journal of Surgical Pathology, 13,
197–201.
Classical nipple adenoma also shares histolog-
Montgomery, N. D., Bianchi, G. D., Klauber-Demore, N.,
ical features with syringomatous nipple tumors. & Budwit, D. A. (2014). Bilateral syringomatous
However, nipple adenomas usually exhibit adenomas of the nipple: Case report with immunohis-
a marked epithelial intraductal hyperplasia (usual tochemical characterization of a rare tumor mimicking
malignancy. American Journal of Clinical Pathology,
ductal hyperplasia) and most of the cases
141, 727–731. S
have a clear relationship with the overlying epi- Oo, K. Z., & Xiao, P. Q. (2009). Infiltrating syringomatous
dermis with ulcerations (Ishikawa et al. 2015; adenoma of the nipple: Clinical presentation and
Montgomery et al. 2014; Oo and Xiao 2009). literature review. Archives of Pathology & Laboratory
Medicine, 133, 1487–1489.
Epithelial hyperplasia (▶ Usual Ductal Hyper-
Page, R. N., Dittrich, L., King, R., Boulos, F., &
plasia (UDH)) and squamous metaplasia occur Page, D. L. (2009). Syringomatous adenoma of the
mostly in the area of acute or chronic inflammation nipple occurring within a supernumerary breast:
and do not show preferential growth around nerve A case report. Journal of Cutaneous Pathology, 36,
1206–1209.
sheets or smooth muscle layers. Additionally, no
Rosen, P. P. (1983). Syringomatous adenoma of the nipple.
bilayered appearance can be identified on conven- The American Journal of Surgical Pathology, 7,
tional morphology at the hyperplastic/metaplastic 739–745.
T
Tall Cell Variant of Papillary • Sex

Breast Carcinoma All patients reported in the literature are
females.
Sofia Asioli and Francesca Ambrosi • Site
Department of Biomedical and Neuromotor Breast without a prevalence of a specific mam-
Sciences (DIBINEM)-Surgical Pathology mary quadrant.
Section, Alma Mater Studiorum – University of • Treatment
Bologna, Bologna, Italy Because of indolent clinical behavior, wide
excision is the best choice of treatment and
axillary dissection is generally avoided.
Synonyms Although, some patients also received chemo-
and radiation therapy, these treatments might
Tall cell thyroid-like papillary carcinoma not be appropriate.
• Outcome
Tall cell variant of papillary breast carcinoma
Definition shows a consistent indolent clinical behavior.
In literature, of 30 cases with an available
Tall cell variant of papillary carcinoma is a unique follow-up, only 1 case developed bone metas-
special type of primary breast neoplasm not tases 32 months after surgery (Cameselle-
related to a thyroid gland neoplasm, showing Teijeiro et al. 2006). Another case of tall cell
very frequently a triple-negative profile, but low variant of papillary breast carcinoma was
aggressive potential and a good prognosis. described in a patient presenting a metastasis
to an intramammary lymph node, but the nod-
ule had been clinically present for 10 years
Clinical Features before surgery; this patient was alive and free
of local or distant recurrence 10 years later
• Incidence (Tosi et al. 2007). The last case with aggressive
Thirty-seven cases of this special type of pri- behavior showed a local recurrence 5 years
mary breast carcinoma have been reported in after presentation and one axillary metastatic
the literature. lymph node out of 10. Both lesions were
• Age surgically removed. This patient was alive
Median age at presentation is 61 years, ranging and free of disease 4 years later (Foschini
from 45 to 85 years. et al. 2017). The remaining 27 patients were
https://doi.org/10.1007/978-3-319-62539-3
372 Tall Cell Variant of Papillary Breast Carcinoma
reported to be alive and free of disease with a

mean follow-up of 77 months after surgery.
Macroscopy
Tumors generally present either as palpable and

well-defined nodules or less frequently as screen-
detected nonpalpable lesions, thus the size of the
lesion may be variable (range 0.6–4.1 cm). On
mammography or ultrasound examination, tall cell
variant of papillary breast carcinomas are com-
monly interpreted as benign, due to their regular
margins. Tall Cell Variant of Papillary Breast Carcinoma,
Fig. 1 At low power, the present case of tall cell variant
of papillary carcinoma, shows a multilobar architecture;
margins are mostly pushing, with focal infiltrative area
Microscopy (H&E)
At low power, tall cell variant of papillary breast

carcinoma shows usually a multilobar architecture;
margins are mostly pushing, with focal infiltrative
areas. All the cases described in literature exhibit
striking common histological features and closely
mimic the features of the tall cell variant of papillary
thyroid carcinoma. In particular, neoplastic cells are
mainly arranged in papillary fronds, with a thin
fibrovascular core. Most of the papillae are closely
packed mimicking solid or trabecular structures that
appear as irregular nests of cohesive neoplastic cells
surrounded by loose to dense stroma rich in small
capillary-like vessels that, in a delicate-garland-like
fashion, envelopes all the epithelial structures. True Tall Cell Variant of Papillary Breast Carcinoma,
follicular-like structures may be seen (Figs. 1 and 2). Fig. 2 The present case of tall cell variant of papillary
These contain eosinophilic, amorphous material, carcinoma shows neoplastic cells arranged in follicular-like
structures that contain eosinophilic, amorphous material, very
very similar to thyroid colloid, including the
similar to colloid, including the scalloped periphery (H&E)
scalloped periphery (Fig. 3). A mixture of three
architectural patterns (papillary, solid, and follicular)
is generally present, one of which may be predom- of the cell height. Nuclear grooves and pseudo-
inant. Most of the cases show psammoma bodies as inclusions are frequently seen. Mitotic figures are
well as granular calcifications, both located within rare. The histological grade, according to Elston and
the colloid-like material or within the proliferating Ellis grading system of breast cancer (Elston and
epithelium. Neoplastic cells are columnar to cuboi- Ellis 1991), is grade 1. Vascular or perineural inva-
dal in shape and perpendicularly oriented toward the sion is usually absent. Clear-cut features of an in-situ
fibrovascular cores. The cytoplasm is frequently carcinoma have been reported in 7.7% of cases (Tosi
granular eosinophilic and occasionally homoge- et al. 2007). Foci of flat epithelial atypia at
neous and strongly eosinophilic. Pale, elongated the periphery have been observed in 15.4% of
nuclei are dislodged to the apical pole of neoplastic cases (Foschini et al. 2017). Metastatic deposits
cells or centrally located and occupy about one-third within lymph nodes, if present, exhibit identical
Tall Cell Variant of Papillary Breast Carcinoma 373
or a rim of basal lamina at the periphery of neo-

plastic epithelium. The intracytoplasmic granules,
mostly condensed at the basal pole of cells, are
strongly positive for mitochondrion antigen.
Immunohistochemical markers suggestive of
thyroid origin, that is, thyroglobulin and TTF1,
had been reported as consistently negative in
these tumors (Eusebi et al. 2003; Foschini
et al. 2017).
Molecular Feature
Tall Cell Variant of Papillary Breast Carcinoma, RET/PTC and BRAF genes alterations commonly
Fig. 3 The neoplastic cells are columnar to cuboidal in
shape, with granular eosinophilic cytoplasm. The nucleus seen in papillary thyroid carcinomas have been
occupies about 1/3 of the cell height and it is centrally explored, with negative results (Cameselle-
located, elongated and has clear chromatin. Nuclear Teijeiro et al. 2006; Eusebi et al. 2003; Hameed
grooves and pseudoinclusions are present (H&E) et al. 2009). Mutations in isocitrate dehydroge-
nase 2 (IDH2) have been reported. In particular,
morphological and immunohistochemical features Chiang et al. (2016) detected hotspot mutations at
with the primary neoplasm. R172 IDH2 gene in 10 out of 13 cases of tall cell
variant of papillary breast carcinomas. Eight of
the 10 mutated cases displayed concomitant path-
Immunophenotype ogenic mutations at PIK3CA or PIK3R1. In addi-
tion, the same authors, through functional studies,
Estrogen and progesterone receptors are demonstrated that IDH2 and PIK3CA hotspot
completely missing or rarely (7.6% of cases) mutations were crucial in the neoplastic transfor-
expressed in less than 1% of the total neoplastic mation of tall cell variant of papillary breast car-
proliferation and HER2 is negative, so that tall cinoma and probably responsible of its peculiar
cell variant of papillary breast carcinoma is phenotype.
classified as triple-negative. Androgen receptor
is negative as well excluding an apocrine nature.
Ki67 proliferative index is low. Differential Diagnosis
Cytokeratin 7 expression is strong and diffuse
within the neoplastic cells, while occasional Lymph node metastases of papillary thyroid car-
focal positivity for GCDFP-15, mammaglobin, cinoma have to be considered in the rare occa-
and GATA 3, which are “luminal” type markers, sion of metastatic tall cell papillary carcinoma of T
may be observed. On the other hand, immunocy- the breast. However, the site of metastases, the
tochemical expression of “nonluminal/basal-like” absence of history of a primary thyroid carci-
markers such as cytokeratin 14 and cytokeratin noma, the immunohistochemical expression of
5/6 has been reported in 8 cases (Eusebi et al. GCDFP-15, GATA3, and mammaglobin, and the
2003; Tosi et al. 2007; Foschini et al. 2017). negativity of markers of thyroid origin as TTF1
Myoepithelial markers such as p63, calponin, and thyroglobulin and the absence of common
and smooth muscle actin are negative or mark molecular alterations seen in papillary thyroid
rare myoepithelial cells that surround occasional carcinomas help distinguish between these two
neoplastic areas. entities. A possible differential diagnosis may
Collagen IVand laminin highlight the fibrovas- be required with the solid papillary variant of
cular cores present within the solid papillary nests breast carcinoma (▶ Solid Papillary Carcinoma).
374 Toker Cells of the Nipple
The latter, at difference with the tall cell variant K. Y., Jungbluth, A. A., Balss, J., Pusch, S., Baker, G.
of papillary breast carcinoma, is positive for M., Cole, K. S., von Deimling, A., Batten, J. M.,
Marotti, J. D., Soh, H-C., McCalip, B. L., Serrano, J.,
hormone receptor expression and frequently Lim, R. S., Siziopikou, K. P., Lu, S., Liu, X., Hammour,
exhibits neuroendocrine marker expression. T., Brogi, E., Snuderl, M., Iafrate, A. J., Reis-Filho, J.
S., Schnitt, S. J. (2016). IDH2 mutations define a
Tall cell variant of papillary breast carcinoma: fact unique subtype of breast cancer with altered nuclear
sheet polarity. Cancer Research, 76, 1–12.
Definition Elston, C. W., & Ellis, I. O. (1991). Pathological prognostic
– Very rare type of primary breast neoplasm not related factors in breast cancer. 1. The value of histological
to a thyroid gland neoplasm, showing very frequently a grade in breast cancer: Experience from a large
triple-negative profile study with long-term follow-up. Histopathology, 19,
Age distribution 403–410.
– Median age: 61 years (range 45–85 years) Eusebi, V., Damiani, S., Ellis, I. O., Azzopardi, J. G.,
Rosai, J. (2003). Breast tumor resembling the tall cell
Clinical features
variant of papillary thyroid carcinoma: Report of
– Palpable and well-defined nodules with regular
5 cases. The American Journal of Surgical Pathology,
margins
27, 1114–1118.
Microscopic findings Foschini, M. P., Asioli, S., Foreid, S., Cserni, G., Ellis, I.
– Three architectural patterns: papillary, solid, and O., Eusebi, V., Rosai, J. (2017). Solid papillary breast
follicular carcinomas resembling the tall cell variant of papillary
– Neoplastic cells: columnar to cuboidal in shape, with thyroid neoplasms: A unique invasive tumor with indo-
granular eosinophilic cytoplasm lent behavior. The American Journal of Surgical
– Presence of nuclear grooves, pseudoinclusions, and Pathology, 41, 887–895.
psammoma bodies Hameed, O., Perry, A., Banerjee, R., Zhu, X., Pfeifer, J. D.
– Mitosis is rare, and vascular invasion is uncommon (2009). Papillary carcinoma of the breast lacks evi-
Immunohistochemical findings dence of RET rearrangements despite morphological
– Estrogen, progesterone, androgen receptors, and similarities to papillary thyroid carcinoma. Modern
HER2: negative Pathology, 22, 1236–1242.
– “Luminal” type markers (cytokeratin 7, GCDFP-15, Tosi, A. L., Ragazzi, M., Asioli, S., Del Vecchio, M.,
mammaglobin, and GATA 3): variably positive Cavalieri, M., Eusebi, L. H. U., Foschini, M. P.
– Myoepithelial markers (p63, calponin, and smooth (2007). Breast tumor resembling the tall cell variant
muscle actin): negative of papillary thyroid carcinoma: Report of 4 cases with
– Thyroglobulin and TTF1: negative evidence of malignant potential. International Journal
Molecular findings of Surgical Pathology, 15, 14–19.
– Absence of alterations of RET/PTC and BRAF genes
– Mutations of IDH2 gene in 77% of cases tested
Differential diagnosis
– Solid papillary carcinoma of the breast
– Metastasis from papillary thyroid carcinomas Toker Cells of the Nipple
Prognosis and treatment
– Wide excision without aggressive treatment Luca Di Tommaso
strategies Pathology Unit, Humanitas Clinical and Research
– Indolent clinical behavior
Center, Department of Biomedical Sciences,
Humanitas University, Milan, Rozzano, Italy

Synonyms
Cameselle-Teijeiro, J., Abdulkader, I., Barreiro-
Morandeira, F., Ruiz-Ponte, C., Reyes-Santías, R., Clear cells of the nipple
Chavez, E., Sobrinho-Simões, M. (2006). Breast
tumor resembling the tall cell variant of papillary thy-
roid carcinoma: A case report. International Journal of Definition
Surgical Pathology, 14, 79–84.
Chiang, S., Weigelt, B., Wen, H. C., Pareja, F.,
Raghavendra, A., Martelotto, L. G., Burke, K. A., Toker cells (TC) are clear elements that can be
Basili, T., Li, A., Geyer, F. C., Piscuoglio, S., Ng, C. seen in the lower layers of the epidermis of the
Toker Cells of the Nipple 375
Toker Cells of the Nipple, Fig. 1 (H&E) Toker cells higher magnification single elements and small glands are
(TC) of the nipple. (a) Occasional clear cells are seen in the characterized by bland cytological features
lower layers of the epidermis of the nipple (arrows); (b) at
nipple as single elements and, more rarely, as Clinical Features

small glands (Toker 1970).
Hyperplastic TC lacks a definition. It has been • Incidence
suggested to consider hyperplastic cases showing Dr. Cyril Toker was the first to describe the
(a) clusters of >7 TC (van der Putte et al. 1995), or presence of clear cells in the nipple. Studying
(b) 10–20 single cells and 3–10 glands H&E sections of 190 autopsies, he demon-
(Di Tommaso et al. 2008), or (c) clusters of >3 strated TC in 12% of the cases (Toker 1970).
CK7+ cells (Nofech-Mozes and Hanna 2009). This finding was later confirmed in a morpho-
From a practical point of view, normal TC disap- logical study on 390 nipples from surgical spec-
pear after few recuts, while hyperplastic TC are imens (Di Tommaso et al. 2008). The use of T
retained or even increased after several recuts. CK7 immunostaining may help to recognize
Atypical TC are those exhibiting “cytologic TC. Thus, not surprisingly, CK7 reveals TC in
atypism of a degree insufficient for an un- equiv- 83% of autopsy cases (Lundquist et al. 1999)
ocal diagnosis of cancerous change” (Toker and in 88% of surgical specimens (Nofech-
1970). This mild to moderate atypia shows up in Mozes and Hanna 2009). The number of TC
terms of irregular nuclear contour, increased cells disclosed by CK7 staining is about 10 per
nuclear size, and small eosinophilic nucleoli. low power field (10x) and mostly showing as
Also, atypical TC are retained after several recuts isolated elements. Finally, hyperplastic and
(Figs. 1, 2, 3, and 4). atypical TC have been reported, respectively,
A classification of normal, hyperplastic, and in 8–27% and 3–12% of the series (Toker
atypical TC is proposed in Table 1. 1970; Di Tommaso et al. 2008).
Toker Cells of the Nipple, Fig. 2 (H&E) Hyperplastic TC. (a) Numerous TC are easily seen at low magnification; (b)
while most of TC are still devoid of atypia, scattered prominent nucleoli and irregular nuclear profile can be observed
Toker Cells of the Nipple, Fig. 3 Atypical TC. (a) The TC show one or two prominent eosinophilic nucleoli
basal layer of this nipple is characterized by the presence of (H&E) (c) and demonstrate a faint, continuous
several TC, isolated and in small clusters (H&E); (b) most immunostaining for HER2
• Age and Sex were represented by eight males and ten

In his seminal paper, Toker described the pres- females with a mean age of 50 years (range,
ence of TC in the nipples of 18 patients. These 26–76 years). A similar distribution was
Toker Cells of the Nipple 377
Toker Cells of the Nipple, Fig. 4 Phenotypical features of TC. These hyperplastic TC show strong immunoreactivity to
estrogen receptors (a) and faint immunoreactivity to progesterone receptors (b)
confirmed by Lundquist in his autopsy series explanation on TC origin came from an embry-
(Lundquist et al. 1999). Subsequent studies ological study conducted on the anogenital
investigated the presence of TC in patients region of female and male fetus (van der
undergoing mastectomy for breast cancer: epi- Putte 2011). This study demonstrated that
demiological features of TC were confounded the primordial follicular cells involved in the
by those of the underlining neoplastic disease. formation of apocrine and mammary-like
Indeed, patients showing TC are significantly glands are displaced into the epidermis where
younger if undergoing prophylactic mastec- they proliferate and differentiate as
tomy for BRCA mutation rather than mastec- TC. Accordingly, it was speculated that TC of
tomy for breast cancer (Nofech-Mozes and the anogenital region may likely represent the
Hanna 2009). precursors of primary anogenital Paget disease. T
• Site and Origin Similarly, TC of the nipple may represent the
TC have been reported not only in the nipple precursors of primary Paget disease of the
but also in the areola, in the accessory nipple, nipple.
in the axilla, and in the vulva. Accordingly, it
has been suggested that TC represent (1) ele-
ments that migrated from mammary excretory Microscopy
ducts into the epidermis of the nipple, or
(2) abortive mammary differentiation within TC are cells larger than keratinocytes, round to
the basal layer of the epidermis, or (3) embry- polygonal in shape, with faintly eosinophilic or
onic nests of cells related to eccrine and apo- clear cytoplasm, oval nuclei, and small nucleoli.
crine structures. A possible comprehensive Electron microscopy showed that the clear
Toker Cells of the Nipple, Table 1 Proposed criteria for the classification of normal, hyperplastic, and atypical TC
Normal TC Hyperplastic TC Atypical TC
Isolated TC (n ) <10 10–20 Any; usually 10–20
Clusters of TC (n ) <3 3–10 Any; usually 3–10
TC after recuts Disappear Conserved/increased Conserved/increased
Cytological atypia Absent Absent Mild to moderate
Toker Cells of the Nipple, Table 2 Phenotypical features of Toker cells (TC) and Paget disease (PD) cells
ER (%) PgR (%) HER2/neu (%) p53 (%)
Normal TC 100 70 0 na
Hyperplastic TC 100 90 10 0
Atypical TC 100 100 80 0
PD (without coexisting carcinoma) 50–60 20 70–100 80
PD (with coexisting carcinoma) 10–40 0–20 80–100 10–60
Abbreviation: ER estrogen receptors, PgR progesterone receptors, na not available, DCIS ductal carcinoma in situ
cytoplasm is due to paucity of organelles and their role in the differential diagnosis with ▶ Paget
filaments (Marucci et al. 2002). TC are seen Disease (PD). Hyperplastic and atypical TC are
within the basal and/or spinous layers; they pre- always p53 negative; a faint immunoreactivity for
sent as single elements or as small glands. Hyper- HER2 is frequently seen in atypical TC and, more
plastic TC retain cytological and architectural rarely, in hyperplastic conditions.
features of normal TC. The distinctive diagnostic Table 2 illustrates the immunohistochemical
feature is the increased number of single cells profile of TC (normal, hyperplastic, and atypical)
and/or glands within the lower layers of the epi- as compared to PD (without or with a coexisting
dermis, which makes these cases easily recogniz- carcinoma in the underlining breast parenchyma: for
able at H&E as compared to normal TC even at a detailed explanation, see Differential Diagnosis).
scanning magnification. Atypical TC are charac-
terized by nuclei with irregular contour and eosin-
ophilic nucleoli but with preserved nucleus/ Differential Diagnosis
cytoplasmic ratio. There are no signs of architec-
tural disorder, being most of the cell still localized As mentioned, the main differential diagnosis
in the lower layers of the epidermis. of TC is PD of the nipple. In most of the cases,
PD represents an epidermotropic migration of
cancer cells from an underlying breast carci-
Immunophenotype noma. However, the existence of PD with
extensive involvement of the epidermidis
TC are consistently immunoreactive with CK7. lacking any carcinoma in the parenchyma or
This marker, as well as EMA, can be used to that of PD in the areola in patient with con-
reveal TC or to disclose additional TC at the genital absence of the nipple does not support
periphery of those seen on H&E. Interestingly, the epidermotropic hypothesis. The few reports
CK7 also highlights the dendritic profile about PD associated with TC hyperplasia in the
of rare TC. TC are p63 negative/ER positive/ areola and that of PD indistinguishable from
PgR positive: a phenotype further reinforcing TC hyperplasia in supernumerary nipple fur-
the difference with keratinocytes and supporting ther reinforce the hypothesis that rare
a mammary or mammary-like origin. Additional cases of PD may represent a malignant
markers tested in TC, mostly in the hyperplastic transformation of TC, as suggested by Toker
and atypical groups, are p53 and HER2, due to himself (Toker 1970). This hypothesis was
Tubular Adenoma of the Breast 379
further strengthened by the observation that

intraepidermal cells of PD can be genetically Tubular Adenoma of the
different from those of the underlying Breast
carcinoma, thus possibly representing the
neoplastic transformation of TC (Morandi Nicola Fusco and Chiara Corti
et al. 2003). Division of Pathology, Fondazione IRCCS Ca’
PD usually presents with exudative crust, ery- Granda – Ospedale Maggiore Policlinico,
thema, pruritus, and/or bleeding of the nipple University of Milan, Milan, Italy
while in normal, hyperplastic, and atypical TC,
the nipple is grossly unremarkable. PD cells have
abundant, weakly eosinophilic cytoplasm, pleo- Synonyms
morphic nuclei, large eosinophilic nucleoli, and
overgrowth in any layer of the epidermis; none of Pure adenoma of the breast; True adenoma of the
these features are observed in TC. Finally, breast
PD cells are mostly p53+ and HER2+ as opposite
to TC. However, from a practical point of view,
PD is in most of the cases a clinical condition, Definition
while TC is always an occasional histopathologi-
cal finding. Tubular adenoma of the breast is a rare benign
lesion that is characterized by a nodular prolifer-
ation of compact tubular structures lined by epi-
References and Further Reading thelial and myoepithelial cells with no nuclear
atypia (Foschini et al. 2012). Since its first
Di Tommaso, L., Franchi, G., Destro, A., Broglia, F., description in 1968 as “pure adenoma of the
Minuti, F., Rahal, D., & Roncalli, M. (2008). Toker
cells of the breast. Morphological and immunohisto-
breast” (Persaud et al. 1968), only a few cases
chemical characterization of 40 cases. Human Pathol- have been described (O’Hara and Page 1985;
ogy, 39, 1295–1300. Maiorano and Albrizio 1995; Rovera et al.
Lundquist, K., Kohler, S., & Rouse, R. V. (1999). 2006; Düşünceli et al. 2012; Sengupta
Intraepidermal cytokeratin 7 expression is not restricted to
et al. 2014).
Paget cells but is also seen in Toker cells and Merkel cells.
American Journal of Surgical Pathology, 23, 212–219.
Marucci, G., Betts, C. M., Golouh, R., Peterse, J. L., Foschini,
M. P., & Eusebi, V. (2002). Toker cells are probably pre- Clinical Features
cursors of Paget cell carcinoma: a morphological and ultra-
structural description. Virchows Archiv, 441, 117–123. • Incidence
Morandi, L., Pession, A., Marucci, G. L., Foschini, M. P.,
Pruneri, G., Viale, G., & Eusebi, V. (2003). The introduction of mammography-based
Intraepidermal cells of Paget’s carcinoma of the breast breast cancer screening programs has
can be genetically different from those of the underly-
ing carcinoma. Human Pathology, 34, 1321–1330.
increased the detection of breast tubular ade- T
nomas. However, given the lack of large pop-
Nofech-Mozes, S., & Hanna, W. (2009). Toker cells
revisited. The Breast Journal, 15, 394–398. ulation studies focused on this benign
Toker, C. (1970). Clear cells of the nipple epidermis. condition, its incidence is substantially
Cancer, 25, 601–610. unknown. The prevalence of breast tubular
van der Putte, S. C. (2011). Clear cells of adenoma is reported to range from 0.1% to
Toker in the developing anogenital region of
male and female fetuses. American Journal of 2.8% of all benign breast lesions (Sengupta
Dermatopathology, 33, 811–818. et al. 2014; Foschini et al. 2012).
van der Putte, S. C., Toonstra, J., & Hennipman, • Age
A. (1995). Mammary Paget’s disease confined to the Tubular adenoma of the breast occurs mainly
areola and associated with multifocal Toker cell
hyperplasia. American Journal of Dermatopathology, during reproductive ages (Salemis et al. 2012).
17, 487–493. It is rare before menarche and after menopause
380 Tubular Adenoma of the Breast
(Foschini et al. 2012) and vanishingly rare in in pregnant and puerperal women (Salemis
elderly people (Nishimori et al. 2000; Rovera et al. 2012).
et al. 2006). Pregnancy-associated tubular ade- The imaging features of breast tubular ade-
nomas can be observed and may show rapid noma are nondiagnostic and consistent to
enlargement in tumor size (Nagata et al. 1998; those of a benign breast lesion. At mammog-
O’Hara and Page 1985; Salemis et al. 2012). raphy, it appears as a well-circumscribed
• Sex fibroadenoma-like nodule (Fig. 1a). Calcifica-
Despite tubular adenoma has been described tions have been rarely observed, particularly
only in females, the possible occurrence in in elderly women (Soo et al. 2000; D’Orsi
male individuals should not be excluded. et al. 2013). Ultrasonography reveals a well-
• Site defined hypoechoic mass with a relatively
Akin to most benign breast lesions, tubular homogeneous internal texture, showing low-
adenomas arise within the terminal duct- to-mild posterior enhancement (Irshad et al.
lobular unit (Foschini et al. 2012; Sciarra 2008) (Fig. 1b).
et al. 2017). They preferentially involve the • Treatment
upper and outer quadrants of the breasts Given its benign clinicoradiological features
(Sengupta et al. 2014). and low tendency to increase in size, clinical
• Clinical Presentation observation usually suffices for the proper
Breast tubular adenoma is usually asymptom- management of these patients. However, in
atic and detected incidentally during screening high-risk individuals (e.g., elderly women and
examinations (Rovera et al. 2006). When pre- young women with strong family history for
sent, the symptoms are nonspecific, being breast cancer), or in cases of fast-growing
related to the mass effect. They include a pal- lesions with significant mass effect, a diagnos-
pable smooth, mobile, well-defined nodular tic core biopsy or surgical excision should be
mass and breast tenderness in the area of the performed (Salemis et al. 2012; Sengupta et al.
lump (Salemis et al. 2012; Sengupta et al. 2014; Rovera et al. 2006; Calderaro et al.
2014). These benign alterations cause no nip- 2010).
ple discharge or pain. Although the majority of • Outcome
tubular adenomas grow slowly, they can also Tubular adenoma of the breast has an indo-
present as a fast-growing nodule, particularly lent clinical course (Foschini et al. 2012).
Tubular Adenoma of the

Breast, Fig. 1 (a)
Mammography shows a
relatively dense, lobulated,
round lump. (b) Ultrasound:
uniform hypoechoic mass
with well-defined borders,
in the absence of a
consistent capsule –
arrowheads indicate the
lesion (Both images are
Courtesy of Dr. Luca
Despini; Fondazione
IRCCS Ca’
Granda – Ospedale
Maggiore Policlinico,
Milan, Italy)
After surgical excision with clear margins, Microscopy

no recurrences have been described. This
benign lesion is not associated with an Tubular adenomas of the breast are morphologi-
increased risk of breast cancer development. cally characterized by a lobulocentric prolifera-
However, rare cases of ductal carcinoma in tion of closely packed, small, round tubular
situ (DCIS) and/or invasive carcinoma of no structures composed of epithelial (luminal) and
special type arising within tubular adenomas myoepithelial (basal) cells, showing no signs of
have been reported (Hill and Miller 1954; atypia (Fig. 2). Occasional larger tubules can give
Case 1977; Domoto et al. 2002; Saimura rise to thin branches resembling those of benign
et al. 2015). These conditions are currently fibroepithelial lesions. The luminal epithelium is
considered “collision” tumors, given that characteristically cuboidal-to-columnar and is
their clonal relationship has never been rimmed by a well-preserved myoepithelial layer
demonstrated. composed of cells with clear-to-pale cytoplasm.
The epithelium may display vesicular nuclei with
visible, although not prominent, nucleoli that can
Macroscopy
be potentially worrying when observed at high
magnification. Nuclear pleomorphism and archi-
Grossly, tubular adenomas are firm and well-
tectural complexity are absent, while mitoses, if
circumscribed nodules ranging from 1 to 8 cm
present, are typical and unremarkable. Apocrine
in greatest dimensions. Smaller lesions should be
and/or lactating features may be observed, partic-
classified within the fibrocystic changes contin-
ularly in young individuals. Lactational changes
uum (Shet and Rege 1998; Tavassoli 1999).
can be present in pregnant or peripartum women
Notably, “giant” tubular adenomas (14 cm in
and pose diagnostic challenges, particularly on
tumor size) have anecdotally been described
small biopsy samples, given their close similarity
(Düşünceli et al. 2012). The cut surface is uni-
to those of lactational adenomas or normal breast
formly white-to-yellowish and shows macro-
tissue during pregnancy. The stroma within the
scopic resemblance to that of fibroadenomas
tubules is typically inconspicuous but not absent,
and lactating adenomas, in the absence of a
although variable in proportion, with rare
fibrotic capsule (Rosen 2014; Tavassoli 1999;
myofibroblasts immersed in PAS-positive colla-
Foschini et al. 2012). The overlying skin and
gen bundles separating the tubules. Although
nipple usually show no alterations (Hertel et al.
tubular adenomas showing a prominent stromal
1976; Nishimori et al. 2000).
reaction, in which the tubules are arranged in an
Tubular Adenoma of the

Breast, Fig. 2 (H&E)
shows a pure epithelial
proliferation where T
densely-packed tubular
structures are lined by
epithelial and myoepithelial
cells with no nuclear atypia.
Inset: the nuclear
expression of ER at
immunohistochemistry is
diffuse and non-uniformly
intense, akin to the normal
breast tissue (Courtesy of
Dr. Gianluca Lopez,
University of Milan, Milan,
Italy)
382 Tubular Adenoma of the Breast
intracanalicular growth pattern, have been rarely Differential Diagnosis

reported, there is currently no biological evidence
for their classification in the nosology of breast The diagnosis of breast tubular adenoma is
fibroepithelial lesions (Maiorano and Albrizio morphology-based and usually straightforward
1995). Akin to other benign conditions, a lympho- when clinicoradiological correlations are present.
cytic infiltrate of variable degree may be present. However, its close resemblance to other benign
The tubular clefts are often empty, although eosin- conditions of the breast may pose diagnostic chal-
ophilic proteinaceous material can be found lenges. Its main differential diagnosis is with the
(Foschini et al. 2012). Various degrees of ische- normal breast tissue and fibrocystic/apocrine
mic fibrosis can be observed (Tavassoli 1999), in changes (Sciarra et al. 2017). In this respect,
the absence of clear hemorrhage or necrosis detailed clinicoradiological information, particu-
(Hertel et al. 1976). larly in small biopsy samples, are warranted to
Fine needle aspiration (FNA) cytology of achieve the diagnosis of breast tubular adenoma
tubular adenomas is nonspecific and could lead (Hertel et al. 1976).
to overdiagnosis (Moross et al. 1983). The main The amount and cellularity of the stroma,
cytological findings include cells arranged in together with the tubular architecture of the
small, three-dimensional clusters and tubular ducts, are key features in the differentiation of
structures. Cells have finely vacuolated cyto- tubular adenoma from fibroadenoma
plasm, uniform nuclei with fine chromatin, and (▶ Fibroadenoma) of the breast (Saimura et al.
inconspicuous nucleoli. Artefactual nuclear 2015; Irshad et al. 2008). From a molecular stand-
atypia can be present (Calderaro et al. 2010; point, while the clonal and neoplastic origin of
Sengupta et al. 2014). Hence, a diagnosis of breast tubular adenoma has not been demon-
tubular adenoma in FNA cytological specimens strated, somatic mutations in exon 2 of the medi-
is extremely challenging, not to say virtually ator complex subunit 12 (MED12) have been
unachievable. identified in 60% of breast fibroadenomas and
likely constitute their driving genetic event
(Piscuoglio et al. 2015). It is of note that lesions
Immunophenotype showing either tubular adenoma and
fibroadenoma features have been described
Since tubular adenoma of the breast is composed (Komaki et al. 1992). In these cases, histology
of small ducts surrounded by a scarce stromal revealed the presence of two discrete morpholog-
tissue, its immunophenotype is consistent with ical patterns in close proximity, suggesting a com-
that of the normal breast tissue. The presence of bined tumor rather than a hybrid lesion.
the basal cell layer can be demonstrated by the Adnexal tumors of the breast comprise a spec-
immunoreactivity for myoepithelial markers, such trum of lesions that may have histological features
as p63, CK5/6, and S100 (Böcker et al. 1992; Yeh similar to those of tubular adenomas. Among
and Mies 2008; Maiorano and Albrizio 1995). them, breast cylindroma is a non-encapsulated
Immunohistochemistry of the luminal (epithelial) but relatively well-demarcated lesion with irregu-
population includes strong positivity for CK7 and lar borders composed of nests and trabeculae of
E-cadherin and a nonhomogeneous low-to-mild cells arranged in a jigsaw puzzle pattern (Fusco
nuclear positivity for the estrogen receptor et al. 2016). Akin to tubular adenomas, these nests
(ER) (Fig. 2). and trabeculae are surrounded by thick eosino-
philic PAS-positive hyaline bands and are com-
posed of a dual cell population, epithelial and
Molecular Features myoepithelial, showing no nuclear atypia and
scarce mitoses. Within the nests, duct-like tubular
There are no available data on the molecular fea- structures filled up with eosinophilic material can
tures of breast tubular adenoma. be found. Despite the overlapping morphology of
breast tubular adenoma and cylindroma, the latter Schmid, K. W. (1992). An immunohistochemical
is consistently ER-negative and shows recurrent study of the breast using antibodies to basal and luminal
keratins, alpha-smooth muscle actin, vimentin, colla-
splice-site somatic mutations in the tumor sup- gen IV and laminin. Part II: Epitheliosis and ductal
pressor cylindromatosis gene (CYLD). carcinoma in situ. Virchows Archive. A, Pathological
The presence of luminal eosinophilic secre- Anatomy and Histology, 421, 323–330.
tions in the duct-like structures of tubular adeno- Case, T. C. (1977). Adenocarcinoma of breast arising in
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mas has allowed some authors to speculate on its 2122–2123.
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adenoma (O’Hara and Page 1985). However, Andreiuolo, F., Suciu, V., Delaloge, S., Vielh, P. (2010).
based on their pathophysiology and morphology, Tubular adenoma of the breast with associated mucin-
ous features: A cytological diagnostic trap. Cytopathol-
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Lagoudianakis, E. (2012). Tubular adenoma of the and in mammographic screening programs
breast: A rare presentation and review of the literature. (Anderson et al. 2004; Rakha et al. 2010).
Journal of Clinical Medicine Research, 4, 64–67.
• Age
Sengupta, S., Pal, S., Biswas, B. K., Phukan, J. P., Sinha,
A., & Sinha, R. (2014). Preoperative diagnosis of tubu- Approximately 60–70% of tubular carcinomas
lar adenoma of breast – 10 years of experience. The present as non-palpable, mammographically
Tubular Carcinoma 385
detected lesions and are more common in stromal desmoplasia. Foci of hemorrhage are usu-
women in their sixth or seventh decade who ally attributable to a prior diagnostic needling
are undergoing breast cancer screening. procedure. Necrosis is not a feature of tubular
• Sex carcinoma. Calcification is common in tubular
Female. Rare in male as for other forms carcinoma and may be the presenting sign on
of breast cancer. mammography.
• Site
Anywhere in the breast but most frequent in the
upper outer quadrant like other types of breast Microscopy
cancer. Multifocality has been reported in up to
20% of tubular carcinomas. The characteristic feature of tubular carcinoma
• Treatment is the predominance of tubules composed of
Local control and hormone therapy are the a single layer of epithelial cells with open lumen
main treatment options. Even when patients (Fig. 1). The tubules are arranged haphazardly;
have axillary metastases from tubular carci- are generally oval, rounded, and angulated in
noma, the prognosis is very good, and the shape; and lack peripheral myoepithelial cells.
axillary node dissection could be considered The cells are small to moderate in size, regular
unnecessary, and the use of systemic adjuvant with little nuclear pleomorphism, inconspicuous
chemotherapy is typically not needed in pure nucleoli, and scanty mitotic figures. Apical snouts
tubular carcinomas (Diab et al. 1999; are seen in up to a third of cases but are not
Papadatos et al. 2001; Fedko et al. 2010). pathognomonic. Multilayering of nuclei, marked
• Outcome nuclear pleomorphism, and high mitotic activity
Tubular carcinoma has an exceptionally good are contraindications for a diagnosis of tubular
long-term prognosis (Diab et al. 1999; carcinoma. The characteristic tubules of tubular
Papadatos et al. 2001; Anderson et al. 2004; carcinoma comprise more than 90% of the tumor.
Fedko et al. 2010; Rakha et al. 2010), and in Adherence to the 90% rule is essential to correctly
some series, the outcome is similar to age- identify tubular carcinoma which carries an excel-
matched population without breast cancer lent prognosis. A tumor that shows features of
(Diab et al. 1999; Sullivan et al. 2005; Fedko tubular carcinoma in 50–90% of the tumor and
et al. 2010; Rakha et al. 2010). The risk of another breast tumor type in the remainder of
local recurrence is so low that some centers the tumor, usually ▶ Invasive Carcinoma NST is
consider adjuvant radiotherapy unnecessary. regarded as a tubular mixed carcinoma.
Ten-year disease-free and overall survival The stroma is typically cellular and
rates after mastectomy or breast-conserving desmoplastic and commonly accompanying
surgery were reported to be 93.1–99.1% and the tubular structures. A consistent feature of
99–100%, respectively. Axillary node metasta- tubular carcinoma and one that is particularly
ses occur infrequently (average 10%; range useful on needle core biopsy is the extension of T
0–22%) and rarely involve more than one or tubules into surrounding fat.
two axillary lymph nodes. Tubular carcinoma frequently coexists with
other low-nuclear-grade breast lesions including
▶ Columnar Cell Lesions, flat epithelial atypia,
Macroscopy ▶ Atypical Ductal Hyperplasia, low-grade
▶ Ductal Carcinoma In Situ, and ▶ Lobular In
Tubular carcinoma presents as an ill-defined Situ Neoplasia. These lesions share morphologi-
gray to white, firm or hard mass with irregular cal, immunophenotypic, and molecular character-
outlines measuring between 0.1 cm and 2 cm in istics and constitute the so-called low-nuclear-
diameter; the majority are 1.5 cm or less. The grade neoplasia family. An association with
consistency is generally hard due to prominent ▶ Radial Scar has also been proposed.
386 Tubular Carcinoma
Tubular Carcinoma, Fig. 1 (H&E) A case of tubular (shown in Fig. 1c) and desmoplastic stroma. Tubular car-
carcinoma showing haphazardly arranged tubules lacking cinoma is associated with columnar cell change, flat epi-
myoepithelial cells and with characteristically open lumina thelial atypia, and low-grade DCIS (Figs. 1a and b )
Immunophenotype followed by 1q (gain) (50–62%), and they usually

occur concomitantly. Other alterations include
Tubular carcinoma is a special type of low-grade 16p gain and loss of 8p, 3p (FHIT gene locus),
invasive breast carcinoma that typically displays and 11q (ATM gene locus). Global gene expres-
a luminal A phenotype with high expression sion profiling studies have demonstrated that
of hormone receptors, luminal cytokeratins, and tubular carcinoma belongs to the “luminal A”
E-cadherin. Tubular carcinoma does not molecular class of breast cancer.
express basal cytokeratins, lacks HER2 gene
amplification, and is usually negative for
epidermal growth factor receptor, p-cadherin Differential Diagnosis
and p53.
Tubular carcinoma should be differentiated
from ▶ Sclerosing Adenosis,▶ Complex Scleros-
Molecular Features ing Lesion, and ▶ Microglandular Adenosis.
Tubular carcinoma should also be differentiated
Tubular carcinoma has a low frequency of genetic from grade 1 NST carcinomas that have worse
alterations with the most frequent genetic alter- prognosis compared to tubular carcinoma by the
ations seen at chromosomes 16q (loss) (78–86%), 90% rule of tubule formation. Sclerosing adenosis
Tubular Carcinoma 387
is characterized by the lobular architecture and the carcinoma. Cancer Epidemiology, Biomarkers &
compression and distortion of glandular struc- Prevention, 13, 1128–1135.
Diab, S. G., Clark, G. M., Osborne, C. K., Libby, A.,
tures. Myoepithelial cells are always present. Allred, D. C., & Elledge, R. M. (1999). Tumor
Complex sclerosing lesions/radial scars have cen- characteristics and clinical outcome of tubular and
tral fibrosis and elastosis containing a few small, mucinous breast carcinomas. Journal of Clinical
often distorted, tubular structures around which Oncology, 17, 1442–1448.
Fedko, M. G., Scow, J. S., Shah, S. S., Reynolds, C.,
myoepithelial cells are present. The peripheral Degnim, A. C., Jakub, J. W., & Boughey, J. C.
glandular structures in a radial scar show varying (2010). Pure tubular carcinoma and axillary nodal
degrees of dilatation and ductal epithelial hyper- metastases. Annals of Surgical Oncology, 17(Suppl 3),
plasia. Microglandular adenosis that typically 338–342.
Papadatos, G., Rangan, A. M., Psarianos, T., Ung, O.,
shows haphazard, diffuse, infiltrative pattern Taylor, R., & Boyages, J. (2001). Probability of axil-
with tubules lacking peripheral myoepithelial lary node involvement in patients with tubular carci-
cells shows more rounded and regular tubules noma of the breast. British Journal of Surgery, 88,
that often contain colloid-like secretory material. 860–864.
Rakha, E. A., Lee, A. H., Evans, A. J., Menon, S.,
Microglandular adenosis also lacks desmoplastic Assad, N. Y., Hodi, Z., Macmillan, D.,
stroma characteristic of tubular carcinoma. Blamey, R. W., & Ellis, I. O. (2010). Tubular carcinoma
of the breast: Further evidence to support its excellent
prognosis. Journal of Clinical Oncology, 28, 99–104.
Sullivan, T., Raad, R. A., Goldberg, S., Assaad, S. I.,
References and Further Reading Gadd, M., Smith, B. L., Powell, S. N., Taghian, A. G.
(2005). Tubular carcinoma of the
Anderson, W. F., Chu, K. C., Chang, S., Sherman, M. E. breast: A retrospective analysis and review of the
(2004). Comparison of age-specific incidence rate literature. Breast Cancer Research and Treatment, 93,
patterns for different histopathologic types of breast 199–205.
T
U
Usual Ductal • Incidence

Hyperplasia (UDH) UDH is a common finding in fibrocystic
changes of the breast and may be seen in
Anna Sapino1,2, Davide Balmativola1, Maria papillomas.
Giulia Disanto1 and Caterina Marchiò1,2,3 • Age
1
Unit of Pathology, Candiolo Cancer Institute All ages may be affected. Infiltrative
FPO IRCCS, Candiolo, Italy epitheliosis is more frequent in postmeno-
2
Department of Medical Sciences, University of pausal age (range 54–80 years).
Turin, Turin, Italy • Sex
3
Institut Curie, Paris, France It usually occurs in female breast, but it can be
rarely observed in male breast.
• Site
Synonyms No specific site is identified; this lesion
can occur anywhere within the breast
Epithelial ductal hyperplasia; Epitheliosis; Florid parenchyma.
ductal hyperplasia; Hyperplasia of usual type; • Imaging
Intraductal hyperplasia; Papillomatosis Specific radiological patterns are not described
for UDH. Infiltrative epitheliosis may rarely
mimic invasive tumor at mammography.
Definition • Treatment
UDH does not require treatment. Infiltrative
Benign proliferative lesion within terminal ductal epitheliosis if discovered on preoperative core
lobular units that typically shows lumen filled by biopsy specimens should be excised to exclude
cells arranged in a streaming-like fashion and an invasive carcinoma.
peripheral slit-like spaces. Rarely usual ductal • Outcome
hyperplasia (UDH) may show an infiltrative pat- Relative risk of breast cancer for UDH is low
tern of growth. (1.5- to 2-fold).
Clinical Features Macroscopy
Impalpable lesion. No specific clinical features are UDH is discovered at microscopy, the gross fea-
described being a microscopic finding. ture is not specific.
https://doi.org/10.1007/978-3-319-62539-3
390 Usual Ductal Hyperplasia (UDH)
Microscopy stromal changes seen throughout the lesion, adja-

cent to epithelial foci, rather than confined to a
UDH may affect multiple terminal ductal structures, central scleroelastotic nidus as in radial scars
which appear irregularly distended by a heteroge- (RS) (▶ Radial Scar), and (3) frequent presence of
neous cell population that occupies the lumen. Cells a desmoplastic stromal reaction and keloid-like
are arranged in a streaming-like fashion and form fibrous bands (Fig. 3, H&E). The involved ducts
secondary abortive lumen with nuclei parallel to often have jagged or irregular edges and
lumen long axis and slit-like spaces or cleft at the the proliferating epithelium often appears to “flow-
periphery (Fig. 1, H&E). Cells have indistinct out” into adjacent stroma (Eberle et al. 2016).
border and different shape, nuclei are mainly oval
and normochromatic and may present pale
Immunophenotype
intranuclear inclusions; nucleoli are small or indis-
tinct. Cells lining peripheral clefts may show apical
UDH shows a heterogeneous ER and PR
snouts (Fig. 2, H&E). Foci of infiltrative epitheliosis
staining limited to about 10–15% of cells, with
are generally small and discovered within complex
scattered positivity in few contiguous
sclerosing lesions, papillomas and usual epitheliosis
areas. HER2 is negative. Ki67 positive cells
is frequently present all around.
are rare. High molecular weight cytokeratins
Eusebi and Millis (2010) described the histologic
(34betaE12, CK14, CK5/6) are expressed in a
features of infiltrative epitheliosis, which is similar
mosaic-like fashion (Otterbach et al. 2000;
to that described in complex sclerosing lesions
Martinez et al. 2016) (Fig. 4, CK14). Alpha-
(▶ Complex Sclerosing Lesion): (1) bulk of the
smooth muscle actin and p63 and p40
lesion composed of florid UDH, with frequent
stain myoepithelial cells at the periphery of
focal squamoid appearance; (2) scleroelastotic
the lesion. Infiltrating epitheliosis may show rare
or no p63/p40-positive myoepithelial cells and ER
may be completely absent (Eberle et al. 2016)
(Fig. 5a, ER) or both ER and p63/p40 may be
heterogeneously expressed (Fig. 5b, p63).
Molecular Features
Activating PIK3CA mutations have been

documented in UDH (Ang et al. 2014).
PIK3CA hotspot mutations, and/or PIK3R1
somatic mutations, have been found in all
infiltrating epitheliosis (Eberle et al. 2016).
UDH should be differentiated from atypical duc-

tal hyperplasia (ADH) (▶ Atypical Ductal
Hyperplasia). ADH have features that may over-
lap with those of low-grade ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ): homogenous
cell population that produces cribriform spaces,
Usual Ductal Hyperplasia (UDH), Fig. 1 Duct shows homogeneous expression of ER, and is
distended by UDH (H&E) negative for basal cell markers. Loss of
Usual Ductal Hyperplasia (UDH) 391
Usual Ductal
Hyperplasia (UDH),
Fig. 2 UDH showing
typical peripheral slit-like
spaces lined by luminal
cells with occasional apical
snouts. (High
magnification, H&E)
Usual Ductal
Hyperplasia (UDH),
Fig. 3 Florid UDH and
infiltrating epitheliosis
within keloid like stroma.
(H&E)
Usual Ductal
Hyperplasia (UDH),
Fig. 4 Mosaic like CK14
immunostaining of cells
in UDH
U
392 Usual Ductal Hyperplasia (UDH)
Usual Ductal Hyperplasia (UDH), Fig. 5 (a) ER immunostaining is almost negative in a field of infiltrating UDH.
(b) p63 highlights myoepithelial cells
heterozygosity on chromosomes 16q and 17p is phosphatidylinositol-3-kinase mutations in prolifera-

reported in ADH at high frequency and is rare in tive breast lesions. Modern Pathology, 27, 740–750.
Eberle, C. A., Piscuoglio, S., Rakha, E. A., Ng, C. K.,
epitheliosis. Geyer, F. C., Edelweiss, M., Sakr, R. A., Weigelt, B.,
UDH involving papilloma (▶ Intraductal Pap- Reis-Filho, J. S., & Ellis, I. O. (2016). Infiltrating
illoma) should be differentiated from solid papil- epitheliosis of the breast: Characterization of histolog-
lary ductal in situ carcinoma (▶ Solid Papillary ical features, immunophenotype and genomic profile.
Histopathology, 68, 1030–1039.
Carcinoma) (Rabban et al. 2006). Basal Eusebi, V., & Millis, R. R. (2010). Epitheliosis, infiltrating
cytokeratin 5/6 and 14, expressed in a mosaic- epitheliosis, and radial scar. Seminar in Diagnotic
like fashion in UDH, are negative in the luminal Pathology, 27, 5–12.
neoplastic proliferation of solid papillary ductal in Martinez, A. P., Cohen, C., Hanley, K. Z., & Li, X. B. (2016).
Estrogen receptor and cytokeratin 5 are reliable markers to
situ carcinoma. separate usual ductal hyperplasia from atypical ductal
The overall appearance of infiltrating epitheliosis hyperplasia and low-grade ductal carcinoma in situ.
may simulate invasive carcinoma (▶ Invasive Archive of Pathology and Laboratory Medicine, 140,
Carcinoma NST), in particular ▶ low grade 686–689.
Otterbach, F., Bankfalvi, A., Bergner, S., Decker, T.,
adenosquamous carcinoma both morphologically Krech, R., & Boecker, W. (2000). Cytokeratin 5/6
and immunophenotypically. immunohistochemistry assists the differential diagno-
sis of atypical proliferations of the breast. Histopathol-
ogy, 37, 232–240.
Rabban, J. T., Koerner, F. C., & Lerwill, M. F. (2006). Solid
References and Further Reading papillary ductal carcinoma in situ versus usual ductal
hyperplasia in the breast: A potentially difficult distinc-
Ang, D. C., Warrick, A. L., Shilling, A., Beadling, C., tion resolved by cytokeratin 5/6. Human Pathology, 37,
Corless, C. L., & Troxell, M. L. (2014). Frequent 787–793.
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Encyclopedia of Pathology

Series Editor: J. H. J. M. van Krieken

More information about this series at http://www.springer.com/series/14876

With 282 Figures and 29 Tables

ISBN 978-3-319-62538-6 ISBN 978-3-319-62539-3 (eBook)

© Springer Nature Switzerland AG 2020

Nijmegen, The Netherlands J. H. J. M. van Krieken

This new book on breast pathology as part of the Encyclopedia of Pathology

Candiolo, Italy Anna Sapino

Pathology (EScoP). She serves as member of editorial boards of many scien-

Dr. Janina Kulka studied medicine at Semmelweis University, Budapest.

140 peer-reviewed scientiﬁc papers and contributed lectures to more than

J. H. J. M. van Krieken is a pathologist with special expertise in the ﬁelds of

Francesca Ambrosi Department of Biomedical and Neuromotor Sciences

Isabel Amendoeira Centro Hospitalar de São João (CHSJ), Porto, Portugal

Laura Annaratone Department of Medical Sciences, University of Turin,

Davide Balmativola Unit of Pathology, Candiolo Cancer Institute FPO-

Jean-Pierre Bellocq Department of Pathology, Strasbourg University Hos-

Simonetta Bianchi Division of Pathological Anatomy, Department of Sur-

Werner Boecker Gerhard Domagk-Institute of Pathology, University of

Horst Bürger Institute of Pathology Paderborn/Höxter, Paderborn, Germany

Grace Callagy Discipline of Pathology, NUI Galway, Galway, Ireland

Eliano Cascardi Department of Emergency and Organ Transplantation,

Isabella Castellano Department of Medical Sciences, University of Turin,

Suzanne Chartier Institut Curie, Paris, France

Catherine N. Chinyama Department of Pathology, Princess Elizabeth Hos-

Ewa Chmielik Tumor Pathology Department, Maria Sklodowska-Curie

Chiara Corti Division of Pathology, Fondazione IRCCS Ca’ Granda –

Gábor Cserni Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary

Margaret C. Cummings Centre for Clinical Research, Faculty of Medicine,

Clare D’Arcy Department of Histopathology, Irish National Breast Screen-

Dario de Biase Department of Pharmacy and Biotechnology, University of

Laurence de Leval Institute of Pathology, University Hospital Lausanne,

James S. DeGaetano Pathology Department, Mater Dei Hospital, Msida,

Luca Di Tommaso Pathology Unit, Humanitas Clinical and Research Cen-

Maria Giulia Disanto Unit of Pathology, Candiolo Cancer Institute

Ian Ellis Department of Histopathology, City Hospital Campus, Nottingham

Vincenzo Eusebi Department of Pathology, University of Bologna, Bologna,

Margarida Sá Fernandes Centro Hospitalar de São João (CHSJ), Porto,

Paulo Figueiredo Instituto Português de Oncologia de Coimbra, Coimbra,

Maria P. Foschini Department of Biomedical and Neuromotor Sciences

Gaetano Magro Department of Medical and Surgical Sciences and

Costantino Ricci Department of Biomedical and Neuromotor Sciences

Anne Vincent-Salomon Institut Curie, Paris, France

Abscess Puerperal Abscess

© Springer Nature Switzerland AG 2020

also occur at weaning, when the breasts

1–2% of all symptomatic breast processes

Peripheral non-puerperal abscesses are rare and

Unusual Breast Infections Definition

References and Further Reading • Incidence

and then better delineated by Damiani et al. Macroscopy

Acinic Cell Carcinoma,

Acinic Cell Carcinoma,

Acinic Cell Carcinoma,

2000). The microglandular component is char-

Immunohistochemical proﬁle is important to

Acinic Cell Carcinoma,

In addition an MLL3 splicing mutation, a TSC2